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Transcript of UCSF HELEN DILLER FAMILY COMPREHENSIVE CANCER...
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
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.
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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Contents
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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Contents
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):
22
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.
24
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):
25
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.
26
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.
27
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):
36
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):