JAK inhibitors for myeloproliferative neoplasms: clarifying facts from myths

Tefferi, Ayalew

doi:10.1182/blood-2011-11-395228

Cited by 160 publications

(147 citation statements)

References 77 publications

(110 reference statements)

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“…12). Previous study reported that ruxolitinib causes hematologic adverse events, including anemia and thrombocytopenia (30,31). In this study, our observations clearly showed that ruxolitinib inhibits the cell proliferation induced by not only the JAK2 V617F mutant but also Epo stimulation, and these data seem to clearly explain the reason why ruxolitinib causes these hematopoietic side effects.…”

Section: Phosphorylation Of Tyr-343 Tyr-460 and Tyr-464 Of Epor Is supporting

confidence: 68%

“…Ruxolitinib Inhibits the Cell Proliferation Induced by Not Only the JAK2 V617F Mutant but Also Epo Stimulation-A JAK2 inhibitor, ruxolitinib, showed significant therapeutic benefit for the patients with MPN (30,31). We investigated the effect of ruxolitinib on the proliferation of (A2) Ϫ/EpoR cells, (A5) WT/EpoR cells, and (A8) V617F/EpoR cells in the absence and presence of Epo stimulation.…”

Section: Phosphorylation Of Tyr-343 Tyr-460 and Tyr-464 Of Epor Is mentioning

confidence: 99%

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Three Tyrosine Residues in the Erythropoietin Receptor Are Essential for Janus Kinase 2 V617F Mutant-induced Tumorigenesis

Ueda

Tago

Tamura

et al. 2017

Journal of Biological Chemistry

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Edited by Alex TokerThe erythropoietin receptor (EpoR) regulates development of blood cells, and its full activation normally requires the cytokine erythropoietin (Epo). In the case of myeloproliferative neoplasms (MPN), Epo-independent signaling through EpoR can be caused by a point mutation, V617F, in the EpoR-interacting tyrosine kinase Janus kinase 2 (JAK2). In cells expressing the JAK2 V617F mutant, eight tyrosine residues in the intracellular domain of EpoR are phosphorylated, but the functional role of these phosphorylations in oncogenic signaling is incompletely understood. Here, to evaluate the functional consequences of the phosphorylation of these tyrosine residues, we constructed an EpoR-8YF mutant in which we substituted all eight tyrosine residues with phenylalanine. Co-expression of EpoR-8YF with the JAK2 V617F mutant failed to induce cytokine-independent cell proliferation and tumorigenesis, indicating that JAK2-mediated EpoR phosphorylation is the reason for JAK2 V617F mutant-induced oncogenic signaling. An exhaustive mutational analysis of the eight EpoR tyrosine residues indicated that three of these residues, Tyr-343, Tyr-460, and Tyr-464, are required for the JAK2 V617F mutant to exhibit its oncogenic activity. We also showed that phosphorylation at these three residues was necessary for full activation of the transcription factor STAT5, which is a critical downstream factor of JAK2 V617F-induced oncogenic signaling. In contrast, Epo stimulation could moderately stimulate the proliferation of cells expressing wild type JAK2 and EpoR-8YF, suggesting that the requirement of the phosphorylation of these three tyrosine residues seems to be specific for the oncogenic proliferation provoked by V617F mutation. Collectively, these results have revealed that phosphorylation of Tyr-343, Tyr-460, and Tyr-464 in EpoR underlies JAK2 V617F mutant-induced tumorigenesis. We propose that the targeted disruption of this pathway has therapeutic utility for managing MPN.The proliferation and differentiation of hematopoietic cells are regulated by various cytokines that act through their specific receptors (1, 2). Erythropoietin (Epo) 2 is a pleiotropic cytokine that exhibits hematopoietic functions such as the development of erythrocytes through the erythropoietin receptor (EpoR) (3). Once Epo binds to EpoR, the non-receptor tyrosine kinase, Janus kinase 2 (JAK2), which interacts with EpoR, is activated. Activated JAK2 then immediately phosphorylates multiple tyrosine residues in the cytoplasmic domain of EpoR (4).EpoR contains the following eight tyrosine residues in its intracellular domain that are phosphorylated by JAK2: Tyr-343, Tyr-401, Tyr-429, Tyr-431, Tyr-443, Tyr-460, Tyr-464, and Tyr-479. The JAK2-induced phosphorylation of these tyrosine residues in EpoR provides a platform for the recruitment and activation of signaling mediators and is critical for Epo-induced cellular proliferation (3, 5, 6). Previous studies clarified that the transcription factor, signal transducer and activator of transcript...

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Section: Phosphorylation Of Tyr-343 Tyr-460 and Tyr-464 Of Epor Is supporting

confidence: 68%

Section: Phosphorylation Of Tyr-343 Tyr-460 and Tyr-464 Of Epor Is mentioning

confidence: 99%

Three Tyrosine Residues in the Erythropoietin Receptor Are Essential for Janus Kinase 2 V617F Mutant-induced Tumorigenesis

Ueda

Tago

Tamura

et al. 2017

Journal of Biological Chemistry

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“…Despite some controversies, current drug therapy for PMF is not curative and is unlikely to prolong survival; JAK inhibitors have so far not shown disease-modifying activity, including reversal of bone marrow fibrosis or induction of complete or partial remissions [123]. ASCT is the only treatment modality that can either cure or prolong life and is therefore recommended in either DIPSS-plus high (i.e., presence of at least four of the 8 DIPSS-plus risk factors) [68] or molecularly high (absence of type 1/type 1-like CALR mutation and presence of ASXL1 or related high risk mutation) [81] risk disease (Fig.…”

Section: Myelofibrosismentioning

confidence: 99%

Myeloproliferative neoplasms: A decade of discoveries and treatment advances

2015

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Myeloproliferative neoplasms (MPN) are clonal stem cell diseases, first conceptualized in 1951 by William Dameshek, and historically included chronic myeloid leukemia (CML), polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). In 1960, Nowell and Hungerford discovered an invariable association between the Philadelphia chromosome (subsequently shown to harbor the causal BCR‐ABL1 mutation) and CML; accordingly, the term MPN is primarily reserved for PV, ET, and PMF, although it includes other related clinicopathologic entities, according to the World Health Organization (WHO) classification system. In 2005, William Vainchenker and others described a Janus kinase 2 mutation (JAK2V617F) in MPN and this was followed by a series of additional descriptions of mutations that directly or indirectly activate JAK‐STAT: JAK2 exon 12, myeloproliferative leukemia virus oncogene (MPL) and calreticulin (CALR) mutations. The discovery of these, mostly mutually exclusive, “driver” mutations has contributed to revisions of the WHO diagnostic criteria and risk stratification in MPN. Mutations other than JAK2, CALR and MPL have also been described in MPN and shown to provide additional prognostic information. From the standpoint of treatment, over the last 50 years, Louis Wasserman from the Unites States and Tiziano Barbui from Italy had skillfully organized and led a number of important clinical trials, whose results form the basis for current treatment strategies in MPN. More recently, allogeneic stem cell transplant, as a potentially curative treatment modality, and JAK inhibitors, as palliative drugs, have been added to the overall therapeutic armamentarium in myelofibrosis. In the current review, I will summarize the important advances made in the last 10 years regarding the science and practice of MPN. Am. J. Hematol. 91:50–58, 2016. © 2015 Wiley Periodicals, Inc.

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“…In the COMFORT-2 trial that compared the drug with "best available therapy" (n 5 219) [76], the spleen response was 28.5% with ruxolitinib versus 0% otherwise but the drug was detrimental in terms of thrombocytopenia (44.5% vs. 9.6%), anemia (40.4% vs. 12.3%), and diarrhea (24.0% vs. 11.0%). The long-term outcome of ruxolitinib therapy in MF was recently reported and disclosed a very high treatment discontinuation rate (92% after a median time of 9.2 months) and the occurrence of severe withdrawal symptoms during ruxolitinib treatment discontinuation ("ruxolitinib withdrawal syndrome") characterized by acute relapse of disease symptoms, accelerated splenomegaly, worsening of cytopenias, and occasional hemodynamic decompensation, including a septic shock-like syndrome [50]. The 3-year follow-up information on COMFORT-2 suggested a 55% drug discontinuation rate and a slight but significant improvement in survival, which is however confounded by the crossover design of the study and lack of substantial drug effect on JAK2V617F allele burden or bone marrow fibrosis [48].…”

Section: /Asxl1mentioning

confidence: 99%

“…Current drug therapy for PMF is not curative and has not been shown to prolong survival; although there is controversy regarding the value of JAK inhibitors, in this regard, these drugs have not been shown to display disease-modifying activity, including reversal of bone marrow fibrosis or induction of complete or partial remissions [48][49][50][51]. ASCT for PMF is potentially curative but dangerous; transplant-related death or severe morbidity occurs in about half of transplanted patients, regardless of the intensity of conditioning regimens used [52].…”

Section: Risk-adapted Therapymentioning

confidence: 99%

Primary myelofibrosis: 2014 update on diagnosis, risk‐stratification, and management

Tefferi

2014

American J Hematol

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Disease overview: Primary myelofibrosis (PMF) is a myeloproliferative neoplasm characterized by stem cell‐derived clonal myeloproliferation, abnormal cytokine expression, bone marrow fibrosis, anemia, splenomegaly, extramedullary hematopoiesis (EMH), constitutional symptoms, cachexia, leukemic progression, and shortened survival. Diagnosis: Diagnosis is based on bone marrow morphology. The presence of JAK2, CALR, or MPL mutation is supportive but not essential for diagnosis; approximately 90% of patients carry one of these mutations and 10% are “triple‐negative.” None of these mutations are specific to PMF and are also seen in essential thrombocythemia (ET). Prefibrotic PMF mimics ET in its presentation and the distinction, enabled by careful bone marrow morphological examination, is prognostically relevant. Differential diagnosis also includes chronic myeloid leukemia, myelodysplastic syndromes, chronic myelomonocytic leukemia, and acute myeloid leukemia.Risk Stratification: The Dynamic International Prognostic Scoring System‐plus (DIPSS‐plus) uses eight predictors of inferior survival: age >65 years, hemoglobin <10 g/dL, leukocytes >25 × 109/L, circulating blasts ≥1%, constitutional symptoms, red cell transfusion dependency, platelet count <100 × 109/L, and unfavorable karyotype (i.e., complex karyotype or sole or two abnormalities that include +8, −7/7q−, i(17q), inv(3), −5/5q−, 12p−, or 11q23 rearrangement). The presence of 0, 1, “2 or 3,” and ≥4 adverse factors defines low, intermediate‐1, intermediate‐2, and high‐risk disease with median survivals of approximately 15.4, 6.5, 2.9, and 1.3 years, respectively. High risk disease is also defined by CALR−/ASXL1+ mutational status. Risk‐Adapted Therapy: Observation alone is adequate for asymptomatic low/intermediate‐1 risk disease, especially with CALR+/ASXL1− mutational status. Stem cell transplant is considered for DIPSS‐plus high risk disease or any risk disease with CALR−/ASXL1+ mutational status. Investigational drug therapy is reasonable for symptomatic intermediate‐1 or intermediate‐2 risk disease. Splenectomy is considered for drug‐refractory splenomegaly. Involved field radiotherapy is most useful for post‐splenectomy hepatomegaly, non‐hepatosplenic EMH, PMF‐associated pulmonary hypertension, and extremity bone pain. Am. J. Hematol. 89:916–925, 2014. © 2014 Wiley Periodicals, Inc.

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JAK inhibitors for myeloproliferative neoplasms: clarifying facts from myths

Cited by 160 publications

References 77 publications

Three Tyrosine Residues in the Erythropoietin Receptor Are Essential for Janus Kinase 2 V617F Mutant-induced Tumorigenesis

Three Tyrosine Residues in the Erythropoietin Receptor Are Essential for Janus Kinase 2 V617F Mutant-induced Tumorigenesis

Myeloproliferative neoplasms: A decade of discoveries and treatment advances

Primary myelofibrosis: 2014 update on diagnosis, risk‐stratification, and management

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