UCSF HELEN DILLER FAMILY COMPREHENSIVE CANCER...

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American Society of Hematology Annual Meeting UCSF HELEN DILLER FAMILY COMPREHENSIVE CANCER CENTER December 5-8, 2015 Orlando, FL UCSF Abstract Brochure

Transcript of UCSF HELEN DILLER FAMILY COMPREHENSIVE CANCER...

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American Society of Hematology Annual Meeting

UCSF HELEN DILLER FAMILY COMPREHENSIVE CANCER CENTER

December 5-8, 2015Orlando, FLUCSF Abstract Brochure

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As president of the UCSF Helen Diller Family Comprehensive Cancer

Center, one of my key priorities is to initiate and advance programs

that are developing new anticancer drugs making significant impact

on helping cancer patients live longer and better lives. I recognize this

goal is best accomplished by working in partnership with the broader

life science industry. This searchable abstract book of UCSF research

presented at ASH is a resource for potential partners interested in

identifying world-class faculty engaged in basic science and clinical

hematological malignancies research.

As an NCI-designated comprehensive cancer center, UCSF is

recognized for our outstanding science, extensive resources, depth

and breadth of our research in basic, clinical, and population sciences,

as well as cutting edge research that bridges these scientific areas.

Practically this means that our clinicians and basic scientists work

closely together to (1) identify, develop, and optimize novel therapeutics

for biological efficacy and clinical utility, (2) assess tumor status and

responsiveness to current therapies, (3) develop biomarkers for patient

stratification and therapeutic response, and (4) advance supportive

care options to mitigate the toxicities associated with chemotherapy.

UCSF is home to many of world’s finest oncology clinicians and

scientists. I invite you learn more about our work and expertise

by reaching out to our faculty during this meeting. If you have any

additional questions or need any assistance with your outreach,

please contact the Director of Strategic Alliances for the Cancer

Center: Cammie Edwards ( ).

Wishing you a very productive meeting and we look forward to future

discussions and collaborations.

Alan Ashworth, PhD, FRSPresident, UCSF Helen Diller Family Comprehensive Cancer Center

Committed to Advancing Development of Improved Cancer Therapies, Imaging Modalities, and Biomarkers

Alan Ashworth, PhD, FRSPresident, UCSF Helen Diller Family Comprehensive Cancer Center

Senior Vice President for Cancer Services, UCSF Health

Professor of Medicine, Division of Hematology/Oncology, Department of Medicine

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The “comprehensive” designation—NCI’s highest ranking, awarded only after a rigorous evaluation process—recognizes UCSF’s excellence in basic research, clinical research, population based research, outreach and education, and our ability to integrate these diverse research approaches to cancer and turn them into clinical practice.

A Designated NCI Comprehensive Cancer Center Since 1999

HDFCCC Overview

Our Success is Driven by Our FacultyHDFCCC Membership: 395 Members & Associate Members2 Nobel Laureates

3 Albert Lasker Award winners

8 Howard Hughes Medical Investigators

13 Members of the National Academy of Sciences

20 Members of the Institute of Medicine

18 Fellows of the American Academy of Arts and Sciences

4 Fellows of the Royal Society

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Working Together Advancing the Understanding and Treatment of Cancer

HDFCCC Overview

Blood Malignancies and DiseasesUCSF has over 50 scientists and clinicians working in the areas of myelodysplastic syndromes, myeloproliferative disorders, lymphomas, leukemias, myelomas, blood and marrow transplant, hemophilia, and amyloidosis. With our growing programs, combined expertise, and access to resources, UCSF faculty continue to make significant strides in understanding the biology of hematological diseases and improving patient outcomes with advanced clinical care.

Multi-Disciplinary Research Programs• Breast Oncology

• Cancer Control

• Cancer Genetics

• Cancer, Immunity, and Microenvironment

• Developmental Therapeutics

• Hematopoietic Malignancies

• Neurologic Oncology

• Pediatric Malignancies

• Prostate Cancer

• Tobacco Control

Emerging Initiatives• Cancer Imaging

• Cancer Immunotherapeutics

• Global Oncology

• Center for BRCA Research

• UCSF 500

• Target Validation Initiative

Multi-Disciplinary Clinical Programs • GU Oncology (non Prostate)

• GI (includes Pancreas Cancer)

• Thoracic Oncology

• Cutaneous Oncology

• Head and Neck Cancer

• Sarcoma

• Endocrine

• Gynecologic Oncology

• Breast Oncology

• Prostate Cancer

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• Biostatistics

• Clinical Research Support

• Genome Analysis

• Laboratory for Cell Analysis

• Immunohistochemistry & Molecular Pathology

• Mouse Pathology

• Preclinical Therapeutic Testing

• Bio-specimen Banking

• Tobacco Biomarkers

• Bioinformatics

• Computational Biology

UCSF consistently ranks among

the top U.S. biomedical research

organizations in cancer-specific

federal funding. In 2014, UCSF

received more than $88M from the

National Cancer Institute.

HDFCCC Overview

Core Capabilities Supporting Our Programs

Approximately one-quarter of the

University’s ~2,200 full-time faculty

members work in cancer research or

cancer care.

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UCSF faculty have a long history of working with industry partners translating discoveries into products that ultimately improve patient care. We are experienced in establishing and executing on a wide range of successful partnerships. If you are interested in learning more about working with the HDFCCC and its faculty, please contact:

Cammie Edwards, PhDDirector of Strategic Alliances, HDFCCC

• On average, UCSF has 200-300 new invention disclosures per year

• An estimated 90 life science start-up companies have been spawned from the University’s labs, including Genentech, Chiron, and Intellikine

• Included among UCSF patents are top revenue producers, such as- Hepatitis B vaccine

- Bovine growth hormone

- Barrier repair lipids

- Yeast expression vector

- Magnetic resonance imaging

Abbreviated list of current industry partners

Partnering with UCSF HDFCCC

AbbVie

Celgene

Daiichi-Sankyo

GlaxoSmithKline

Genentech

MedImmune

Pfizer

Quest

Sanofi

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Contents

Abstracts

DECEMBER 5, 2015 PAGE NO. TITLE

8:30AM

11 17 Identification of TKI-Sensitive Point Mutations That Activate c-ABL Kinase Activity and Transformation Potential and Confer in Vitro Resistance to the Allosteric ABL Inhibitor GNF-5 Oral presentation

Bianca J. Lee/Neil P. Shah, MD, PhD

5:30-7:30PM

12 1072 Correlation between Factor (F)XIa, FIXa and Tissue Factor and Trauma Severity Poster presentation

Saulius Butenas, PhD/Mitchell Jay Cohen, MD

13 1255 B-Lymphoid Transcription Factors Restrict Glycolytic Energy Supply for Oncogenic Signaling Poster presentation

Lai N. Chan, PhD/Markus Müschen, MD, PhD

14 1256 Negative Feedback By Dusp6 Modulates Myeloproliferation Induced By Oncogenic Nras Poster presentation

Charisa Cottonham, PhD/Benjamin S. Braun, MD, PhD

15 1325 IFITM3 (CD225) Links the B Cell Antigen CD19 to PI3K-AKT Signaling in Human ALL Cells Poster presentation

Jae-Woong Lee, PhD/ Markus Müschen, MD, PhD

16 1337 Panobinostat Augmented Cytarabine and Daunorubicin Induction for Older Patients with AML or High-Risk MDS Is Well Tolerated and Results in Favorable Clinical Outcomes: The Panda Trial Poster presentation

Matthew Wieduwilt, MD (UCSD)/Charalambos Andreadis, MD

17 1420 Quantification of Acute Lymphoblastic Leukemia Clonotypes in Leukapheresed Peripheral Blood Progenitor Cells Predicts Relapse Risk Following Autologous Hematopoietic Cell Transplantation

Poster presentation

Gabriel N. Mannis, MD

View full abstracts on line at: https://ash.confex.com/ash/2015/webprogram/start.html

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18 1423 Identifying Drug-Resistant Mutations in Ebf1-Pdgfrb Ph-like Acute Lymphoblastic Leukemia Poster presentation

Thai Hoa Tran, MD/Mignon L. Loh, MD

19 1434 CD25 (IL2RA) Orchestrates Negative Feedback Control and Stabilizes Oncogenic Signaling Strength in Acute Lymphoblastic Leukemia Poster presentation

Jae-Woong Lee, PhD/ Markus Müschen, MD, PhD.

DECEMBER 6, 2015PAGE NO. TITLE

8:15AM

20 166 Exposure to Inflammatory Immune Responses As Driver of Clonal Evolution in Childhood Acute Lymphoblastic Leukemia Oral presentation

Lars Klemm, MSc/ Markus Müschen, MD, PhD

4:30PM

21 337 Bortezomib Maintenance (BM) Versus Consolidation (BC) Following Aggressive Immunochemotherapy and Autologous Stem Cell Transplant (ASCT) for Untreated Mantle Cell Lymphoma (MCL): CALGB (Alliance) 50403 Oral presentation

Lawrence D. Kaplan, MD

5:45PM

22 360 Inhibition of Akt Signaling Alleviates MDS/MPN Driven By KrasD12 or Nf1 Loss Oral presentation

Jon Akutagawa/Benjamin S. Braun, MD, PhD

6:00-8:00PM

23 2755 Pathway-Directed High Throughput Drug Screen Identifies PI3K Inhibitors That Synergistically Potentiate Anti-Tumor Activity of HDAC Inhibitors in Mycosis Fungoides and Sezary Syndrome Poster presentation

Chen-Yen Yang/Wei Ai

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24 3266 Radiologist-Performed Musculoskeletal Ultrasound (MSKUS) for Evaluation of Joint and Soft Tissue Pain Episodes in Patients with Bleeding Disorders Poster presentation

Anjlee Mahajan, MD/Adam Giermasz, MD, PhD

DECEMBER 7, 2015PAGE NO. TITLE

8:00AM

25 509 A Dose Finding Phase II Trial of Isatuximab (SAR650984, Anti-CD38 mAb) As a Single Agent in Relapsed/Refractory Multiple Myeloma Oral presentation

Thomas G. Martin, MD

10:30AM-12:00PM

26 Spotlight Session Beyond Transcription: Translational Control of Gene Expression in Development and Disease Oral presentation

Davide Ruggero, PhD

11:15AM

27 556 Identification of BCL6 As a Therapeutic Target in RAS-Driven Acute Lymphoblastic Leukemia Oral presentation

Qiang Li, PhD/Markus Müschen, MD, PhD

3:45PM

28 677 Recurrent Mutations in CCND3 Confer Clinical Resistance to FLT3 Inhibitor Oral presentation

Catherine Smith, MD/Neil Shah, MD, PhD

5:15PM

29 778 Interleukin-1 Drives Precocious Myeloid Differentiation of Hematopoietic Stem Cells at the Expense of Self-Renewal Oral presentation

Eric Martin Pietras, PhD/Emmanuelle Passegué, PhD

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Contents

6:30PM

30 902 PP2A Is Required for B Cell Survival and Represents a Therapeutic Target in Acute Lymphoblastic Leukemia Oral presentation

Gang Xiao, PhD/Markus Müschen, MD, PhD

6:00-8:00PM

31 3672 CblY371H Transgene Combined with Hematopoietic Deletion of the Endogenous c-Cbl Gene Results in GM-CSF Hypersensitivity and Leukocytosis Poster presentation

Kenneth Lieuw, MD, PhD/Mignon L. Loh, MD

32 3716 Targeted Activation of B Cell Autoimmunity Checkpoints in Acute Lymphoblastic Leukemia Poster presentation

Zhengshan Chen, MD-PhD/Markus Müschen, MD, PhD

33 3900 Expression of B and T Lymphocyte Attenuator (BTLA) Correlates with CNS Metastasis and Adverse Prognosis in Activated B-Cell Lymphoma and Acute Lymphoblastic Leukemia Poster presentation

Huimin Geng, PhD/James Rubenstein, MD, PhD.

34 4350 Multigene MRD Assessment Improves AML Relapse Risk Stratification in Autologous Hematopoietic Cell Transplantation Poster presentation

Matthew P. Mulé/Gabriel N. Mannis, MD.

35 4458 Frequency, Risk Factors and Mortality Effect of Venous Thromboembolism in Adult Patients with Central Nervous System Lymphoma Poster presentation

Anjlee Mahajan, MD/Richard Fong, PharmD

DECEMBER 8, 2015 PAGE NO. TITLE

9:45-11:15AM

36 Presidential Symposium Through the Lens of Germline Predispositions to Leukemia: How Kids Teach Adults Oral presentation

Mignon L. Loh, MD

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Abstract#:17 PresentationType:OralAbstract

SessionName:631.ChronicMyeloidLeukemiaPresentationDate/Time:Saturday,December5,2015,8:30AM

Location:OrangeCountyConventionCenter,W340,Level3

PresentationTitle:IdentificationofTKI-SensitivePointMutationsThatActivatec-ABLKinaseActivityandTransformationPotentialandConferinVitroResistancetotheAllostericABLInhibitorGNF-5LeadPresenter/PrincipalInvestigator:BiancaJ.Lee/NeilP.ShahAbstract(Limit2000characters):Pathologicallyactivatedtyrosinekinasesrepresentattractivetherapeutictargets,withderegulatedABLkinaserepresentingoneofthebest-validatedexamples.ABLfusionproteinsareconstitutivelyactivatedbyoligomerizationdrivenbythefusionpartner,aswellasbylossofkinaseautoinhibitionduetoremovalofanautoinhibitorymyristatesiteattheN-terminusofc-ABL.Recentroutinegenomictumorsequencingofvarioushumanmalignancieshasidentifiedpointmutationsofunknownsignificanceinnumerouskinases,includingc-ABL,anditisexpectedthattheincreasinglycommonpracticeoftumorgenomesequencingwillprovidenewopportunitiesfortailoredtargetedtherapy.Wesoughtto:(i)testthetransformingpotentialofselectclinicallydetectedc-ABLmutants,(ii)prospectivelyidentifynoveladditionalactivatingc-ABLpointmutations,and(iii)determineifactivemutantc-ABLisoformsretainsensitivitytoABLTKIs.Wehaveidentifiedeightnovelactivatingpointmutationsinc-ABL(threefoundinclinicalisolates)thatarepotentialtherapeutictargetsofABLTKIs.Activatingc-ABLmutants,includingT315I,confersubstantialresistancetotheallostericABLinhibitorGNF-5regardlessofproximitytotheinhibitor-bindingsite,implyingresistancemechanismsbeyondmeresterichindrance.Thus,mutationsmayinducedistalconformationalchangesbydisruptingakinaseconformationrequiredforallostericcompoundinhibition.InasubsetofCMLcases,c-ABLpointmutantsareco-expressedfromthesamealleleasBCR-ABL,suggestingthatthelocationofthechromosome9breakpointmaynegativelyimpactclinicalresponsivenesstoallostericABLinhibitors.Sequenceanalysisofc-ABLinpatientswithresistancetoallostericABLinhibitorsisrequiredtovalidatec-ABLpointmutantsasaclinicallyimportantmechanismofresistancetothisemergingclassoftargetedtherapeutics.

Website:http://bms.ucsf.edu/directory/faculty/neil-shah-md-phd

FacultyLabInterests(Limit600characters):TheShahlabisinterestedinadvancingtargetedtherapeuticsforhematologicmalignanciesthroughbasicstudiesofinvitroandinvivomodelsystemstogainabetterunderstandingcriticalvulnerabilitiesofmalignantcells,andthroughtranslational/clinicalstudiesofsamplesobtainedfrompatientsparticipatinginearlyphasemonotherapyclinicalstudiestoidentify,validateandoverridemechanismsofresistancetotheseagents.

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Abstract#:1072 PresentationType:PosterAbstract

SessionName:321.BloodCoagulationandFibrinolyticFactors:PosterI(61abstracts)PresentationDate/Time:Saturday,December5,2015,5:30PM-7:30PM

Location:HallA,Level2(OrangeCountyConventionCenter)

PresentationTitle:CorrelationbetweenFactor(F)XIa,FIXaandTissueFactorandTraumaSeverityLeadPresenter/PrincipalInvestigator:SauliusButenas,PhD/MitchellJayCohen,MDAbstract(Limit2000characters):Traumapatientsoftendisplayanelevatedprocoagulantactivity.Thisactivityisthoughttobecausedinpartbytissuefactor(TF)locatedontheendothelium,bloodcellsandmicroparticles.Wealsoobservedinourpreviousstudiesthattraumapatientswiththermal,bluntandpenetratinginjurieshaveactiveFIXaandFXIaintheirplasma,oftenpersistentforseveraldaystoweeks.Inthecurrentstudyweevaluatedhowtheseverityofaninjurywithorwithoutaccompanyingshockaffectsthefrequency&concentrationofTF,FIXaandFXIainplasma.80traumapatientswereenrolled:62males&18females.Theageofpatientsvariedbetween18&90yearsandtheInjurySeverityScore(ISS)variedbetween1&75(average19.3±17.2).Bloodwascollectedimmediatelyuponemergencydepartmentarrivalpriortoanyresuscitationorbloodproducttransfusion.Wedividedcohortsinto4groups(20patients/group)basedonISSandpresenceofshock(basedeficitBD):Group1:Non-severeinjury,noshock(ISS≤15;BD>-6),Group2:Non-severeinjury,withshock(ISS≤15;BD≤-6),Group3:Severeinjury,noshock(ISS>15;BD>-6),Group4:Severeinjury,withshock(ISS>15;BD≤-6).TherewasagoodcorrelationbetweenFIXa&FXIaconcentrations(R2=0.33)withtraumaseverity,butnocorrelationbetweenTF&FIXaorFIXa,suggestingthatFXIaintraumapatientbloodisgeneratedprimarilythroughthecontactpathway,althoughtheinputoftheTFpathwaytoFXIactivationcannotbeexcluded.Conclusions.Frequency&concentrationofTFishigherinpatientswithahighertraumaseverity,butitisindependentofshock;ThevastmajorityofplasmasamplesfromtraumapatientscontainactiveFIXa&FXIa;ConcentrationofFXIaishigherinpatientswithshock&doesnotappeartobeaffectedbythetraumaseverity.Takentogether,thesedatasuggestseparatemechanismsforcontactpathwayactivationafterinjurydrivenbyshock&TFpathwayactivationdrivenbytissueinjury.

Website:http://cohenlab.surgery.ucsf.edu/

FacultyLabInterests(Limit600characters):TheCohenlabisfocusedonthestudyofcoagulationandinflammatoryperturbationsaftertrauma.Specificallyweareinterestedinunderstandingthemechanismsofacutetraumaticcoagulopathyahypocoaguablestatewhichoccursafterseveretissueinjuryandshock.Wetranslationallystudycoagulationandendothelialbiologyafterinjurybeginningwithclinicalcharacterization,progressingthroughinvivoandinvitromechanisticstudiesaugmentedbyinsilicomodelingallofwhichistranslatedbacktothebedsidetowardsimprovedresuscitativecareofinjuredpatientsatSFGH.

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Abstract#:1255 PresentationType:PosterAbstract

SessionName:603.OncogenesandTumorSuppressors:PosterIPresentationDate/Time:December5,2015/5:30PM-7:30PM

Location:OrangeCountyConventionCenter,HallA,Level2

PresentationTitle:B-LymphoidTranscriptionFactorsRestrictGlycolyticEnergySupplyforOncogenicSignalingLeadPresenter/PrincipalInvestigator:LaiN.Chan,PhD/MarkusMüschen,MD-PhDAbstract(Limit2000characters):OncogeniclesionsinhematopoieticprogenitorcellsgiverisetoB-cellormyeloidmalignancies.Whileoftentransformedbythesameoncogenes,B-cellandmyeloidleukemiasmarkedlydifferinbiologicalandclinicalcharacteristics.OurmetabolicanalysesrevealedthatB-cell–unlikemyeloid-leukemiacellsaremassivelyrestrictedintheirglycolyticcapacity.LowglycolyticreservesinBcellsresultedinastateofchronicenergydepletionandengagedtheenergysensorLKB1-AMPK.Myeloidcellsstronglyactivatedglucosetransportthroughinsulinreceptor(INSR)-AKTsignalingandlackedactivityofLKB1-AMPK,reflectingenergyabundance.Conversely,B-cellslackedINSR-AKTsignalingandwerecriticallydependentonLKB1-AMPK-mediatedglucoseuptake.Cre-mediateddeletionofLkb1causedacuteglycolyticexhaustionandcelldeathinB-lineagebutincreasedglycolysis,energylevelsandproliferationinmyeloidleukemia.C/EBPa-mediatedconversionofB-cellintomyeloididentityreversedthedetrimentaleffectsofLkb1-deletionandrestoredglycolysis,energylevelsandsurvivalofB→myeloidreprogrammedcells.In>80%ofB-lineageleukemiacases,wefoundgeneticlesionsoftranscriptionfactors(e.g.deletionofPAX5,IKZF1,rearrangementofMLL)thatcausedaB→myeloidlineageshift.Whilepreviouslyofunknownfunctionalsignificance,theselesionsrelievedB-cell-specifictranscriptionalrepressionofmoleculesthatmediateglucoseuptakeandutilization(INSR,GLUT1,HK2,G6PD)andamplifiedglycolyticenergysupplyfortransformingoncogenes.Likewise,glucocorticoidreceptor(NR3C1)-mediatedinhibitionofglucoseuptakeandglycolysiswasstrictlydependentonaB-lymphoidtranscriptionalprogram.B→myeloidlineageconversionabolishedNR3C1expressionandactivity,whichprovidesamechanisticexplanationfortheempiricfindingthatglucocorticoidsarehighlyactiveinthetreatmentofB-cell-butnotmyeloidmalignancies.

Website:http://lymphoblasts.org/

FacultyLabInterests(Limit600characters):TheMüschenlabisinterestedincomparativeanalysesofnormallymphocytedevelopmentandmalignanttransformationtowardsleukemia.ThelabcoverresearchareaswithrelevancetobothImmunologyandHematology/CancerBiology.Therefore,thelabfocusesonthebasicscienceofsignaltransductionprocessesinnormalandleukemicBcellsaswellastranslationalresearchdirectedtowardschildhoodacutelymphoblasticleukemia(ALL).

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Abstract#:1256 PresentationType:PosterAbstract

SessionName:603.OncogenesandTumorSuppressors:PosterIPresentationDate/Time:Saturday,December5,2015,5:30PM-7:30PM

Location:HallA,Level2(OrangeCountyConventionCenter)

PresentationTitle:NegativeFeedbackByDusp6ModulatesMyeloproliferationInducedByOncogenicNrasLeadPresenter/PrincipalInvestigator:CharisaCottonham,PhD/BenjaminS.Braun,MD,PhDAbstract(Limit2000characters):NrasG12D/+expressionfromtheendogenouslocusinmicecausesaspectrumofneoplasticphenotypes:somemicedevelopamyeloproliferativeneoplasm(MPN)thatrecapitulateshumanchronic&juvenilemyelomonocyticleukemia&othersdeveloplymphoidneoplasia.Recentfindingsshowthathematologicaldisease(MPN&T-ALL)isacceleratedinMx1-CreNrasG12D/G12Dmice,demonstratingthatRasexpressionleveliscriticaltoRas-inducedtransformation.Rassignaloutputistightlyregulatedbynegativefeedbackmechanisms.Dusp6isbothatranscriptionaltargetofRas&anErk1/2phosphatase,effectivelyforminganegativefeedbackloop.However,thephysiologicalfunctionofDusp6inRastransformation&hematologicaldiseaseremainspoorlycharacterized.WeexaminedthefunctionalconsequenceofDusp6lossinNras-drivendisease.WemadeDusp6knockoutmicethatconditionallyexpressNrasG12D/+fromtheendogenouslocus&foundthat,althoughsurvivalisminimallyimpacted,Dusp6lossinthehematopoieticcompartmentacceleratesthedevelopmentofMPN.Peripheralbloodfrom32wk-oldDusp6-/-;Mx1-CreNrasG12D/+miceshowedanelevatedleukocytecountcomparedtoage-matchedDusp6+/+;Mx1-CreNrasG12D/+mice&wild-type(wt)mice.Ineffectiveerythropoiesisisevidentat32wks:thelevelofhemoglobin(Hb)wasdecreasedinDusp6-/-;Mx1-CreNrasG12D/+mice,whereasDusp6+/+;Mx1-CreNrasG12D/+&wtmiceshowedsimilarHblevels.AconcomitantreticulocytesrisewasobservedinDusp6-/-;Mx1-CreNrasG12D/+miceonly.WhileDusp6+/+;Mx1-CreNrasG12D/+miceshowedsplenomegaly,spleensfromDusp6-/-;Mx1-CreNrasG12D/+micewere3.5Xlarger.Nodifferenceinthymusweightwasnoted,suggestingthatDusp6lossdoesnotacceleratelymphoproliferation.ThesedatashowthatwhiletheroleofDusp6inanemiaisconsistentinbothKrasG12D/+&NrasG12D/+models,theleukocytosisinNrasG12D/+micedemonstratesafunctionalroleforDusp6inmodulatingmyeloidphenotypesinMPN.

Website:http://cancer.ucsf.edu/people/profiles/braun_benjamin.3714

FacultyLabInterests(Limit600characters):TheBraunlabstudiestheroleofRassignalingintwopediatricmalignancies,juvenilemyelomonocyticleukemia(JMML)andrhabdomyosarcoma.WeareusinggeneticallyengineeredmousemodelsofthesediseasestoinvestigatehowRascontributestocancerdevelopment,andhowsignaltransductioninhibitorsmightcontributetonoveltherapiesforthesediseases.

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Abstract#:1325 PresentationType:PosterAbstract

SessionName:614.AcuteLymphoblasticLeukemia:Therapy,excludingTransplantationPresentationDate/Time:December5,2015,5:30-7:30PM

Location:HallA,Level2(OrangeCountyConventionCenter)

PresentationTitle:IFITM3(CD225)LinkstheBCellAntigenCD19toPI3K-AKTSignalinginHumanALLCellsLeadPresenter/PrincipalInvestigator:Jae-WoongLee,PhD/MarkusMüschen,MD-PhDAbstract(Limit2000characters):Background:IFITM3wasidentifiedasinterferon-induciblemoleculeinthecontextofviralinfection.IFITM3encodesasurfacereceptor,basallyexpressedontheplasmamembrane,thatisassociatedwithknownBcellco-receptorsincludingCD19,CD81andCD21.Results:StudyingIFITM3mRNAlevelsinALLcellsatthetimeofdiagnosisinclinicaltrialsforchildhood(COGP9906)andadultALL(ECOGE2993),wefoundthathigherthanmedianexpressionlevelsofIFITM3predictedshorteroverallandrelapse-freesurvival(P=0.014).TostudythefunctionofIfitm3inamodelforhumanpre-BALL,pre-BcellsfromIfitm3-/-miceweretransformedwithBCR-ABL1.Strikingly,deletionofIFITM3resultedinlossofCD19expressiononthesurfaceofnormalandleukemicpre-Bcells.Besideslossofsurfaceexpression,lossofIfitm3alsocausedimpairedphosphorylationofCD19-Y513,whichmediatesdownstreamactivationofPI3K-AKTsignalinginbothBcellprogenitorsandpre-BALLcells.ThesechangeswereparalleledbyG0/1cellcyclearrest(P<0.001),lossofcolonyformationcapacity(P=0.0004)andactivationofcheckpointmoleculesp53andp21,reductionofBCL2andBCLXLlevelsandincreasedpropensitytoapoptosis.Conversely,forcedexpressionofIFITM3inpatient-derivedpre-BALLcellsincreasedphosphorylationofCD19-Y513togetherwithdownstreamSRC,SYK,PI3Ksignaling.AlthoughhumanIFITM1hasknownasacomponentofBcellreceptorcomplex,co-immunoprecipitationexperimentsrevealedthatthecytoplasmictailofIFITM3interactswithCD19,LYN,SYK,PI3Kp110δandAKT.Inaddition,agonisticantibodiesagainstIFITM3/CD225triggerCD19/PI3K-AKTsignaling,whichcausedincreasedproliferationofpre-BALLcells.ThesefindingsindicateaspecificroleofIFITM3inregulatingCD19/PI3K-AKTsignalinginmalignantpre-BALLcellscomparedtotheirnormalpre-Bcellcounterparts.

Website:http://www.lymphoblasts.org/

FacultyLabInterests(Limit600characters):TheMüschenlabisinterestedincomparativeanalysesofnormallymphocytedevelopmentandmalignanttransformationtowardsleukemia.ThelabcoverresearchareaswithrelevancetobothImmunologyandHematology/CancerBiology.Therefore,thelabfocusesonthebasicscienceofsignaltransductionprocessesinnormalandleukemicBcellsaswellastranslationalresearchdirectedtowardschildhoodacutelymphoblasticleukemia(ALL).

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Abstract#:1337 PresentationType:PosterAbstract

SessionName:615:AML:Commerciallyavailabletherapy,excludingTransplantationPresentationDate/Time:December5th,2015;5:30pm

Location:HallA,Level2(OrangeCountyConventionCenter)

PresentationTitle:Panobinostat-AugmentedCytarabineandDaunorubicinInductionforOlderPatientswithAMLorHigh-RiskMDSIsWellToleratedandResultsinFavorableClinicalOutcomes:ThePandaTrialLeadPresenter/PrincipalInvestigator:MatthewWieduwilt/CharalambosAndreadisAbstract(Limit2000characters):Patientsaged>60ywithacutemyeloidleukemia(AML)haveinferioroutcomescomparedtothose<60y.TheHDACinhibitorpanobinostat(pano)potentiatesanthracyclineandara-Ccytotoxicity,likelythroughenhancementofDNAdouble-strandbreaks.Wehypothesizedthatadditionofshort-courseHDACinhibitionwithpanopriortoandduring7+3inductiontherapywouldbewell-toleratedandleadtofavorableoutcomesinthispatientpopulation.WeconductedaphaseIstudyinpatients>60ywithnewlydiagnosedAMLorhigh-riskMDScombiningpanoatdosesrangingfrom20mgto60mggivenorallyondays1,3,5,and8ofinductionwithdaunorubicin(dauno)60mg/m2ondays3–5andara-C100mg/m2continuouslyondays3–10(p+7+3).UponattainmentofCR/CRi,patientswereofferedasecondp+7+3oralternativeconsolidationincludingallogeneicstemcelltransplantation(alloHCT).Treatmentwaswell-toleratedinalldose-cohorts(22patientstotal)andtheMTDwasnotreached.Wetreated6patientseachatthe60mgand50mgdoseinthedoseexpansionphaseduetorecurrentgr.1bradycardia.Themedianagewas67y.11patientshaddenovoAML,7hadAMLwithmyelodysplasiarelatedchanges,2had2aryAMLfromMPD,1tx-associatedmyeloidneoplasm,and1hadRAEB-2.Twopatientshadprogressedonhypomethylatingagents.Therewerenopatientswithfavorablecyto.Of20evaluablepatients,8(40%)achievedCR/CRi.Onepatientreceivedstudytreatmentasconsolidation,3receivedintermediate/high-doseara-C,1receivedahypomethylatingagent,2underwentalloHCTand1hadnofurthertherapy.Medianoverallsurvivalwas10mos(ITT)and16mosforthosewhoachievedaCR/CRi(p=0.005).Medianrelapse-freesurvivalwas10mos,range3–27mos.OngoingstudiesareevaluatingmarkersofDNAdamageresponseandapoptosisinpatientstreatedwithPanDAvs.concurrent7+3controls.(FullabstractavailableinASHabstractbook.)

Website:http://cancer.ucsf.edu/people/profiles/andreadis_babis.3784

FacultyLabInterests(Limit600characters):Myclinicalresearchisfocusedontheinterplayofcancergeneticsandtraditionalpharmacogeneticsasitpertainstoprognosisandtreatmentresponseinpatientswithcancer.Iseektoincorporatethesefindingsinthetherapyofpatientswithhematologicmalignancies.Iconductandconsultonnumerousearlyandlatephaseclinicalresearchstudieswithfederalandnon-profitfunding.Iamtheco-directorofthehematologicmalignanciesclinicalresearchunitatUCSFandthePrincipalInvestigatortotheAlliancewhereIdesignandperformnovelcooperativegroupstudies.

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Abstract#:1420 PresentationType:PosterAbstract

SessionName:618.ALL:Biology,CytogeneticsandMolecularMarkersPresentationDate/Time:Saturday,December5,2015;5:30PM-7:30PM

Location:OrangeCountyConventionCenter,HallA,Level2

PresentationTitle:QuantificationofAcuteLymphoblasticLeukemiaClonotypesinLeukapheresedPeripheralBloodProgenitorCellsPredictsRelapseRiskFollowingAutologousHematopoieticCellTransplantationLeadPresenter/PrincipalInvestigator:GabrielN.Mannis,MDAbstract(Limit2000characters):Background:Althoughpriorstudieshaveshownsuperiorityofallogeneichematopoieticcelltransplant(alloHCT)overautologoushematopoieticcelltransplant(autoHCT)forpatients(pts)withhigh-riskacutelymphoblasticleukemia(ALL),thesefindingsmaybeexplained,inpart,bycontaminationoftheperipheralbloodprogenitorcell(PBPC)leukapheresisproductbyresidualleukemiccellsinptsundergoingautoHCT.Methods:Weretrospectivelyevaluatedminimalresidualdisease(MRD)vianext-generationsequencing(NGS)(AdaptiveBiotechnologies)inthePBPCleukapheresisproductsfrom32ALLptswhounderwentan“intensified”autoHCT.Allptshadhigh-riskALL.Results:Twenty-eightpts(88%)haddiagnosticmarrowsampleswithquantifiableimmunoglobulinorTcellreceptor(Ig/TCR)generearrangementssuitableforMRDquantificationinthePBPCproducts.Twelve(38%)hadPh+B-ALL,12(38%)hadPh-negB-ALL,and4(14%)hadT-cellALL.ThemajorityofptsweremaleandinfirstCR,withamedianageatautoHCTof32(range19-55).Withamedianf/uof41months(range3-217),medianrelapse-freesurvival(RFS)andoverallsurvival(OS)fortheentirecohortare3.2and4.2years,respectively.WhenstratifiedbygraftMRDburden,themedianRFSforptswithMRDdetectableatalevel≥10-6(n=13)was6.5months,andhasnotbeenreachedforptswithoutdetectableMRDabovethisthreshold(n=15;p=0.0005).Ofthe4Ph+ptswithdetectableMRDwhoreceivedaTKI,2(50%)remainlong-termrelapse-freesurvivors.Ofthe6ptswithoutMRDwhoweretreatedwithapost-autoHCTTKI,5(83%)remainrelapse-free.Conclusions:NGS-basedimmunosequencingplatformcanidentifyALLMRDinleukapheresedPBPCcollections,andtheabsenceofMRDmayidentifyasubsetofhigh-riskptslikelytoachievelong-termremissionswithoutalloHCT.TKItherapyforptswithPh+B-ALLmay,insomecases,abrogatetheneedforalloHCT,evenwithquantifiableMRDpriortoautoHCT.

Website:http://profiles.ucsf.edu/gabriel.mannis

FacultyLabInterests(Limit600characters):Dr.Mannisisaclinical/translationalinvestigatorwhoseresearchaimstoimproveoutcomesforpatientsviamorepersonalizedtreatmentstrategies,includingthestudyofnovelimmunotherapeuticapproachesandmolecularlytargetedagents.Accordingly,hisresearchincludesadiversearrayofhematologicmalignancies,mostcommonlyacuteleukemias,myelodysplasticsyndromes,myeloproliferativeneoplasms,andplasmacelldisorders.

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Abstract#:1423 PresentationType:PosterAbstract

SessionName:618:AcuteLymphoblasticLeukemia:Biology,Cytogenetics&

MolecularMarkersPresentationDate/Time:Saturday,December5,2015,5:30PM-7:30PM

Location:HallA,Level2(OrangeCountyConventionCenter)

PresentationTitle:IdentifyingDrug-ResistantMutationsinEbf1-PdgfrbPh-likeAcute

LymphoblasticLeukemia

LeadPresenter/PrincipalInvestigator:ThaiHoaTran,MD/MignonL.Loh,MD

Abstract(Limit2000characters):Agroupofrecently-definedpatientsdisplayageneexpressionprofile(GEP)similartothatofPhiladelphia-chromosomepositive(Ph+)acutelymphoblastic

leukemia(ALL)patientsinapproximately15%ofchildren&over25%ofyoungadultswithB-ALL;

knownasPh-likeALL.ThelatterhasaworseprognosiscomparedtothosewithoutthePh-likeGEP

withconventionalchemotherapy.RecentstudieshaveshownthatPh-likeALLischaracterizedby

geneticalterationsactivatingkinasesignalingpathwayspredictedtorespondtotyrosinekinase

inhibitors(TKIs).InlightoftheremarkableoutcomesofPh+ALLpatientsthroughincorporationof

TKI,theCOGALLCommitteeisactivelyworkingtoincorporatedasatinibforPh-likeALLpatients

harboringABL-classkinasefusions(ABL1,ABL2,PDGFRB,CSF1R)&eventually,ruxolitinibfor

thosewithlesionsthatarepredictedtorespondtoJAKinhibition.Whileitishopedthatmanyof

thesepatientswillbecuredwiththeadditionofrelevantTKIstochemotherapy,wehypothesize

thataproportionofpatientswilldevelopresistancetoTKI.Hence,investigatingtheunderlying

mechanismsgoverningtherapyresistanceinPh-likeALLbecomescriticalforproactively

developingnoveltherapeuticstrategiesintherelapsedsetting.Weareidentifyingthefullspectrum

ofmutationsconferringresistancetoclinically-activeTKIsinPh-likeALL&tocharacterizetheir

relativebiochemicalresistancetodifferentTKIs&firstfocusedontheEBF1-PDGFRB

rearrangementsincethisisthemostcommonrecurrentkinase-activatingfusiongenesinpediatric

Ph-likeALL.Ourin-vitroscreensshowedthatthevastmajorityofdrug-resistantclonesharbora

kinasedomain(KD)pointmutation,ofwhichT681Iwasthepredominantoneconferringresistance

toimatinib(94%)ordasatinib(81%).N666SwasthesecondmostcommonKDmutation(6%).KD

pointmutationsmayrepresenttheprimarymechanismofacquiredTKIresistanceinEBF1-PDGFRB

Ph-likeALL.

Website:http://cancer.ucsf.edu/people/profiles/loh_mignon.3407

FacultyLabInterests(Limit600characters):

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Abstract#:1434 PresentationType:PosterAbstract

SessionName:618.AcuteLymphoblasticLeukemia:Biology,CytogeneticsandMolecularMarkPresentationDate/Time:December5,2015,5:30PM-7:30PM

Location:OrangeCountyConventionCenter,HallA,Level2

PresentationTitle:CD25(IL2RA)OrchestratesNegativeFeedbackControlandStabilizesOncogenicSignalingStrengthinAcuteLymphoblasticLeukemiaLeadPresenter/PrincipalInvestigator:Jae-WoongLee,PhD/MarkusMüschen,MD-PhDAbstract(Limit2000characters):Background:CD25(IL2RA)representstheαchainoftheinterleukin2receptoronTcellsandplaysaroleinthemaintenanceofregulatoryTcells.Inacomprehensivegeneexpressionanalysis,wefoundthatCD25isspecificallyupregulatedbypre-Bcellreceptor(pre-BCR)signalingduringearlyBcelldevelopmentandinPh+ALLandPh-likeALL.InadultswithPh+ALL(ECOG;MDACC)andchildrenwithPh-likeALL(P9906)patientswithCD25expressionatthetimeofdiagnosishaveaparticularlypooroutcome(n=416;P=0.005).Results:UnlikeTcells,CD25(IL2RA)doesnotfunctionasIL2receptorchaininBcellsandB-lineageALL.Il2ra-/-Bcellswerearrestedatthepre-Bcellstagewithhyperactivepre-BCRdownstreamsignalingincludingSRC,BTKandERK.IntheabsenceofCD25(Il2ra-/-),thepre-BCRsignalsautonomously,resultinginuncoordinatedCa2+oscillations.WhileCD25doesnotfunctionasIL2receptorchaininBcells,itcoordinatespre-BCR-dependentsignaltransductionandregulatesitsintensity.ImmunoprecipitationrevealedstronginteractionsofPP2A,PTEN,SHP1andSHIP1withcytoplasmictailofCD25.Importantly,reconstitutionofmyristoylatedCD25tailbutnotamutantconstructlackingS268/T271rescuedproliferationandsurvivaldefectsofIl2ra-/-ALLcells.TheabilityofCD25tostabilizeoncogenicsignalingstrengthinPh+ALLwasimportantforleukemia-initiationanddevelopmentoffataldisease.IntheabsenceofCD25,Il2ra-/-ALLcellsshowedimpairedproliferationandcolonyformation.SerialtransplantationexperimentsrevealedaprofounddefectofIl2ra-/-ALLcellstoinitiateleukemia.Inaddition,CD25expressionmediateddrug-resistanceinALLcells:Inpatient-derivedpre-BALLcells,vincristineselectivelyinducedapoptosisinCD25LowcellsbutsparedCD25HighALLcells.Combinationwithananti-CD25immunotoxinefficientlyeradiatedCD25HighleukemiacellsandsensitizedtheALLcellpopulationtotreatmentwithvincristine.

Website:http://www.lymphoblasts.org/

FacultyLabInterests(Limit600characters):TheMüschenlabisinterestedincomparativeanalysesofnormallymphocytedevelopmentandmalignanttransformationtowardsleukemia.ThelabcoverresearchareaswithrelevancetobothImmunologyandHematology/CancerBiology.Therefore,thelabfocusesonthebasicscienceofsignaltransductionprocessesinnormalandleukemicBcellsaswellastranslationalresearchdirectedtowardschildhoodacutelymphoblasticleukemia(ALL).

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Abstract#:166 PresentationType:OralAbstract

SessionName:601.ChromosomalRearrangementsandDNARepair:Clonalevolution

PresentationDate/Time:Sunday,December6,2015/8:15AM

Location:OrangeCountyConventionCenter,W312,Level3

PresentationTitle:ExposuretoInflammatoryImmuneResponsesAsDriverofClonalEvolutioninChildhoodAcuteLymphoblasticLeukemiaLeadPresenter/PrincipalInvestigator:LarsKlemm,MSc/MarkusMüschen,MD-PhDAbstract(Limit2000characters):Background:Pediatricpre-Bacutelymphoblasticleukemia(ALL)maydevelopfromprenatalchromosomaltranslocationsacquiredinutero.Forinstance,theETV6-RUNX1generearrangement(~25%ofchildhoodALL)isfoundintheumbilicalcordbloodandGuthriebloodspotsof1in100healthynewborns,however,only1in14,000carriersdevelopovertleukemia.Themolecularmechanismsdrivingclonalevolutiontowardsovertleukemiawerenotclear.Rationale:ActivationInducedCytidineDeaminase(AID)andRecombinationActivationGenes1and2(RAG1-RAG2)aregeneticmodifiersoftheimmunoglobulin(Ig)genesthatareexpressedduringnormalBcelldevelopment.AlthoughAIDandRAG1/RAG2arethoughttobesegregatedtoearly(RAG1/RAG2)andlate(AID)stagesofBcelldevelopment,respectively,wefoundthatthetwoenzymescanbeconcurrentlyexpressedduringearlyB-lymphopoiesisinthecontextofrepeatedinflammatorystimuli.Conclusion:Theimpactofinflammatorystimulionleukemogenesishasbeenpreviouslyimplicatedinmultipleepidemiologicalstudies.Forinstance,day-careattendanceprimedtheimmunesystemduringearlychildhoodandisthoughttoprotectagainstexacerbationofBcellresponsesandtopreventcollateraldamagedrivingclonalevolutiontowardsleukemia.Althoughinflammation(LPSstimulation)seemstoplayaroleinacceleratingpre-Bleukemogenesisinourmodel,furtherexperimentstestingactualinfectiouspathogensareneededtocorroboratethisconcept.Moreover,itiscrucialtotestwhetherleukemogenesisisacceleratedinindividualsinfectedwithrestrictedclassesofpathogens,notallofwhichmayactivateAIDinpre-Bcells.

Website:http://www.lymphoblasts.org/

FacultyLabInterests(Limit600characters):TheMüschenlabisinterestedincomparativeanalysesofnormallymphocytedevelopmentandmalignanttransformationtowardsleukemia.ThelabcoverresearchareaswithrelevancetobothImmunologyandHematology/CancerBiology.Therefore,thelabfocusesonthebasicscienceofsignaltransductionprocessesinnormalandleukemicBcellsaswellastranslationalresearchdirectedtowardschildhoodacutelymphoblasticleukemia(ALL).

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Abstract#:337 PresentationType:OralAbstract

SessionName:623.Lymphoma:Chemotherapy,excludingPre-ClinicalModelsPresentationDate/Time:Sunday,December6,2015:4:30PM

Location:HallE2,Level2(OrangeCountyConventionCenter)

PresentationTitle:BortezomibMaintenance(BM)VersusConsolidation(BC)FollowingAggressiveImmunochemotherapyandAutologousStemCellTransplant(ASCT)forUntreatedMantleCellLymphoma(MCL):CALGB(Alliance)50403

LeadPresenter/PrincipalInvestigator:LawrenceD.Kaplan,MD

Abstract(Limit2000characters):Aggressivechemo-immunotherapyfollowedbyperipheralbloodstemcellautografting(ASCT)inCALGB59909achievedamedianprogression-freesurvival(PFS)inMCLof5years,butlaterecurrencesoccurred.Bortezomib(btz)hasa33%responserateinrelapsed/refractoryMCL.UsingtheCALGB59909treatmentbackbone,weevaluatedtolerabilityandefficacyofaddingpost-transplantBCorBMinarandomizedphaseIItrial.TheprimaryendpointwasPFSestimatedfromstudyentryforeachtreatmentarm.Inductiontherapywaswith2–3cyclesofaugmentedR-CHOP&methotrexatefollowedbyhigh-dosecytarabine/etoposide/rituximab(R)/filgrastim(EAR)stemcellmobilization&cyclophosphamide/carmustine/etoposide(CBV)ASCT.After2dosesofpost-transplantR,patientswererandomizedtoBC(1.3mg/m2days1,4,8,11ofa3weekcyclefor4cycles)orBM(1.6mg/m2weekly4of8weeksfor18months)beginningatapproximatelyday90.Minimalresidualdisease(MRD)wasanalyzed.147patientsreceivedtreatment.118(88%)underwentASCT&102(68%)wererandomized.Followingrandomization,34(65%)completedBM&33(66%)completedBC.Medianfollow-upwas5.5yearsfromregistration.MedianPFSwassignificantlygreaterthanthenullhypothesis(4years)forbothBM&BC.The5-yearPFSestimatesfromstudyentryintheBM&BCarmswere70%(55-81%)&69%(54-80%),respectively.Progressionoccurredin17BM(12post-treatment)&19BCpatients(allpost-treatment).Five-yearPFSfromtimeoftransplantationinCALGBstudies50403(n=118)&59909(n=66)was72.7%(63-80%)&51.5%(36.7-62%),respectivelyfavoringthe50403trialwhichdifferedfrom59909onlybytheadditionofpost-transplantbtz.MRDresultswereavailablein47patients.Five-yearPFSfromstudyentrywas93%ifMRD-negative(n=15)&51%ifMRD-positive(n=32)followinginductionchemo-immunotherapy.Thecomparisonbetweenstudies50403&59909suggestsaPFSbenefitfromtheadditionofBCorBM.

Website:http://cancer.ucsf.edu/people/profiles/kaplan_lawrence.3797

FacultyLabInterests(Limit600characters):

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Abstract#:360 PresentationType:OralAbstract

SessionName:636.MyelodysplasticSyndromes–BasicandTranslationalStudies:EmergingParadigmsinMDSPathobiologyPresentationDate/Time:Sunday,December6,2015:5:45PM

Location:ValenciaD(W415D),Level4(OrangeCountyConvent

PresentationTitle:InhibitionofAktSignalingAlleviatesMDS/MPNDrivenByKrasD12orNf1LossLeadPresenter/PrincipalInvestigator:JonAkutagawa/BenjaminS.Braun,MD,PhDAbstract(Limit2000characters):Juvenile&chronicmyelomonocyticleukemias(JMML&CMML)areaggressivemyeloidmalignanciescategorizedasmyelodysplasticsyndromes/myeloproliferativeneoplasms(MDS/MPN).JMML&CMMLareassociatedwithNRAS,KRAS,PTPN11,CBL,orNF1mutationsthatactivateRassignaling.ConditionalMx1-Cre,KrasLSLD12(KrasD12)micedevelopanaggressive&fullypenetrantMDS/MPNcharacterizedbyleukocytosis,splenomegaly,anemia&deathby10-16wks.Mx1-Cre,Nf1flox/-mice(Nf1Δ/-)undergoconditionallossofNf1.ThesemicealsodevelopMDS/MPN,butthediseaseismoreindolent.InvestigatingthedownstreameffectornetworksofRas,suchastheRaf/MEK/ERK(MAPK)&PI3K/Aktpathways,wepreviouslyshowedthattheMEKinhibitorPD0325901inducedsustainedhematologicimprovementinbothKrasD12&Nf1Δ/-mice.WealsoreportedthattheclassIPI3KinhibitorGDC-0941improveshematologicfunction&prolongssurvivalinKrasD12mice.However,thebenefitfromGDC-0941couldhavebeenduetoitsmodulationofRaf/MEK/ERKsignaling.Here,wespecificallytesttheimportanceofAktsignalinginMDS/MPNinKrasD12&Nf1mousemodelsusingtheallostericinhibitorMK-2206,whichisspecifictoAkt1,Akt2,&Akt3.BothKrasD12&Nf1Δ/-micetreatedwithMK-2206hadreductioninleukocytosis,reticulocytosis&splenomegaly,increasedhemoglobinconcentration&prolongedsurvival.Furthermore,combinedinhibitionofMEK&AktwithPD0325901+MK-2206yieldedagreaterimprovementinsplenomegalythaneitheragentalone.OfAkt’smultipleeffectors,mTORisofparticularinterestfortargetedcancertherapy.Therefore,wetestedtheresponseofKrasD12micetorapamycin&observedthatapproximatelyhalftheKrasD12miceunderwentacomplete&durablehematologicresponsewhiletheremainderhadnoresponse.ThesestudiesimplicatePI3K/AktsignalingasapathogeniceffectordownstreamofRasinMDS/MPN&suggestthatinhibitingthispathwaymayhavearoleinJMMLorCMMLtreatment.

Website:http://cancer.ucsf.edu/people/profiles/braun_benjamin.3714

FacultyLabInterests(Limit600characters):TheBraunlabstudiestheroleofRassignalingintwopediatricmalignancies,juvenilemyelomonocyticleukemia(JMML)andrhabdomyosarcoma.WeareusinggeneticallyengineeredmousemodelsofthesediseasestoinvestigatehowRascontributestocancerdevelopment,andhowsignaltransductioninhibitorsmightcontributetonoveltherapiesforthesediseases.

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Abstract#:2755 PresentationType:PosterAbstract

SessionName:Lymphoma:Pre-Clinical–ChemotherapyandBiologicAgents:PosterIIPresentationDate/Time:Sunday,December6,2015,6:00-8:00PM

Location:OrangeCountyConventionCenter,HallA,Level2

PresentationTitle:Pathway-DirectedHighThroughputDrugScreenIdentifiesPI3KInhibitorsThatSynergisticallyPotentiateAnti-TumorActivityofHDACInhibitorsinMycosisFungoidesandSezarySyndromeLeadPresenter/PrincipalInvestigator:Chen-YenYang/WeiAiAbstract(Limit2000characters):IntroductionandObjectives:MycosisfungoidesandSezarysyndrome(MF/SS)representagroupofheterogeneousdiseases.RecentstudiesdemonstrateddysregulationofseveralsignalingpathwaysinMF/SS.WeperformedahighthroughputdrugscreentodeterminethepotentialofnovelagentstargetingsignalingpathwaysforthetreatmentofMF/SS.MaterialsandMethods:Wecompiledalibraryof94compoundstargetingpathwaysknowntoberelevantincancerbiology,includingkinasesinvolvedingrowthfactorreceptorsignaling,HDACs,proteasome,DNArepairandregulatorsofapoptosis.Thecompoundswerescreenedforanti-proliferativeactivityagainstfourMF/SScelllinesinhighthroughputproliferationassays.SelectedhitswerefurtherstudiedinxenograftmodelsofMF/SSandinprimaryTcelllymphomas.Promisingcandidateswerealsotestedincombinationtherapydesignedtodetectsynergisticactivities.Results:Fromthehighthroughputscreen,weidentified14compoundswithanti-proliferativeactivityinMF/SS,includingmultipleinhibitorsofthePI3Kpathway.Fromthisclass,thePI3KinhibitorBKM120wasselectedforinvivostudies.InaxenograftmodelofMF,BKM120exhibitedstrikinganti-tumoractivitymeasuredbyamarkedsuppressionoftumorgrowthandprolongedsurvivaloftumor-bearingmicecomparedwithvehiclecontrol.Inasearchforevenmoreeffectivecombinationtherapies,weidentifiedthatBKM120andtheHDACinhibitorclassofcompoundsexhibitsynergisticanti-proliferativeeffectsinMF/SStumorcells.EachofthreeHDACinhibitorsincludingLBH,RomidepsinandVorinosatshowedsynergisticactivityinbothgrowthinhibitionandapoptoticassays.Conclusion:BKM120ishighlyactiveinpreclinicalmodelsofMF/SS.Furthermore,itsynergisticallypotentiatestheeffectofHDACinhibitorsagainstMF/SStumorcells.ThesearehighlypromisingapproachesforthetreatmentofMF/SSandwarrantclinicalinvestigation.

Website:http://cancer.ucsf.edu/people/profiles/ai_weiyun.3791

FacultyLabInterests(Limit600characters):Dr.WeiAiisanassociateprofessoratUCSF,Hematology/Oncology.SheearnedaPh.D.andanMDdegreefromStanfordUniversitySchoolofMedicine.ShecompletedresidencyatUCSFandfellowshipatStanford.Dr.AispecializesinHodgkin’s,non-Hodgkin’slymphomasandbonemarrowtransplant.Herresearchisfocusedonimprovinglymphomatherapy.Herlaboratoryperformsstudiesinrelevantcelllineandtumormodelsystemsanduseshumantumorspecimenstoclinicallytranslatetheirfindings.Theirstudiesoftenleadtoclinicaltrialstestingnovelmolecularly-targetedcancertherapies.

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Abstract#:3266 PresentationType:PosterAbstract

SessionName:901.HealthServicesandOutcomesResearch–Non-Malignant

Conditions:PosterIIIPresentationDate/Time:Sunday,December6,2015,6:00PM-8:00PM

Location:HallA,Level2(OrangeCountyConventionCenter)

PresentationTitle:Radiologist-PerformedMusculoskeletalUltrasound(MSKUS)forEvaluationof

JointandSoftTissuePainEpisodesinPatientswithBleedingDisorders

LeadPresenter/PrincipalInvestigator:AnjleeMahajan,MD/AdamGiermasz,MD,PhD

Abstract(Limit2000characters):Joint&softtissuebleedsareasignificantcauseofmorbidityin

patientswithbleedingdisordersleadingtodisablingarthropathy&significanteconomicburdenrelatedtotreatment.Pointofcaremusculoskeletalultrasound(MSKUS)hasbeenshowntobeavaluabletoolinevaluationofpainfulepisodesinpatientswithbleedingdisorders.However,operatorerror&existingpathologiescanbechallengingfornon-radiologisttrainedproviders.Weevaluatedtheuseofradiologist-performedMSKUSforthediagnosis&followupofjoint&softtissuepainepisodesinpediatric&adultpatientswithbleedingdisorders.RetrospectivechartreviewwasperformedforpatientswithbleedingdisorderswhopresentedwithpainsymptomssuspiciousforjointorsofttissuebleedsattheUCSFHemophiliaTreatmentCenterbetween4/2012-6/2015.48patients(44withHemophilia,4withvonWillebrandDiseaseorotherplateletdisorders)&69MSKUS(40joint&29softtissue)wereincludedinthisstudy.64ultrasoundsweredonetoevaluateacuteepisodesofpain&5weredoneforchronicpain.Ofthe69evaluations,28(40.6%)wereradiologistconfirmedbleedingepisodes.41(59.4%)ultrasoundsdidnotconfirmbleeds&ofthese,10(24%)showedotherfindingsrelatedtoinflammationincludingsynovitis,arthritis,tendonitis,bursitis,&cellulitis.Theapplicationofotherinterventions(antibiotics,systemicsteroidsorsteroidinjections,nonsteroidalanti-inflammatorymedication,physicaltherapy&orthopedicsreferrals)occurredin19ofthe41(46%)patients.Serialultrasoundswereperformedin12patientswithconfirmedbleeds.OurstudyhighlightstheimportanceofultrasoundintheevaluationofpatientswithbleedingdisordersasitisoftenamoreaccessibleimagingmodalityascomparedtoMRIorCT.Wewereabletonotonlyverifybleeds&mitigatethecostoftreatment,butalsodiscoverunexpectedpathologythatchangedmanagementofpainfulepisodes.

Website:

FacultyLabInterests(Limit600characters):

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Abstract#:509 PresentationType:OralAbstract

SessionName:653.Myeloma:Therapy,excludingTransplantation:NovelCombinationsinImmuno-OncologyPresentationDate/Time:Monday,December7,2015,8:00AM

Location:OrangeCountyConventionCenter,HallE1,Level2

PresentationTitle:ADoseFindingPhaseIITrialofIsatuximab(SAR650984,Anti-CD38mAb)AsaSingleAgentinRelapsed/RefractoryMultipleMyelomaLeadPresenter/PrincipalInvestigator:ThomasG.MartinAbstract(Limit2000characters):Isatuximab(SAR650984)isahumanizedIgG1MAbagainstCD38.InthePh1doseescalationpartofthetrialisatuximab≥10mg/kg,IVgiveneveryotherweek(q2w)or10mg/kgweekly(qw),inducedresponsesin6/19recipients(ORR32%).MTDwasnotreached.Mostcommontreatment-emergentAEs(TEAEs)werefatigue&nausea;fewseriousgrade3/4TEAEswerereported.Mostcommondrug-relatedTEAEinvolvedinfusionreactions(IARs).BasedonpromisingPh1activity,aPh2dose-findingstudywasaddedtoinvestigatesingle-agentisatuximabinpatientswithrelapsedorrefractorymyeloma.InPh2,patientswererandomlyassigned(1:1:1)tooneof3txgroups:3mg/kgq2w,10mg/kgq2w,&10mg/kgq2wx4dosesthenq4w.A4thtxgroupwasenrolledatahigherisatuximabdosewithanoptimizedscheduleof20mg/kgqwx4dosesthenq2w.Patientassignmentwasstratifiedbyprioranti-myelomatherapy.Patientscontinuedtherapyuntildiseaseprogression,unacceptableAEsorphysician/patientdecision.Eligiblepatientshadmeasurabledisease,priorexposureto≥3linesoftherapyorweredouble-refractorytoimmunomodulatorydrugs&proteasomeinhibitors.Patients(n=96):medianage62.5yrs(38–85);mediantimefrominitialdiagnosistostudytx5.85yrs(1.2–24.1);76%hadIgA/GMM;24%hadlight-chainonlydisease.Mediannumberofpriortherapieswas5(2–14).Mediannumberofcycleswas3(1–9),withmediantxdurationof11.7wks.Mostcommondrug-relatedTEAEswerenausea(14.6%),chills(14.6%),dyspnea(13.5%),chestdiscomfort(10.4%),flushing(7.3%),headache(7.3%),cough(6.3%)&vomiting(5.2%).MajorityofthesymptomswereattributedtoIARs,werepredominantlygrade1/2&mostlylimitedtoCycle1.Pneumonia(6.3%)&sepsis(5.2%)werethemostcommonseriousTEAEs.6deathsoccurredwithin30daysoflastdose,4duetodiseaseprogression&2duetoSAEsunrelatedtostudytherapy.Resultsbytxarm,includinginterimanalysisresponsedata,willbepresented.

Website:http://cancer.ucsf.edu/research/multiple-myeloma/mmti/

FacultyLabInterests(Limit600characters):Dr.Martinisboardcertifiedininternalmedicine,hematology,andmedicaloncology.HeisamemberoftheClinicalResearchOfficeofUCSFCancerCenter,AmericanSocietyofHematologyandtheAmericanSocietyforBloodandMarrowTransplantation.Heco-leadstheUCSFStephenandNancyGrandMultipleMyelomaTranslationalInitiative,amulti-disciplinaryprogramaddressingarangeofimportantbiologicalquestionsinmultiplemyeloma.Dr.Martinhasservedasprincipalinvestigatorfornumerousclinicalstudiesinmyeloma,acuteleukemia,andstemcelltransplantation.

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Abstract#:

PresentationType:OralAbstract

SessionName:SpotlightSessionPresentationDate/Time:Monday,December7,2015:10:30AM-12:00PM

Location:W314,Level3(OrangeCountyConventionCenter))

PresentationTitle:BeyondTranscription:TranslationalControlofGeneExpressioninDevelopmentandDisease

LeadPresenter/PrincipalInvestigator:DavideRuggero,PhD

Abstract(Limit2000characters):Hematopoietictissuesareparticularlysensitivetochangesinthecellularproteinsynthesismachinery.Mutationsinthetranslationalapparatus,includingenzymes

involvedinthemodificationandprocessingofribosomalRNA(rRNA),ribosomeassemblyfactors,andribosomalproteins,causespecificbloodphenotypesdespitetheubiquitousexpressionofthe

affectedgenes.Thesehumansyndromeshavecollectivelybeenlabeled“ribosomopathies”and

representaparadigmtostudythemechanismsbywhichperturbationofribosomeactivityandtranslationcontrolcausespecificpathologiesincludinghighpredispositiontohematological

malignancies.Furthermore,recentstudiesalsodemonstrateaneedfortightregulationofoverallproteinsynthesisinhematopoieticstemcells.Itremainsunclearwhyribosomedefectsleadto

anemiaandpredispositiontohematopoieticdisorders.Newadvancesinnovelorganismalmodelsto

studytranslationcontrolinhematopoiesis,aswellasgenome-widetranslationalprofiling,mayoffernewinsightsintothesequestions.

Dr.RuggerowilldiscussnovelmechanismsbywhichmRNAtranslationalcontrolprovidesanimportantlevelofregulationtoerythropoiesis.Thisresearchhelpstoclosealargegapinour

understandingofhowmutationsinthetranslationmachineryunderliehematopoieticdisorders,collectivelyknownas“ribosomopathies”.Inparticular,hewilldiscusssurprisingfindingsof

dynamicregulationintheactivityofcoretranslationfactorsduringerythroiddifferentiation.In

addition,hewilldiscusshowemployingstate-of-the-artproteomicsoferythroidcellshasrevealedthattranslationalregulationsupportsrapidcelldifferentiationandmatureredcellproductionasa

mechanismtofaithfullyintegrateextracellularsignals.

Website:http://ruggerolab.ucsf.edu/

FacultyLabInterests(Limit600characters):TheRuggerolabemploysamultidisciplinaryapproach,suchasdevelopingthefirstgeneticlossandgain-offunctionmousemodelsofdistinctcomponents

ofthetranslationinitiationmachineryincombinationwithnewquantitativemeasuresofthe

translationallandscapeofgeneregulation,tounderstandtheoriginsofcancerandhumandiseases.Inparticular,thisresearchhasrevealedafundamentalnewwayofthinkingabouthowchangesin

thetranslationmachinerydirectlycausecellulartransformationandhumanpathologies,therebyopeningthedoorfornoveltherapies.

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Abstract#:556 PresentationType:OralAbstract

SessionName:603.OncogenesandTumorSuppressorsPresentationDate/Time:December7,2015,11:15AM

Location:OrangeCountyConventionCenter,W308,Level3

PresentationTitle:IdentificationofBCL6AsaTherapeuticTargetinRAS-DrivenAcuteLymphoblasticLeukemiaLeadPresenter/PrincipalInvestigator:QiangLi,PhD/MarkusMüschen,MD-PhDAbstract(Limit2000characters):In~50%ofcasesofacutelymphoblasticleukemia(ALL),activatinglesionsinRASpathwayarefound.TranscriptionalrepressorBCL6isreportedasakeyfactortoovercomep53dependentsenescenceandenableRAS-mediatedtransformationofmouseembryonicfibroblasts.HerewetestedthehypothesisthatBCL6representsatherapeutictargetinALLwithRASpathwaylesions.WefoundthatinducibleexpressionofoncogenicNRAS-G12DincreasedBCL6mRNAlevelsby~350-foldandproteinlevelsby~50-fold.WecomparedALLcellsthatwereisolatedatthetimeofinitialdiagnosis(D),andatthetimeofrelapse(R)fromthesamepatient.Interestingly,thepatienthadacquiredaKRAS-G12Vmutationatthetimeofrelapse.Wefoundbothhyper-phosphorylationofERKandoverexpressionofBCL6intherelapsecells(KRAS-G12V),butnotindiagnosissample(KRASwild-type).R-ALLcellsharboringtheKRAS-G12VmutationweremoresensitivetothetreatmentwiththeMEKinhibitorPD325901andtheBCL6peptideinhibitorRI-BPIthanD-ALLcells.BCL6inhibitionalsomarkedlyincreasedsurvivalrateofNOD/SCIDmicexenograftedwithR-ALLcells.WefurthertesteditsfunctioninamouseALLmodel.Pre-BcellsfrombothBcl6+/+andBcl6-/-micecouldbetransducedbyNRAS-G12D,however,Bcl6-/-NRAS-G12DALLcellsfailedtoinitiatefatalleukemiainNOD/SCIDtransplantrecipientmice,whereasBcl6+/+NRAS-G12DALLcellsgaverisetolethalleukemiainalltransplantrecipients.StudyingCre-mediateddeletionofBcl6-fl/flallelesinacomplementarymousemodelrevealedthatcontinuouspresenceofBcl6functionisrequiredfornormalproliferationofALLcells.Cre-mediatedablationofBCL6inNRAS-G12DdrivenALLinducedrapidcelldeathandcompletelyabrogatedtheabilityofNRAS-G12DALLcellstoformcolonies.TheseresultssupportthatBCL6isnotonlyrequiredfortheinitiationofRAS-transformedALLinvivobutalsoforthemaintenanceoffullyestablishedRAS-drivenleukemia.

Website:http://lymphoblasts.org/

FacultyLabInterests(Limit600characters):TheMüschenlabisinterestedincomparativeanalysesofnormallymphocytedevelopmentandmalignanttransformationtowardsleukemia.WecoverresearchareaswithrelevancetobothImmunologyandHematology/CancerBiology.Ourresearchinvolvesexperimentswithprimaryhumanleukemiacells,leukemiaandstemcelltransplantationmodels,mousegenetics,classicalmolecularandcellbiology,astrongemphasisonsignaltransductionandlarge-scaledataanalysisandcomputationalbiology.

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Abstract#:677 PresentationType:OralAbstract

SessionName:604.MolecularPharmacologyandDrugResistanceinMyeloid

Diseases:AcutePresentationDate/Time:Monday,December7,20153:45PM

Location:OrangeCountyConventionCenter,W307,Level3

PresentationTitle:RecurrentMutationsinCCND3ConferClinicalResistancetoFLT3Inhibitors

LeadPresenter/PrincipalInvestigator:CatherineSmith/NeilShah

Abstract(Limit2000characters):ActivatingmutationsinFLT3occurin~30%ofadultacutemyeloid

leukemia(AML)cases.CausesofprimaryclinicalresistancetoFLT3inhibitorshavenotbeen

characterized.Weperformedtargetedsequencingofsortedpre-treatmentblastsfrom8

responding(R)and21non-responding(NR)patientstreatedonthephaseI/IItrialofPLX3397in

FLT3-ITD+AML.ThenumberofmutationsdetectedingenesotherthanFLT3rangedfrom2-18per

sample.Surprisingly,oneofthemostfrequentlymutatedgenesobservedexclusivelyinNRpatients

wasCCND3,thegeneencodingcyclinD3,whichhasrarelybeenreportedtobemutatedinAML,

thoughitismutatedin38%ofsporadicBurkitt’slymphoma(BL).Atotalof4individualmutations

inCCND3(Q276*,Q280fs,R271fs,andT283A)wereidentifiedin3/21NRpatients(onepatienthad

bothQ276*andQ280fs).NoCCND3mutationswerefoundinRpatients.Theidentifiedmutations

werethesamemutationscommonlyfoundinBL,knowntoresultinamorestableisoformofcyclin

D3andretainsensitivitytoCDK4/6inhibitors.ExpressionoftheQ276*andT283Amutationsin

FLT3-ITD+MV4;11cellsconferredresistancetoapoptosisinducedbyseveralFLT3inhibitors

(PLX3397,AC220andcrenolanib).However,inhibitionofCDK4/6activityinCCND3mutant

MV4;11cellsbyeithertheCDK4/6inhibitorpalbocicliborthecombinedFLT3-CDK4/6inhibitor

AMG925(FLX925)wasunabletorestoresensitivitytoFLT3inhibition.Moreover,CCND3mutant

MV4;11cellsdemonstratednoincreaseinRbphosphorylation,suggestingresistancetoFLT3

inhibitorsfacilitatedbyCCND3mutationsisnotpredicatedonCDK4/6activationofRb-dependent

E2F-mediatedtranscription.WeidentifiedrecurrentmutationsinCCND3,agenenotpreviously

knowntobecommonlymutatedinAML,asanovelcauseofclinicalprimaryresistancetoFLT3

inhibitorsinAML.Thisrepresentsthefirstreportofaspecificnon-FLT3dependentmechanismof

clinicalresistancetoFLT3inhibitors.

Website:

FacultyLabInterests(Limit600characters):AML,FLT3,kinaseinhibitors,resistance,CCND3

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Abstract#:778 PresentationType:OralAbstract

SessionName:504:Hematopoiesis:Cytokines,SignalTransduction,ApoptosisandCellCyclePresentationDate/Time:Monday,December7,2015:5:15PM

Location:W312,Level3(OrangeCountyConventionCenter)

PresentationTitle:Interleukin-1DrivesPrecociousMyeloidDifferentiationofHematopoieticStemCellsattheExpenseofSelf-RenewalLeadPresenter/PrincipalInvestigator:EricMartinPietras,PhD/EmmanuellePassegue,PhDAbstract(Limit2000characters):Hematopoieticstemcells(HSCs)maintainlifelongbloodhomeostasis.Whilemanyofthecell-intrinsicmechanismsregulatingHSCfunctionatsteadystatehavebeenwellcharacterized,theroleofinflammatorycytokines&otherenvironmentalfactorsintailoringbloodproductionfollowingphysiologicalinsultshasbecomeatopicofemerginginterest.Thecytokineinterleukin-1(IL-1)isapro-inflammatorycytokinethatplaysakeyroleinhostinflammatoryresponsestoinjuryandinfectionandisassociatedwithelevatedmyeloidcellproduction.Here,weshowatsingle-cellresolutionusingcontinuoustrackingtechnologythatIL-1drivesacceleratedHSCcelldivisionkineticsandmyeloiddifferentiationviatherapidactivationofaprecociousPU.1-dependentmyeloidgeneprogram.ActivationofthisprogramrequiresdirectIL-1RsignalingandsubsequentactivationofIKKkinases,andinstructivelyprimesHSCstoadoptamyeloidfate.WedemonstratethatIL-1producedbymyeloidcellsandendothelialcellsofthebonemarrow(BM)nicheexertssimilareffectsinvivoandisrequiredforefficientmyeloidrecoveryfollowingacutechallenges.Ontheotherhand,wefindthatchronicIL-1exposuresubstantiallyremodelsHSCbloodoutput,resultinginmyeloidoverproduction&expansionofmyeloid-biasedmultipotentprogenitor(MPP)compartmentsattheexpenseoflymphoid&erythroidlineages.ChronicIL-1erodesHSCself-renewal,significantlyimpairingtheirregenerativecapacityfollowingtransplantation.Ontheotherhand,chronicallyexposedHSCsrecovertheirfunctionuponIL-1withdrawal.Collectively,thesefindingsidentifyIL-1asacriticalregulatorofHSCfateandlineagespecificationviaactivationofaPU.1circuit.TheyalsodemonstratearoleforIL-1asadouble-edgedswordinHSCbiology,promotingHSCregenerationinresponsetoacuteinsultswhileseverelydisruptingHSCself-renewalandlineageoutputduringchronicexposure.

Website:http://passeguelab.ucsf.edu

FacultyLabInterests(Limit600characters):ResearchinthePasseguélabfocusesonunderstandingthecellularandmolecularprocessescontrollinghematopoieticstemcell(HSC)activityduringhomeostasis,andaddressinghowtheseregulationsarechangedinmyeloidmalignanciesandphysiologicalaging.Ourgoalistoidentifyaffectedgenesand/orpathwaysthatcanbeusetodevelopnewtherapiestotreathumandiseases.Towardsthisend,weareemployingavarietyofcross-disciplinaryapproachesusingmousemodelsandhumanpatientsamples.

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Abstract#:902 PresentationType:OralAbstract

SessionName:618.ALL:NewInsightsintoALLBiologyandTherapeuticTargetingPresentationDate/Time:December7,2015,6:30PM

Location:OrangeCountyConventionCenter,W308,Level3

PresentationTitle:PP2AIsRequiredforBCellSurvivalandRepresentsaTherapeuticTargetinAcuteLymphoblasticLeukemiaLeadPresenter/PrincipalInvestigator:GangXiao,PhD/MarkusMüschen,MD-PhDAbstract(Limit2000characters):Background:PP2AattenuatesactivityofRAS-ERKandPI3K-AKTsignalingpathwaysandfunctionsasimportanttumorsuppressorinchronicmyeloidleukemia(CML).RestorationofPP2AactivityhasbeenproposedforthetreatmentofCML.WhilethetumorsuppressorfunctionofPP2Awasindependentlyconfirmedbymultiplegroups.Results:WestudiedthefunctionofPP2AinageneticmousemodelforCre-induceddeletionofPpp2r1ainBCR-ABL1(Ph+)ALL.Cre-mediateddeletionincreasedphosphorylationlevelsofp70S6KandS6ribosomalprotein.AcutedeletionofPpp2r1afl/flinBcell-lineageALLcellsdramaticallyaffectedsurvivalandcolonyformation,bothofwhichcouldberescuedbyoverexpressionofwildtypePP2A.However,Cre-mediateddeletionhadnodeleteriouseffectsinaPpp2r1afl/flCMLmodel.Cre-mediateddeletionsignificantlyprolongedoverallsurvivalofrecipientmicethatweretransplantedwithPpp2r1afl/flALLcells.UponPP2A-deletion,ALLcellsshowedhigherglycolyticfluxshuntedintolactateratherthanNADPHproduction.LowerNADPH/NADPratioandhigherROSlevelinPP2A-deletedALLcells,togetherwithdecreasedanti-oxidantgeneexpression,increasedH2AXphosphorylationandp53expressionindicatedimpairedbalanceofglycolyticfluxmayaccountforincreaseddeathofthosecells.ThefunctionofPP2AinPh+ALLwasfurthervalidatedbyCRISPR-Cas9mediateddisruptionofPPP2R1AinALLxenograftsderivedfrompatients.APP2AspecificinhibitorLB-100(inclinicaltrialforsolidtumors)inducedcelldeathinpatient-derivedALLxenograftsinparallelwithROS-accumulationandincreasedS6andH2AXphosphorylation.Conclusion:Cre-mediatedablationofPP2AinmousePh+ALLcellsinducedrapidcelldeaththroughexcessivelyoxidativestressbutnotinCMLcells.Weconfirmedthispro-survivalroleofPP2AinhumanPh+ALL-patientsderivedleukemiacells.OurfindingshighlightPP2AasatherapeutictargetwithpotentialrelevanceinPh+ALL.

Website:http://lymphoblasts.org/

FacultyLabInterests(Limit600characters):TheMüschenlabisinterestedincomparativeanalysesofnormallymphocytedevelopmentandmalignanttransformationtowardsleukemia.TheycoverresearchareaswithrelevancetobothImmunologyandHematology/CancerBiology.Theirresearchinvolvesexperimentswithprimaryhumanleukemiacells,leukemiaandstemcelltransplantationmodels,mousegenetics,classicalmolecularandcellbiology,astrongemphasisonsignaltransductionandlarge-scaledataanalysisandcomputationalbiology.

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Abstract#:3672 PresentationType:PosterAbstract

SessionName:603.OncogenesandTumorSuppressors:PosterIIIPresentationDate/Time:Monday,December7,2015,6:00PM-8:00PM

Location:HallA,Level2(OrangeCountyConventionCenter)

PresentationTitle:CblY371HTransgeneCombinedwithHematopoieticDeletionoftheEndogenousc-CblGeneResultsinGM-CSFHypersensitivityandLeukocytosis

LeadPresenter/PrincipalInvestigator:KennethLieuw,MD,PhD/MignonL.Loh,MD

Abstract(Limit2000characters):JuvenileMyelomonocyticLeukemia(JMML)isamixedmyeloproliferative/myelodysplasticdiseasethatisrapidlyfatalwithinfiltrationofmyeloidcellsintomultipleorgans.About15%ofJMMLpatientscontainamutationinc-Cbl&germlinemutationresultsinthepredispositionfordevelopingJMML.Thec-Cblgeneencodesamultifunctionaladaptorprotein.Ahotspotexistsatresidue371inJMMLpatients,where1/3ofthemutationsareaTyrtoHissubstitution,Y371H.HowmutantCblgivesrisetoJMML&howitactsinconcertwithothergenesinthepathogenesisofJMMLisnotclear.WeoverexpressedoncogenicCblY371Hmutationusingtransgenicmice.OverexpressionofCblY371Hbyitselfinwtmicehadnoapparentphenotype.Therefore,CbltransgenicmicewerebredtoCblheterozygousknockoutmice(Cbl+/-)followedbyfurtherbreedingtogenerateCbltransgenicmicewiththeendogenousCblgeneinactivated(CblY371H;Cbl-/-).Surprisingly,unlikeCblnullmice,whichareviable,overexpressionofmutantCblalleleinCblnullmicecausedembryoniclethalitybetween11.5&12.5dpc.TocircumventthedevelopmentaleffectsofexpressingthemutantCblprotein,weusedaconditionalCblknockoutmousetotissuespecificallydeletetheendogenousCblgene.WechosetheMMTV-Crestrain,whichexpressesCrerecombinaseinonly10%ofhematopoieticstemcells(CD34-;Lin-;Sca-1+;c-Kit+).WithsubsequentbreedingwiththeCblY371Htransgenicmice,wewereabletobypasstheembryoniclethality&producemicewiththecorrectgenotype(MMTV-Cre;CblY371H;Cblfl/fl).Thesemicelooknormalbutdevelopleukocytosis&showGM-CSFhypersensitivityeventhoughonly10%ofhematopoieticstemcellsareaffected.Thesemice,however,appearunaffectedbytheleukocytosis&shownoobviousdifferencewithlittermatesuptooneyearofage.WeconcludethatmutantCblY371HbyitselfisnotsufficientforthedevelopmentofJMMLinthismodel&requiresadditionalcooperatingevents.

Website:http://cancer.ucsf.edu/people/profiles/loh_mignon.3407

FacultyLabInterests(Limit600characters):

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Abstract#:3716 PresentationType:PosterAbstract

SessionName:612.AcuteLymphoblasticLeukemiaPresentationDate/Time:December7,2015/6:00PM-8:00PM

Location:OrangeCountyConventionCenter,HallA,Level2

PresentationTitle:TargetedActivationofBCellAutoimmunityCheckpointsinAcuteLymphoblasticLeukemia

LeadPresenter/PrincipalInvestigator:ZhengshanChen,MD-PhD/MarkusMüschen,MD-PhD

Abstract(Limit2000characters):Background:Unlikeothercelltypes,Bcellsareselectedforanintermediatelevelofsignalingstrength.CriticalsurvivalandproliferationsignalsemanatefromtheBcellreceptor(BCR):IfB-cellsfailtoexpressafunctionalBCR,signalingoutputistooweak,resultingin“deathbyneglect”.IftheBCRbindstoubiquitousself-antigen,BCRsignalsareexceedinglystrong.Bothattenuationbelowminimum(non-functionalBCR;deathbyneglect)andhyperactivationabovemaximum(autoreactiveBCR)thresholdsofsignalingstrengthtriggernegativeselectionandcelldeath.Rationale:Unlikeanyothertypesofcancer,werecentlydiscoveredthatpre-Bacutelymphoblasticleukemia(ALL)cellsareboundbythesamerulesthatalsogovernnormalBcellselection.TheoncogenicBCR-ABL1tyrosinekinasemimicsactivepre-BCRsignalinginPh+acutelymphoblasticleukemiawhichdefinestheALLsubgroupwiththeworstclinicaloutcome.Currenttherapyapproachesarelargelyfocusedonthedevelopmentofmorepotenttyrosinekinaseinhibitors(TKI)tosuppressoncogenicsignaling.HoweverresistancetoTKIisdevelopedinvariably.Here,wetestthehypothesisthattargetinghyperactivationaboveamaximumthresholdwillselectivelykillPh+ALLcellsthroughamechanismthatisfunctionallyequivalenttoremovalofself-reactiveBcells.Conclusion:Theseresultsindicatedthatinhibitoryreceptorsanddownstreamphosphatasesarecriticalregulatorsofpre-BCRsignalingstrengthinPh+ALL,andidentifiedtargetinghyperactivationofpre-BCRsignalingasapotentialnovelclassoftherapeuticstrategy.

Website:http://lymphoblasts.org/

FacultyLabInterests(Limit600characters):TheMüschenlabisinterestedincomparativeanalysesofnormallymphocytedevelopmentandmalignanttransformationtowardsleukemia.WecoverresearchareaswithrelevancetobothImmunologyandHematology/CancerBiology.Ourresearchinvolvesexperimentswithprimaryhumanleukemiacells,leukemiaandstemcelltransplantationmodels,mousegenetics,classicalmolecularandcellbiology,astrongemphasisonsignaltransductionandlarge-scaledataanalysisandcomputationalbiology.

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Abstract#:3900 PresentationType:PosterAbstract

SessionName:622.Non-HodgkinLymphoma:Biology,excludingTherapy:PosterIIIPresentationDate/Time:Monday,December7,2015:6:00-8:00PM

Location:OrangeCountyConventionCenter,HallA,Level2

PresentationTitle:ExpressionofBandTLymphocyteAttenuator(BTLA)CorrelateswithCNSMetastasisandAdversePrognosisinActivatedB-CellLymphomaandAcuteLymphoblasticLeukemia

LeadPresenter/PrincipalInvestigator:HuiminGeng/JamesRubenstein

Abstract(Limit2000characters):Results.WefirsttestedthehypothesisthatgenomicaberrationsmaycontributetotherefractoryphenotypeinaggressiveB-celllymphoma.Topursuethis,wecomparedDNAcopynumberaberrationsinrelapsedlargeB-celllymphomathathadmetastasizedtothebrain(3cases,eachisolatedbyresection)withthegenomicchangesidentifiedinlargeB-celllymphomaatdiagnosis(15cases:12PCNSLand3nodallymphomas;allDLBCL).Weidentifiedafocalrecurrentcopynumbergainatchromosome3qencodingtwocandidateproteins:SIDT1,amediatorofmicroRNAtransport,andBTLA,amemberoftheCD28superfamilyandmodifierofbothB-cellreceptorsignalingaswellasT-cellresponses.ElevatedBTLAtranscriptandproteinexpressioninrelapsedspecimenswasconfirmed.WealsodemonstratedbyimmunohistochemistrythattumorcellexpressionofBTLAbutnotSIDT1correlatedwithshortoverallsurvivalinanindependentsetof40patientswithPCNSLtreateduniformlywithanimmunochemotherapyprotocol.UsingindependentdatabasesofsystemicDLBCL(n=203and69respectively,Lenzetal.PNAS2008;Shaknovichetal.Blood2010),wedeterminedthatexpressionofbothBTLAandSIDT1weresignificantlyhigherinABCcomparedtoGCBDLBCL(p<0.0001)and,inanindependentcohortof73ABCDLBCLcases,highBTLAexpressionwasassociatedwithatrendtowardsshorteroverallsurvival(P=0.059).Finally,highBTLAtranscriptlevels,butnotSIDT1,correlatedwithsignificantlyshorteroverallsurvivalConclusions.TakentogetherthesedatasuggestforthefirsttimethatBTLAexpressionmaycontributetometastasisandCNSprogressionofactivatedB-celllymphomaandtoresistanceinALLandPh+ALL.OurdatasuggestthatBTLAmaynotonlybeausefulbiomarkerintheseaggressiveneoplasms,butalsoapotentialtherapeutictarget.AdditionalstudiesareneededtodeducethemechanismsbywhichBTLAcontributestoresistanceandmetastasisinABCDLBCLandinALL.

Website:https://bms.ucsf.edu/directory/faculty/james-rubenstein-md-phd

FacultyLabInterests(Limit600characters):ThelabofDr.JamesRubenstein,DepartmentofMedicine,worksinthefieldimmunotherapyandcancer.Ourmajorinterestsareintheidentificationofgeneticfactorsassociatedwithrelapse,intumorcelltropismtothebrain,andindefiningthetumormicroenvironmentinordertoimprovetheanti-tumorimmuneresponse.WearesimultaneouslyinvolvedinleadingphaseIandIItrialsinpatients,inconductingcorrelativestudiesoftheimmuneresponseinpatientstreatedwithimmunotherapy,andinthedevelopmentofnovelpreclinicalmodelstounderstanddiseasemechanisms.

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Abstract#:4350 PresentationType:PosterAbstract

SessionName:723.ClinicalAllogeneicandAutologousTransplantation:LateComplicationsPresentationDate/Time:Monday,December7,2015;6:00PM-8:00PM

Location:OrangeCountyConventionCenter,HallA,Level2

PresentationTitle:MultigeneMRDAssessmentImprovesAMLRelapseRiskStratificationinAutologousHematopoieticCellTransplantationLeadPresenter/PrincipalInvestigator:MatthewP.Mulé/GabrielN.Mannis,MDAbstract(Limit2000characters):Autologoushematopoieticcelltransplant(autoHCT)hasnotbeenwidelyadoptedinacutemyeloidleukemia(AML)outofconcernforhighpost-transplantrelapserates.Theserelapsesmaybedue,inpart,toautograftcontaminationwithAML.WeevaluatedautograftsfromAMLpatients(pts)formeasurableresidualdisease(MRD)bybothmolecularmethods(RQ-PCR)andmulti-parameterflowcytometry(MPFC)todetermineiftestingofthegraftpriortoautoHCTcouldpredictrelapse.Seventy-twoptstransplantedatUCSFwereinclduedinthisstudybasedonavailabilityofcryopreservedGCSF-mobilizedautologousperipheralbloodprogenitorcell(PBPCs)specimens.Cytogeneticswereintermediate-riskin69%.FollowingautoHCT,2yearRFSwas40%(2yearrelapserate47%).Wilmstumor1(WT1)isexpressedinupto90%ofAML,butsufficientlyover-expressedinperipheralbloodtohaveutilityasasensitivemarkerofMRDin<50%ofcases.Wepreviouslyreportedthatmulti-genetestingcanaugmentWT1-basedMRDdetectioninAML.TestingforPRAME,MSLN,CCNA1,t(8,21),Inv16,t(15:17)andNPM1mutationsA,BandD,asasupplementforWT1,inpre-HCTPBPCsresultedinsubstantiallyimprovedabilitytopredictpost-autoHCTrelapse(52%sensitivity,80%specificity,PPV:67%,NPV:69%).MPFCcanalsoidentifyresidualAMLwithhighsensitivity.FortyPBPCsamplesfromtheabovecohortwerealsoassessedforMRDusingMPFC.CD34+cellscomprised0.05-12.5%ofautograftspecimenPBPCs.DuetoimmunophenotypicchangeslikelyattributabletoGCSFmobilization,andwithoutLAIPsfromdiagnosisavailable,MPFCwasunabletoidentifyMRDinanyof40ptstested.Insummary,nosingleMRDtestcouldcompletelypredictpost-HCTAMLrelapse.AutoHCTpresentsuniquechallengesforAMLMRDtestingduetomaskingeffectsofGCSFonMPFCandRQ-PCRgeneexpressionsignatures.WeshowthatcombinationsofmolecularMRDassayscanovercomesome,butnotall,oftheselimitations.

Website:http://profiles.ucsf.edu/gabriel.mannis

FacultyLabInterests(Limit600characters):Dr.Mannisisaclinical/translationalinvestigatorwhoseresearchaimstoimproveoutcomesforpatientsviamorepersonalizedtreatmentstrategies,includingthestudyofnovelimmunotherapeuticapproachesandmolecularlytargetedagents.Accordingly,hisresearchincludesadiversearrayofhematologicmalignancies,mostcommonlyacuteleukemias,myelodysplasticsyndromes,myeloproliferativeneoplasms,andplasmacelldisorders.

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Abstract#:4458 PresentationType:PosterAbstract

SessionName:901.HealthServicesandOutcomesResearch–Non-MalignantConditions:PosterIIIPresentationDate/Time:Monday,December7,2015,6:00PM-8:00PM

Location:HallA,Level2(OrangeCountyConventionCenter)

PresentationTitle:Frequency,RiskFactorsandMortalityEffectofVenousThromboembolisminAdultPatientswithCentralNervousSystemLymphoma

LeadPresenter/PrincipalInvestigator:AnjleeMahajan,MD/RichardFong,PharmD

Abstract(Limit2000characters):Venousthromboembolism(VTE)isacancercomplication,withahighincidenceinpatientswithbothlymphoma(5-15%)&gliomas(15-20%).ThisstudyaimistocharacterizethefrequencyofVTEinadultpatientswithCNSlymphomatreatedatalargeacademicmedicalcenter.TheUCSFCancerRegistrywasqueriedforadultCNSlymphomacasesdiagnosedfrom2008-2014.Chartreviewwasperformed&patientswereexcludediftheprimarytreatmentoccurredelsewhere.Demographics,histology,treatment&mortalitydatawereexamined.PresenceofVTEwasdefinedbyradiographicevidenceofapulmonaryembolism(PE)ordeepveinthrombosis(DVT).134adultCNSlymphomacaseswerereported;18patientswereexcluded.Theaveragefollowuptimewas3.8yearsfromdiagnosis.Meanageatdiagnosiswas63.Ofthe116patientincludedinthestudy,77(66%)wereidentifiedashavingPrimaryCNSLymphoma&39(34%)hadSecondaryCNSLymphomaincludingthefollowingsubtypes:DiffuseLargeB-cell,Burkitt’s,Mantlecell,Marginalzone&NKcelllymphoma.Therewere34casesofVTE(29.3%):12werePE&22wereDVT,32(94%)patientswerehospitalizedatthetimeofVTEdiagnosis,28(82%)weresymptomatic,20(29%)wereline-associatedVTE.50%ofVTEcasesoccurredduringcycle1(18%)orcycle2(32%)ofchemotherapy&27patients(79%)receivedsystemicsteroidswithin30daysofVTEdiagnosis.ThemediantimefromdiagnosisofCNSlymphomatoVTEwas70days.Race,sex,smokinghistory&histologywerestudied&nodifferencewasfoundbetweentheVTE&non-VTEgroups.Notably,bodymassindexwassignificantlyhigherintheVTEgroup(29.85,95%CI:26.5-33.2)ascomparedtothenon-VTEgroup(25.66,95%CI:24.76-26.55,p=0.019).TherewasatrendtowardshortertimetodeathafterthediagnosisofCNSlymphomaintheVTEgroup(382days,95%CI:106-657)vs.thenon–VTEgroup(699days,95%CI:348-1049,p=0.18).Therewasnodifferenceinoverallsurvival(logrankp=0.09).

Website:

FacultyLabInterests(Limit600characters):

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Abstract#:

PresentationType:OralAbstract

SessionName:PresidentialSymposiumPresentationDate/Time:Tuesday,December8,2015:9:45AM-11:15AM

Location:HallD,Level2(OrangeCountyConventionCenter)

PresentationTitle:ThroughtheLensofGermlinePredispositionstoLeukemia:HowKidsTeachAdultsLeadPresenter/PrincipalInvestigator:MignonL.Loh,MDAbstract(Limit2000characters):Thepastdecadeofscientificinvestigationhasledtonewunderstandingofsomaticgenomemutationsandtheirroleinhematologicdiseases,aswellasimportantinsightsintotheroleofgermlinemutationsandepigeneticdriversofcancerssuchasleukemia.Ineachoftheseareas,therelativepristinegenomesofpediatriccancersandthesuccessesintreatingmonogenicdiseasesinchildrenwithgeneticallymodifiedcellsandtargetingtheepigenomehaveyieldedinsightsandtoolsthathaveandwillbeusedinadultdiseases.Duringthe2015ASHPresidentialSymposium,threeexpertswilldiscusstheinsightsgainedinthestudyofchildhooddiseasesandtheirimpactonevolvingtherapiesforadulthematologicdisorders.Dr.MignonLohwilldescribehowgermlineandsomaticmutationsinjuvenilemyelomonocyticleukemiahaveledtonewunderstandingoftheevolutionofthisdiseaseandhaveprovidedinsightsintothecomplexityoftargetingRAS-mutatedleukemias.

Website:http://cancer.ucsf.edu/people/profiles/loh_mignon.3407

FacultyLabInterests(Limit600characters):