Loss of Stat1 decreases megakaryopoiesis and favors erythropoiesis in a JAK2-V617F–driven mouse model of MPNs

Duek, Adrian; Lundberg, Pontus; Shimizu, Takafumi; Grisouard, Jean; Karow, Axel; Kubovčáková, Lucia; Hao-Shen, Hui; Dirnhofer, Stephan; Skoda, Radek C.

doi:10.1182/blood-2013-07-514208

Cited by 36 publications

(30 citation statements)

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“…In line with our genetic data, we found that inhibiting Stat3 using the Stat3 inhibitor S3I-201 showed a tendency toward increased platelet counts, but this effect was abolished when Stat1 was absent (Figure 7). Consistent with our published data, 8 the platelet count was overall lower in JAK2-V617F-expressing mice with Stat1 2/2 compared with Stat1 1/2 or Stat1 1/1 backgrounds. Together, these data support the model that enhanced megakaryopoiesis and elevated platelets in JAK2-V617F-driven MPN on Stat3 deletion could be mediated by increased Stat1 activity.…”

Section: Org Fromsupporting

confidence: 82%

“…The latter finding could be explained by the activation of Stat1, as increased erythropoiesis was observed in the SclCre;V617F mice on loss of Stat1. 8 However, we also observed a decrease in the copy number in MxCre;V617F;Stat3 fl/fl mice compared with MxCre;V617F;Stat3…”

Section: Org Frommentioning

confidence: 68%

“…5,6 Furthermore, Stat1 promotes megakaryopoiesis downstream of Gata1, 21 and deletion of Stat1 in the presence of JAK2-V617F reduced megakaryopoiesis and favored erythropoiesis in a mouse model of MPN. 8 We therefore hypothesized that the increased platelet counts in Stat3-deleted JAK2-V617F mice could be due to compensatory increase in the activation of Stat1 proteins. Phosphoflow data in bone marrow and spleen cells showed enhanced pStat1 activity in SclCre;V617F;Stat3 fl/fl vs SclCre;V617F; and Stat3 activation are known to be reciprocally regulated and perturbation in their balanced expression and/or phosphorylation levels may redirect cytokine/growth factor signals.…”

Section: Org Frommentioning

confidence: 99%

“…5,6 Activation of Stat1 constrains erythroid differentiation in MPN patients, 7 and loss of Stat1 decreases megakaryopoiesis and favors erythropoiesis in a JAK2-V617F-driven mouse model of MPN. 8 In contrast, the impact of Stat3 in JAK2-V617F-driven MPN is less well understood. Stat3 was shown to play a role in hematopoiesis in the context of hyperactive gp130 signaling.…”

Section: Introductionmentioning

confidence: 99%

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Deletion of Stat3 in hematopoietic cells enhances thrombocytosis and shortens survival in a JAK2-V617F mouse model of MPN

Grisouard

Shimizu

Duek

et al. 2015

Blood

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Section: Org Fromsupporting

confidence: 82%

Section: Org Frommentioning

confidence: 68%

Section: Org Frommentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Deletion of Stat3 in hematopoietic cells enhances thrombocytosis and shortens survival in a JAK2-V617F mouse model of MPN

Grisouard

Shimizu

Duek

et al. 2015

Blood

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“…Because we observed a trend toward increased pStat1 in western blots of MxCre;Ex12 BM cells, and this finding is unexpected given the proposed role of Stat1 in promoting megakaryopoiesis in the context of JAK2-V617F, 18,19 we sought to clarify the role of Stat1 in Jak2-Ex12 signaling by analyzing Ex12;Stat1 2/2 double-mutant mice ( Figure 6G-H). 15 To obtain sufficient numbers of triple transgenic mice for study, we transplanted BM cells from SclCre;Ex12;Stat1 , and controls, and induced expression of Jak2; Ex12 with tamoxifen.…”

Section: Resultsmentioning

confidence: 94%

JAK2 exon 12 mutant mice display isolated erythrocytosis and changes in iron metabolism favoring increased erythropoiesis

Grisouard

Kubovčáková

et al. 2016

Blood

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Key Points• Mice expressing a JAK2 exon 12 mutation display isolated erythrocytosis similar to the majority of patients with JAK2 exon 12 mutations.• JAK2 exon 12 mutation induces changes in iron metabolism that increase iron availability to allow maximal production of red cells.Mutations in JAK2 exon 12 are frequently found in patients with polycythemia vera (PV) that do not carry a JAK2-V617F mutation. The majority of these patients display isolated erythrocytosis. We generated a mouse model that expresses JAK2-N542-E543del, the most frequent JAK2 exon 12 mutation found in PV patients. Mice expressing the human JAK2-N542-E543del (Ex12) showed a strong increase in red blood cell parameters but normal neutrophil and platelet counts, and reduced overall survival. Erythropoiesis was increased in the bone marrow and spleen, with normal megakaryopoiesis and absence of myelofibrosis in histopathology. Erythroid progenitors and precursors were increased in hematopoietic tissues, but the numbers of megakaryocytic precursors were unchanged. Phosphorylation Stat3 and Erk1/2 proteins were increased, and a trend toward increased phospho-Stat5 and phospho-Stat1 was noted. However, Stat1 knock out in Ex12 mice induced no changes in platelet or red cell parameters, indicating that Stat1 does not play a central role in mediating the effects of Ex12 signaling on megakaryopoiesis or erythropoiesis. Ex12 mice showed decreased expression of hepcidin and increased expression of transferrin receptor-1 and erythroferrone, suggesting that the strong erythroid phenotype in Ex12 mutant mice is favored by changes in iron metabolism that optimize iron availability to allow maximal production of red cells. (Blood. 2016;128(6):839-851)

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JAK/STATSignalling and Haematological Malignancies

Constantinescu

Vainchenker

2015

Encyclopedia of Life Sciences

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A major focus of investigation and drug screening efforts started with the discovery of JAK2V617F as a major driver of the BCR‐ABL‐negative myeloproliferative neoplasms (MPNs). An acquired somatic mutation, JAK2V617F , drives 65% of MPNs. Further studies established that these diseases almost always exhibit mutations leading to persistent JAK2‐STAT5 activation. Sequencing of the four mammalian JAKs (Janus kinases) ( JAK1 , JAK2 , JAK3 and TYK2 ) and of the seven STATs (signal transducers and activators of transcriptions) in a variety of cancers identified the pathologic activation of these JAKs and STATs, by mutations in the genes themselves or in upstream or downstream regulators as significant contributors to several haematological and solid malignancies. The development of JAK2, JAK1, JAK3 and TYK2 kinase inhibitors is unfolding with JAK2, JAK1 and JAK3 inhibitors being approved in certain conditions. Altogether, the JAK/STAT pathway became a new gold mine for discovery and therapy in haematological cancers. Key Concepts The JAK/STAT pathway has a central role in cytokine signalling in normal haematopoiesis. The JAK/STAT pathway is frequently pathologically activated by several mechanisms in many types of haematological malignancies. The JAK/STAT pathway can be targeted by small molecules. The JAK/STAT pathway can be pathologically activated by down‐modulation of negative regulators such as phosphatases. Constitutive STAT activation in blood cancers can be the result of several activated kinases, not only JAKs. JAK2 activation is the main mechanismresponsible of the poorprognosis of mostpediatric B‐cell acute lymphoblasticleukemia.

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Loss of Stat1 decreases megakaryopoiesis and favors erythropoiesis in a JAK2-V617F–driven mouse model of MPNs

Abstract: Key Points Stat1 deletion in the presence of JAK2-V617F alters phenotypic manifestations by reducing megakaryopoiesis and favoring erythropoiesis. IFNγ is elevated in serum of mice with thrombocytosis and in patients with essential thrombocythemia and may drive Stat1 activation.

Cited by 36 publications

References 31 publications

Deletion of Stat3 in hematopoietic cells enhances thrombocytosis and shortens survival in a JAK2-V617F mouse model of MPN

Deletion of Stat3 in hematopoietic cells enhances thrombocytosis and shortens survival in a JAK2-V617F mouse model of MPN

JAK2 exon 12 mutant mice display isolated erythrocytosis and changes in iron metabolism favoring increased erythropoiesis

JAK/STATSignalling and Haematological Malignancies

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