JAK2 Mutations are present in all cases of polycythemia vera

Wang, Y. Lynn; Vandris, Katherine; Jones, Amy V.; Cross, Nicholas C. P.; Christos, Paul J.; Adriano, Fernando; Silver, Richard T.

doi:10.1038/sj.leu.2405047

Cited by 56 publications

(48 citation statements)

References 5 publications

(8 reference statements)

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“…Using a 2-phase liquid culture system, we amplified erythroid progenitor cells isolated from the blood specimens. 55 Although ␤-globin mRNA and Hb production were reduced in thalassemic patients as expected (data not shown), the levels of cell cycle-related mRNAs such as Jak2, Ki-67, CycA, Bcl-X L , and EpoR were significantly The th3/ϩ sample is characterized by the presence of hemoglobinized polychromaticorthochromatic erythroblasts (arrowhead), and some rare proerythroblasts (arrow). In the th3/th3 sample, only proerythroblasts/early basophilic erythroblasts (arrow) were detectable, with no presence of tolidine-positive or enucleated cells.…”

Section: Erythroid Cells From Thalassemic Patients Exhibit Some Of Thsupporting

confidence: 71%

“…However, this is unlikely to be the right scenario, because constitutively active mutant Jak2 tyrosine kinases, such as Jak2V617F, lead to polycythemia vera rather that IE. 55, 56 Alternatively, we suggest that constitutive activation of the Epo-Jak2 pathway is necessary but not sufficient to cause IE. To discriminate between these 2 alternative hypotheses, we administered TG101209 to cohorts of healthy and thalassemic mice of different ages.…”

Section: Exacerbation Of Ie In ␤-Thalassemia 879mentioning

confidence: 82%

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Decreased differentiation of erythroid cells exacerbates ineffective erythropoiesis in β-thalassemia

Libani

Guy

Melchiori

et al. 2008

Blood

149

174

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In ␤-thalassemia, the mechanism driving ineffective erythropoiesis (IE) is insufficiently understood. We analyzed mice affected by ␤-thalassemia and observed, unexpectedly, a relatively small increase in apoptosis of their erythroid cells compared with healthy mice. Therefore, we sought to determine whether IE could also be characterized by limited erythroid cell differentiation. In thalassemic mice, we observed that a greater than normal percentage of erythroid cells was in Sphase, exhibiting an erythroblast-like morphology. Thalassemic cells were associated with expression of cell cycle-promoting genes such as EpoR, Jak2, Cyclin-A, Cdk2, and Ki-67 and the antiapoptotic protein Bcl-X L . The cells also differentiated less than normal erythroid ones in vitro. To investigate whether Jak2 could be responsible for the limited cell differentiation, we administered a Jak2 inhibitor, TG101209, to healthy and thalassemic mice. Exposure to TG101209 dramatically decreased the spleen size but also affected anemia. Although our data do not exclude a role for apoptosis in IE, we propose that expansion of the erythroid pool followed by limited cell differentiation exacerbates IE in thalassemia. In addition, these results suggest that use of Jak2 inhibitors has the potential to profoundly change the management of this disorder. (Blood. 2008;112:875-885) Introduction ␤-Thalassemia, one of the most common congenital anemias, arises from partial or complete lack of ␤-globin synthesis. ␤-Thalassemia major, also known as Cooley anemia, 1 is the most severe form of this disease, and is characterized by ineffective erythropoiesis (IE) and extramedullary hematopoiesis (EMH), requiring regular blood transfusions to sustain life. [1][2][3][4][5] In ␤-thalassemia intermedia, where a larger amount of ␤-globin is synthesized, the clinical picture is milder and the patients do not require frequent transfusions. The ineffective production of red blood cells in both forms of the disease has been attributed to erythroid cell death during the maturation process mediated by apoptosis or hemolysis. It was proposed that accumulation of alpha-globin chains leads to the formation of aggregates, which impair erythroid maturation triggering apoptosis. [6][7][8][9][10][11][12][13] Ferrokinetic studies done in 1970 suggested that 60% to 80% of the erythroid precursors in ␤-thalassemia major die in the marrow or extramedullary sites. 14 However, several observations call into question the view that cell death is the only cause of IE in ␤-thalassemia.First, the number of apoptotic erythroid cells in thalassemic patients is low compared with that anticipated by ferrokinetic studies. 14,15 In fact, only 15% to 20% of bone marrow (BM) erythroid precursors (CD45 Ϫ /CD71 ϩ ) present apoptotic features in aspirates from affected patients. 6,8,16 Second, hemolytic markers in young ␤-thalassemic patients are normal or only slightly increased, unless the patients suffer from splenomegaly or the liver has been damaged by iron overload or viral infections. 17 Third...

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Section: Erythroid Cells From Thalassemic Patients Exhibit Some Of Thsupporting

confidence: 71%

Section: Exacerbation Of Ie In ␤-Thalassemia 879mentioning

confidence: 82%

Decreased differentiation of erythroid cells exacerbates ineffective erythropoiesis in β-thalassemia

Libani

Guy

Melchiori

et al. 2008

Blood

149

174

View full text Add to dashboard Cite

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“…Because our real-time quantitative polymerase chain reaction assay had a sensitivity of approximately 1% and in the absence of bone marrow studies, we however cannot ascertain that the mutated clone was eliminated in our patients. 40 In addition, studies comparing clonality based on X-chromosome inactivation patterns or coexisting cytogenetic abnormalities to JAK2 mutant allele frequency suggest that JAK2V617F could be a secondary genetic event in at least some PV patients. [41][42][43] In those cases, measurement of JAK2V617F would only reflect the evolution of subclones.…”

Section: Discussionmentioning

confidence: 99%

Pegylated interferon-alfa-2a induces complete hematologic and molecular responses with low toxicity in polycythemia vera

Kiladjian

Cassinat

Chevret

et al. 2008

Blood

516

407

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“…Evidence that the JAK2 V617F induces a PV-like phenotype in mouse transplantation models [James et al 2005] and the fact that virtually all patients with PV harbor a JAK2-activating mutation [Wang et al 2008] initially ignited interest that there might be a direct cause and effect relationship between JAK2 V617F and MPN. However, clonal heterogeneity observed within the progenitor cell pool in patients with BCR-ABL negative MPN harboring the JAK2 V617F mutation [Nussenzveig et al 2007;Kralovics et al 2006] suggests that unlike CML where BCR-ABL is the causative event; JAK2 V617F may not be the disease-initiating event.…”

Section: Introductionmentioning

confidence: 99%

Update on JAK2 inhibitors in myeloproliferative neoplasm

Chan

Koren‐Michowitz

2011

Therapeutic Advances in Hematology

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Since the discovery of mutant Janus Kinase 2 (JAK2), JAK2 V617F, in a major proportion of myeloproliferative neoplasm (MPN) patients, there has been a flurry of activity in the development of JAK2 inhibitors. Pan-JAK, predominantly JAK2 and off-target JAK2 inhibitors have been developed in the short span of the past 5 years. These compounds have since been tested to varying success in both in vitro and in vivo settings with several proceeding on to advanced clinical trials. Although it was hoped that these inhibitors would be the silver bullet in the manner than imatinib was to chronic myeloid leukemia, it is becoming apparent that this is not the case for various reasons, chief of which is that a significant reduction of the underlying pathogenic clone is not achieved. In fact, the very notion that the target of JAK2 inhibitors (be it pan-JAK or JAK2 specific) is the mutant JAK2 V617F is being challenged with findings from several clinical trials showing a poor correlation between the reduction in JAK2 V617F mutant allele burden and clinical response. In view of this, it is not surprising that several groups are now investigating combinations of JAK2 inhibitors and other agents in MPN. Although much knowledge has been added in this short span of time, it is apparent that our understanding of the role of JAK2 inhibitors in the treatment scheme of MPN is only beginning.

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JAK2 Mutations are present in all cases of polycythemia vera

Cited by 56 publications

References 5 publications

Decreased differentiation of erythroid cells exacerbates ineffective erythropoiesis in β-thalassemia

Decreased differentiation of erythroid cells exacerbates ineffective erythropoiesis in β-thalassemia

Pegylated interferon-alfa-2a induces complete hematologic and molecular responses with low toxicity in polycythemia vera

Update on JAK2 inhibitors in myeloproliferative neoplasm

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