An Ongoing Story of Discovery: Pathophysiology of Chronic Myeloproliferative Disorders
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Transcript of An Ongoing Story of Discovery: Pathophysiology of Chronic Myeloproliferative Disorders
An Ongoing Story of Discovery:An Ongoing Story of Discovery:
Pathophysiology of Chronic Pathophysiology of Chronic Myeloproliferative DisordersMyeloproliferative Disorders
Katy Moran MDKaty Moran MD
August 30, 2005August 30, 2005
““Imagination is more important than Imagination is more important than knowledge, for knowledge is limited knowledge, for knowledge is limited
while imagination embraces the entire while imagination embraces the entire world.”world.”
Albert EinsteinAlbert Einstein
First, some cases. . .First, some cases. . .
Case #1: 63 yo woman presents to clinic with increasing abdominal girth, Case #1: 63 yo woman presents to clinic with increasing abdominal girth, physical – hepatosplenomegaly. CBC reveals a Hct 52% and Platelet count physical – hepatosplenomegaly. CBC reveals a Hct 52% and Platelet count 900,000 cells/mm900,000 cells/mm33. Diagnosis?. Diagnosis?
Polycythemia veraPolycythemia vera
Case #2: 46 yo man presents to clinic with painful unilateral swelling of the Case #2: 46 yo man presents to clinic with painful unilateral swelling of the right lower extremity for 48 hours. No known risk factors for DVT, right lower extremity for 48 hours. No known risk factors for DVT, ultrasound reveals femoral vein DVT. CBC reveals platelet count 1,200,000 ultrasound reveals femoral vein DVT. CBC reveals platelet count 1,200,000 cells/mmcells/mm33. Diagnosis?. Diagnosis?
Essential thrombocytosisEssential thrombocytosis
Case #3: 65 yo man of Jewish ancestry presents with fatigue, low grade Case #3: 65 yo man of Jewish ancestry presents with fatigue, low grade fever. Mild pancytopenia and teardrop-shaped rbcs are noted on blood fever. Mild pancytopenia and teardrop-shaped rbcs are noted on blood smear. Bone marrow biopsy shows atypical megakaryocytes and stromal smear. Bone marrow biopsy shows atypical megakaryocytes and stromal stranding. Diagnosis?stranding. Diagnosis?
Agnogenic Myeloid Metaplasia Agnogenic Myeloid Metaplasia ≈ Idiopathic Myelofibrosis≈ Idiopathic Myelofibrosis
Case #4: 55 yo man presents with complaints of generalized fatigue, weight Case #4: 55 yo man presents with complaints of generalized fatigue, weight loss and abdominal discomfort with early satiety. Physical exam – afebrile, loss and abdominal discomfort with early satiety. Physical exam – afebrile, thin, massive splenomegaly. No adenopathy is identified, liver is normal in thin, massive splenomegaly. No adenopathy is identified, liver is normal in size. CBC reveals neutrophilic leukocytosis. Diagnosis? size. CBC reveals neutrophilic leukocytosis. Diagnosis?
Chronic myelogenous leukemiaChronic myelogenous leukemia
Tefferi, A. N Engl J Med 2000;342:1255-1265
DiseaseDisease CharacteristicsCharacteristics Transformation Transformation
CMLCML Genetic translocation Genetic translocation Philadelphia chromosome Philadelphia chromosome t(9;22) resulting in fusion t(9;22) resulting in fusion of bcr-abl oncogeneof bcr-abl oncogene
>90% will transform to >90% will transform to acute leukemia if acute leukemia if untreateduntreated
Polycythemia veraPolycythemia vera Elevated red cell mass, Elevated red cell mass, hypercellular marrow, hypercellular marrow, independent of independent of erythropoietinerythropoietin
10% myelofibrosis @10 10% myelofibrosis @10 yrsyrs
25% myelofibrosis @ 25 25% myelofibrosis @ 25 yrsyrs
Essential thrombocytosisEssential thrombocytosis Clonal or autonomous Clonal or autonomous thrombocytosisthrombocytosis
<5% will transform to <5% will transform to acute leukemiaacute leukemia
Agnogenic myeloid Agnogenic myeloid metaplasiametaplasia
(Chronic idiopathic (Chronic idiopathic myelofibrosis)myelofibrosis)
Bone marrow fibrosis not Bone marrow fibrosis not associated with CML or associated with CML or MDSMDS
Mean survival <5 yrsMean survival <5 yrs
AtypicalAtypical Atypical CML, chronic Atypical CML, chronic neutrophilic leukemia, neutrophilic leukemia, systemic mast cell systemic mast cell disease, chronic disease, chronic eosinophilic leukemiaeosinophilic leukemia
VariableVariable
Chronic Myeloproliferative DisordersChronic Myeloproliferative Disorders
Common features:Common features: Overproduction of one or more formed elements in Overproduction of one or more formed elements in
the blood in the absence of an obvious stimulusthe blood in the absence of an obvious stimulus Clonal disorders arising in a single, multipotent Clonal disorders arising in a single, multipotent
progenitor or stem cell progenitor or stem cell proliferates proliferates dominates dominates the marrow and bloodthe marrow and blood
Extramedullary hematopoiesisExtramedullary hematopoiesis Hypercellular marrowHypercellular marrow Hyperplastic megakaryocytes Hyperplastic megakaryocytes myelofibrosis myelofibrosis Clinical tendency toward thrombotic and hemorrhagic Clinical tendency toward thrombotic and hemorrhagic
complicationscomplications
1892 Louis Vasquez of Paris described a pt with cyanotic 1892 Louis Vasquez of Paris described a pt with cyanotic polycythemia, autopsy massive enlargement liver and spleenpolycythemia, autopsy massive enlargement liver and spleen
1903 William Osler at Johns Hopkins reported four patients with 1903 William Osler at Johns Hopkins reported four patients with polycythemia, two with splenomegalypolycythemia, two with splenomegaly
Osler-Vasquez disease (Osler-Vasquez disease ( polycythemia vera) polycythemia vera)
1951 William Dameshek writes an article in 1951 William Dameshek writes an article in BloodBlood grouping PV, grouping PV, idiopathic myelofibrosis, ET, CML, and ‘erythroleukemia’ into a idiopathic myelofibrosis, ET, CML, and ‘erythroleukemia’ into a general category termed myeloproliferative disordersgeneral category termed myeloproliferative disorders
““Perhaps it is possible…not that the various conditions listed are Perhaps it is possible…not that the various conditions listed are different, but that they are closely interrelated. It is possible that these different, but that they are closely interrelated. It is possible that these various conditions – “myeloproliferative disorders”-are all somewhat various conditions – “myeloproliferative disorders”-are all somewhat variable manifestations of proliferative activity of the bone marrow cells, variable manifestations of proliferative activity of the bone marrow cells, perhaps due to a hitherto undiscovered stimulus.”perhaps due to a hitherto undiscovered stimulus.”
SyndromeSyndrome ErythroblastsErythroblasts GranulocyteGranulocyte Mega-Mega-karyocyteskaryocytes
FibroblastsFibroblasts Spleen and Spleen and liverliver
Chronic Chronic Granulocytic Granulocytic
Leukemia Leukemia (CML)(CML)
+/-+/- ++++++ + + to to
++++++
++ ++++
PVPV ++++++ ++++ ++ ++ to to
++++++
+ + to to
++++++
+ + to to
++++++Agnogenic Agnogenic
Myeloid Myeloid MetaplasiaMetaplasia
+/-+/- +/-+/- ++++++ + + to to
++++++
++++++
Mega-Mega-karyocytickaryocytic
LeukemiaLeukemia
+/-+/- +/-+/- ++++++ ++ + + to to
++++++
Dameshek W. Some Speculations on the Myeloproliferative Syndromes. Blood 1951. Adaptation from Table 1:
Myelostimulatory Factor (s)
““Myelostimulatory Factor”Myelostimulatory Factor”
Highly potent since it causes not only normal Highly potent since it causes not only normal bone marrow to become highly proliferative bone marrow to become highly proliferative but also causes activation of sites embryonic but also causes activation of sites embryonic or potential hematopoeisis such as spleen or potential hematopoeisis such as spleen and liverand liver
Theorized of a hormonal or steroid type of Theorized of a hormonal or steroid type of factorfactor
““In the middle of difficulty lies In the middle of difficulty lies opportunity.”opportunity.”
Albert EinsteinAlbert Einstein
1974 NEJM Prchal and Axelrad demonstrate that in 1974 NEJM Prchal and Axelrad demonstrate that in patients with PV erythroid progenitor cells from marrow patients with PV erythroid progenitor cells from marrow or peripheral blood proliferate in serum-containing or peripheral blood proliferate in serum-containing culture in the absence of exogenous erythropoietin culture in the absence of exogenous erythropoietin termed “Endogenous Erythroid Colony” formationtermed “Endogenous Erythroid Colony” formation
1977 J Clin Invest Zanjani shows this phenomenon really 1977 J Clin Invest Zanjani shows this phenomenon really is hypersensitivity to erythropoietin in the culture serum is hypersensitivity to erythropoietin in the culture serum rather than a erythropoietin independent resposerather than a erythropoietin independent respose
1989 Cell D’Andrea – Cloning of EPO receptor1989 Cell D’Andrea – Cloning of EPO receptor No recognizable intracellular signals/pathway No recognizable intracellular signals/pathway
compared with other known receptors such as insulin compared with other known receptors such as insulin
1989 Research continues on a new class of receptors, called type I 1989 Research continues on a new class of receptors, called type I cytokine receptorscytokine receptors
GM-CSF, multiple interleukin receptors, and others are identifiedGM-CSF, multiple interleukin receptors, and others are identified Mechanism via novel kinase/signal transduction pathway Mechanism via novel kinase/signal transduction pathway
1992 Cell Valezquez describe this novel pathway as JAK 1992 Cell Valezquez describe this novel pathway as JAK receptor/signal transducer and activator of transcription (STAT)receptor/signal transducer and activator of transcription (STAT)
JAK – “Just another kinase”JAK – “Just another kinase” Janus kinase – named for Roman god of gates and passagesJanus kinase – named for Roman god of gates and passages
Studies in 1992-1994 demonstrate hypersensitivity of PV erythroid Studies in 1992-1994 demonstrate hypersensitivity of PV erythroid progenitor cells with a variety of growth factors such as IL-3, GM-progenitor cells with a variety of growth factors such as IL-3, GM-CSF, IGF-1CSF, IGF-1
? Downstream effect ? Downstream effect
Tyrosine KinasesTyrosine Kinases
Enzymes that catalyze transfer of Enzymes that catalyze transfer of phosphate from ATP to tyrosine residues phosphate from ATP to tyrosine residues in polypeptidesin polypeptides
2 Classes2 Classes Receptor TK – Transmembrane Protein with Receptor TK – Transmembrane Protein with
extracellular domainextracellular domain Nonreceptor TK – Intracellular - found in Nonreceptor TK – Intracellular - found in
cytosol, nucleuscytosol, nucleus
Janus Kinase ProteinJanus Kinase Protein
Kinase domain (JH1)+ catalytically inactive Kinase domain (JH1)+ catalytically inactive pseudokinase domain (JH2) which acts as a pseudokinase domain (JH2) which acts as a regulatorregulator
Intermediate between membrane receptors and Intermediate between membrane receptors and signaling moleculessignaling molecules
Cytoplasmic region of a membrane receptor – Cytoplasmic region of a membrane receptor – when receptor is activated (for example a when receptor is activated (for example a cytokine binds) JAK is phosphorylated and cytokine binds) JAK is phosphorylated and activated initiating signalling cascade via the activated initiating signalling cascade via the STAT moleculesSTAT molecules STAT molecules enter the nucleus STAT molecules enter the nucleus transcription transcription
Four members of JAK familyFour members of JAK family JAK 1JAK 1 JAK 2JAK 2
• Activated particularly when receptor binds to Activated particularly when receptor binds to hematopoietic growth factors, including hematopoietic growth factors, including erythropoietin, GM-CSF, G-CSF, and erythropoietin, GM-CSF, G-CSF, and thrombopoietinthrombopoietin
JAK 3JAK 3 TYK 2 (tyrosine kinase 2)TYK 2 (tyrosine kinase 2)
Region of JH2 interacts with the activation Region of JH2 interacts with the activation loop of the kinase domain. A specific site loop of the kinase domain. A specific site mutation in the JH2 domain results in mutation in the JH2 domain results in constitutive kinase activity of JH1constitutive kinase activity of JH1
Mutation has been mapped to position 617 Mutation has been mapped to position 617 on the pseudokinase domainon the pseudokinase domain Guanine to thiamine substitution –>Amino Guanine to thiamine substitution –>Amino
acid acid ΔΔ valine to phenylalanine valine to phenylalanine Termed V617FTermed V617F
Goldman, J. M. N Engl J Med 2005;352:1744-1746
Expression of an isolated JAK-2 JH1 kinase domain leads to its constitutive activity
Addition of pseudokinase JH2 domain greatly reduces the level of autoactivation
Schwartz, R. N Engl J Med 2002;347:462-463
Mutation found only in hematopoietic cellsMutation found only in hematopoietic cells Acquired somatic mutationAcquired somatic mutation
• Present in DNA from granulocytes but absent in T Present in DNA from granulocytes but absent in T cellscells
Mechanism for loss of heterozygosity at Mechanism for loss of heterozygosity at chromosome 9pchromosome 9p• Deletion of telomeric part of wild-type chromosome Deletion of telomeric part of wild-type chromosome
9p9p• Events during mitotic recombinationEvents during mitotic recombination
Kralovics R, Passamonti F, Buser AS, et al. A gain-of-function mutation of JAK2 in Kralovics R, Passamonti F, Buser AS, et al. A gain-of-function mutation of JAK2 in myeloproliferative disorders. N Engl J Med. 2005; 352: 1779-1790.myeloproliferative disorders. N Engl J Med. 2005; 352: 1779-1790.
Mechanism of Loss of Mechanism of Loss of Heterozygosity at Chromosome 9pHeterozygosity at Chromosome 9p
What are the implications of What are the implications of this mutation among the this mutation among the chronic myeloproliferative chronic myeloproliferative disorders?disorders?
StudyStudy PurposePurpose PVPV ET ET MFMFCambridge, UK
Baxter EJ, Scott LM, Campbell PJ, et al. Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative diseases. Lancet. 2005; 365: 1054-1061.
Focused on the key role of Focused on the key role of JAK2 in signal transduction JAK2 in signal transduction from multiple hematopoietic from multiple hematopoietic growth factor receptorsgrowth factor receptors
97%97%
N=73N=73
57%57%
N=51N=51
50% 50%
N=16N=16
BostonBostonLevine RL, Wadleigh M, Cools J, et Levine RL, Wadleigh M, Cools J, et al. Activating mutation in the al. Activating mutation in the tyrosine kinase JAK2 in tyrosine kinase JAK2 in polycythemia vera, essential polycythemia vera, essential thrombocytosis, and myeloid thrombocytosis, and myeloid metaplasia with myelofibrosis. metaplasia with myelofibrosis. Cancer Cell (in press).Cancer Cell (in press).
DNA sequence analysis of DNA sequence analysis of activation loops and activation loops and autoinhibitory domains of 85 autoinhibitory domains of 85 tyrosine kinasestyrosine kinases
74% 74%
N=164N=164
32% 32%
N=115N=115
35% 35%
N=46N=46
ParisParisJames C, Ugo V, Le Couedic J-P, et James C, Ugo V, Le Couedic J-P, et al. A unique clonal JAK2 mutation al. A unique clonal JAK2 mutation leading to constitutive signalling leading to constitutive signalling causes polycythemia vera. Nature causes polycythemia vera. Nature (in press).(in press).
Endogenous erythroid Endogenous erythroid colonies inhibitorscolonies inhibitors
88% 88%
N=45N=45
smallsmall smallsmall
Switzerland-ItalySwitzerland-ItalyKralovics R, Passamonti F, Buser Kralovics R, Passamonti F, Buser AS, et al. A gain-of-function AS, et al. A gain-of-function mutation of JAK2 in mutation of JAK2 in myeloproliferative disorders. N Engl myeloproliferative disorders. N Engl J Med. 2005; 352: 1779-1790.J Med. 2005; 352: 1779-1790.
Observed patients with PV Observed patients with PV had loss of heterozygosity in had loss of heterozygosity in chromosome 9p that chromosome 9p that included the site of the JAK2 included the site of the JAK2 genegene
65% 65%
N=128N=128
23%23%
N=93N=93
57%57%
N=23N=23* Carriers of the mutation had more complications such as fibrosis, hemorrhage, and thrombosis and were more likely to receive cytoreductive therapy.
Adaptation from Table 1: Jones A, et al. Widespread occurrence of the JAK2 Adaptation from Table 1: Jones A, et al. Widespread occurrence of the JAK2 V617F mutation in chronic myeloproliferative disorders. Blood 2005 (in press).V617F mutation in chronic myeloproliferative disorders. Blood 2005 (in press).
Disease Disease SubtypeSubtype
NN V617F V617F Positive Positive
number (%)number (%)
V617F V617F Negative Negative
number (%)number (%)
V617F V617F homozygotes homozygotes number (% of number (% of
mutants)mutants)
PVPV 7272 58 (81%)58 (81%) 14 (19%)14 (19%) 24 (41%)24 (41%)
ETET 5959 24 (41%)24 (41%) 35 (59%)35 (59%) 4 (17%)4 (17%)
IMFIMF 3535 15 (43%)15 (43%) 20 (67%)20 (67%) 10 (67%)10 (67%)
Idiopathic Idiopathic Hyper-Hyper-
eosinophilic eosinophilic syndromesyndrome
134134 2 (1.5%)2 (1.5%) 132 (99%)132 (99%) 2 (100%)2 (100%)
MastocytosisMastocytosis 2828 00 -- --
CML-like CML-like MPDsMPDs
9999 17 (17%)17 (17%) 82 (93%)82 (93%) 8 (47%)8 (47%)
Unclassified Unclassified MPDMPD
5353 12 (25%)12 (25%) 40 (75%)40 (75%) 7 (54%)7 (54%)
TotalTotal 480480 129 (27%)129 (27%) 351 (73%)351 (73%) 55 (43%)55 (43%)
Further evidence of V617 mutation Further evidence of V617 mutation contribution to CMPDscontribution to CMPDs
Introduction of mutant clone into irradiated mice led to Introduction of mutant clone into irradiated mice led to substantial erythrocytosissubstantial erythrocytosis
Erythroid progenitor cells carrying the mutation were Erythroid progenitor cells carrying the mutation were able grow in the absence of exogenous erythropoietin able grow in the absence of exogenous erythropoietin
Homozygosity Homozygosity Arise from recombination of chromatids during mitosis rather Arise from recombination of chromatids during mitosis rather
than a second mutation the mutant heterozygous linethan a second mutation the mutant heterozygous line Loss of heterozygosity results in a proliferative advantageLoss of heterozygosity results in a proliferative advantage
• Individuals with one mutant and one wild type gene have reduced Individuals with one mutant and one wild type gene have reduced cellular autonomous JAK2 activity and growth factor independent cellular autonomous JAK2 activity and growth factor independent behavior compared with homozygous individualsbehavior compared with homozygous individuals
James C, Ugo V, Le Couedic J-P, et al. A unique clonal JAK2 mutation leading to constitutive signalling James C, Ugo V, Le Couedic J-P, et al. A unique clonal JAK2 mutation leading to constitutive signalling causes polycythemia vera. Nature (in press).causes polycythemia vera. Nature (in press).
Baxter EJ, Scott LM, Campbell PJ, et al. Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative diseases. Lancet. 2005; 365: 1054-1061
Duration of disease was significantly longer Duration of disease was significantly longer among homozygotes compared to among homozygotes compared to heterozygotesheterozygotes
Patients testing negative for the mutation had Patients testing negative for the mutation had the shortest duration of diseasethe shortest duration of disease Homozygous – mean 48 monthsHomozygous – mean 48 months Heterozygous – mean 23 monthsHeterozygous – mean 23 months Wild type – mean 15 monthsWild type – mean 15 months
Phenotype may be expressed without the Phenotype may be expressed without the mutationmutation
Suggests acquiring the mutation and then Suggests acquiring the mutation and then homozygosity are likely stepwise processes homozygosity are likely stepwise processes
Kralovics R, Passamonti F, Buser AS, et al. A gain-of-function mutation of JAK2 in myeloproliferative Kralovics R, Passamonti F, Buser AS, et al. A gain-of-function mutation of JAK2 in myeloproliferative disorders. N Engl J Med. 2005; 352: 1779-1790.disorders. N Engl J Med. 2005; 352: 1779-1790.
In patients that are found to be positive for In patients that are found to be positive for this mutation by genetic testing, diagnostic this mutation by genetic testing, diagnostic and possibly prognostic information may and possibly prognostic information may be obtained be obtained
Specific therapeutic target at the level of Specific therapeutic target at the level of the mutant kinasethe mutant kinase
More questions. . .More questions. . .
““If the facts don't fit the theory, change If the facts don't fit the theory, change the facts.”the facts.”
Albert EinsteinAlbert Einstein
How does one mutation give rise to these various How does one mutation give rise to these various disorders?disorders?
Additional genetic alterations? Pre-existing or acquired after the Additional genetic alterations? Pre-existing or acquired after the JAK2?JAK2?
Dependent on the subtype of progenitor cell in which the Dependent on the subtype of progenitor cell in which the mutation first arises?mutation first arises?
What is the mechanism for disease in patients who do What is the mechanism for disease in patients who do not carry the V617 mutation?not carry the V617 mutation?
Some answers may lie in further exploration of genes that are Some answers may lie in further exploration of genes that are activated by STAT (signal transducer and activator of activated by STAT (signal transducer and activator of transcription) cascade transcription) cascade
Recently, members of the JAK and STAT families have been Recently, members of the JAK and STAT families have been implicated in cellular decisions on whether to proliferate or enter implicated in cellular decisions on whether to proliferate or enter apoptosisapoptosis
One family of genes called suppressor of cytokine signaling One family of genes called suppressor of cytokine signaling (SOCS) encode proteins that bind to JAKs and receptor sites (SOCS) encode proteins that bind to JAKs and receptor sites and then BLOCK further signalingand then BLOCK further signaling
Receptor JAK STAT SOCS Programmed blockade of further JAK signals
Why do some patients progress from Why do some patients progress from indolent CMPDs such as PV to acute indolent CMPDs such as PV to acute leukemia?leukemia?
Rational approach to therapy?Rational approach to therapy? Tyrosine kinases as potential targetsTyrosine kinases as potential targets Broad spectrum of malignancy mediated via Broad spectrum of malignancy mediated via
this family of proteinsthis family of proteins• Examples: Fms-like tyrosine kinase 3 (FLT3) in Examples: Fms-like tyrosine kinase 3 (FLT3) in
acute myeloid leukemia, epidermal growth factor acute myeloid leukemia, epidermal growth factor receptor in subset NSCLC, c-KIT mutation in GISTreceptor in subset NSCLC, c-KIT mutation in GIST
JAKs mediate intracellular signaling in other JAKs mediate intracellular signaling in other pathways and diseasespathways and diseases Leptin receptorLeptin receptor Growth hormone receptorGrowth hormone receptor Interleukin receptorsInterleukin receptors Cardiovascular signaling systemsCardiovascular signaling systems Inherited JAK3 deficiency has been implicated in Inherited JAK3 deficiency has been implicated in
cases of severe combined immunodeficiencycases of severe combined immunodeficiency
Developing inhibitors that act Developing inhibitors that act specificallyspecifically on on V617F without causing side effects in other V617F without causing side effects in other signaling systems may be challengingsignaling systems may be challenging
SummarySummary Advances in the field of molecular/cell biology Advances in the field of molecular/cell biology
and specifically describing JAK2 have provided and specifically describing JAK2 have provided a valuable window into the mechanism of a valuable window into the mechanism of chronic myeloproliferative diseases including chronic myeloproliferative diseases including PV, ET, and IMF among othersPV, ET, and IMF among others
This information has diagnostic and prognostic This information has diagnostic and prognostic clinical relevance clinical relevance
Tyrosine kinases are vital proteins which have Tyrosine kinases are vital proteins which have broad implications broad implications
Ongoing research in this field will impact how Ongoing research in this field will impact how medicine is practiced for years to comemedicine is practiced for years to come
““If we knew what we were doing, it If we knew what we were doing, it wouldn't be called research, would wouldn't be called research, would
it?” it?”
Albert EinsteinAlbert Einstein
ReferencesReferences Tefferi, A. N Engl J Med 2000;342:1255-1265 Dameshek W. Some Speculations on the Myeloproliferative Syndromes. Blood 1951. Goldman, J. M. N Engl J Med 2005;352:1744-1746 Schwartz, R. N Engl J Med 2002;347:462-463 Baxter EJ, Scott LM, Campbell PJ, et al. Acquired mutation of the tyrosine kinase JAK2 in human
myeloproliferative diseases. Lancet. 2005; 365: 1054-1061. Levine RL, Wadleigh M, Cools J, et al. Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, Levine RL, Wadleigh M, Cools J, et al. Activating mutation in the tyrosine kinase JAK2 in polycythemia vera,
essential thrombocytosis, and myeloid metaplasia with myelofibrosis. Cancer Cell (in press).essential thrombocytosis, and myeloid metaplasia with myelofibrosis. Cancer Cell (in press). James C, Ugo V, Le Couedic J-P, et al. A unique clonal JAK2 mutation leading to constitutive signalling causes James C, Ugo V, Le Couedic J-P, et al. A unique clonal JAK2 mutation leading to constitutive signalling causes
polycythemia vera. Nature (in press).polycythemia vera. Nature (in press). Kralovics R, Passamonti F, Buser AS, et al. A gain-of-function mutation of JAK2 in myeloproliferative disorders. Kralovics R, Passamonti F, Buser AS, et al. A gain-of-function mutation of JAK2 in myeloproliferative disorders.
N Engl J Med. 2005; 352: 1779-1790.N Engl J Med. 2005; 352: 1779-1790. Jones A, et al. Widespread occurrence of the JAK2 V617F mutation in chronic myeloproliferative disorders. Jones A, et al. Widespread occurrence of the JAK2 V617F mutation in chronic myeloproliferative disorders.
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80 (7): 947-958.80 (7): 947-958. Kaushansky K. On the molecular origins of the chronic myeloproliferative disorders: it all makes sense. Blood. Kaushansky K. On the molecular origins of the chronic myeloproliferative disorders: it all makes sense. Blood.
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