Critical requirement for Stat5 in a mouse model of polycythemia vera

Blood - Tập 119 Số 15 - Trang 3539-3549 - 2012
Dongqing Yan1, R. Hutchison2, Golam Mohi1
1Departments of Pharmacology and
2Pathology, State University of New York Upstate Medical University, Syracuse, NY

Tóm tắt

The JAK2V617F mutation has been identified in most cases of Ph-negative myeloproliferative neoplasms (MPNs) including polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). Expression of JAK2V617F results in constitutive activation of multiple signaling molecules/pathways. However, the key signaling downstream of JAK2V617F required for transformation and induction of MPNs remains elusive. Using a mouse genetic strategy, we show here that Stat5 is absolutely required for the pathogenesis of PV induced by Jak2V617F. Whereas expression of Jak2V617F in mice resulted in all the features of human PV, including an increase in red blood cells, hemoglobin, hematocrit, white blood cells, platelets, and splenomegaly, deletion of Stat5 in the Jak2V617F knockin mice normalized all the blood parameters and the spleen size. Furthermore, deletion of Stat5 completely abrogated erythropoietin (Epo)–independent erythroid colony formation evoked by Jak2V617F, a hallmark feature of PV. Re-expression of Stat5 in Stat5-deficient Jak2V617F knockin mice completely rescued the defects in transformation of hematopoietic progenitors and the PV phenotype. Together, these results indicate a critical function for Stat5 in the pathogenesis of PV. These findings also provide strong support for the development of Stat5 inhibitors as targeted therapies for the treatment of PV and other JAK2V617F-positive MPNs.

Từ khóa


Tài liệu tham khảo

James, 2005, A unique clonal JAK2 mutation leading to constitutive signaling causes polycythemia vera., Nature, 434, 1144, 10.1038/nature03546

Levine, 2005, Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis., Cancer Cell, 7, 387, 10.1016/j.ccr.2005.03.023

Baxter, 2005, Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders., Lancet, 365, 1054, 10.1016/S0140-6736(05)71142-9

Kralovics, 2005, A gain-of-function mutation of JAK2 in myeloproliferative disorders., N Engl J Med, 352, 1779, 10.1056/NEJMoa051113

Zhao, 2005, Identification of an acquired JAK2 mutation in polycythemia vera., J Biol Chem, 280, 22788, 10.1074/jbc.C500138200

Akada, 2010, Conditional expression of heterozygous or homozygous Jak2V617F from its endogenous promoter induces a polycythemia vera-like disease., Blood, 115, 3589, 10.1182/blood-2009-04-215848

Wernig, 2006, Expression of Jak2V617F causes a polycythemia vera-like disease with associated myelofibrosis in a murine bone marrow transplant model., Blood, 107, 4274, 10.1182/blood-2005-12-4824

Lacout, 2006, JAK2V617F expression in murine hematopoietic cells leads to MPD mimicking human PV with secondary myelofibrosis., Blood, 108, 1652, 10.1182/blood-2006-02-002030

Bumm, 2006, Characterization of murine JAK2V617F-positive myeloproliferative disease., Cancer Res, 66, 11156, 10.1158/0008-5472.CAN-06-2210

Zaleskas, 2006, Molecular pathogenesis and therapy of polycythemia induced in mice by JAK2 V617F., PLoS One, 1, e18, 10.1371/journal.pone.0000018

Tiedt, 2008, Ratio of mutant JAK2-V617F to wild-type Jak2 determines the MPD phenotypes in transgenic mice., Blood, 111, 3931, 10.1182/blood-2007-08-107748

Shide, 2008, Development of ET, primary myelofibrosis and PV in mice expressing JAK2 V617F., Leukemia, 22, 87, 10.1038/sj.leu.2405043

Xing, 2008, Transgenic expression of JAK2V617F causes myeloproliferative disorders in mice., Blood, 111, 5109, 10.1182/blood-2007-05-091579

Marty, 2010, Myeloproliferative neoplasm induced by constitutive expression of JAK2V617F in knockin mice., Blood, 116, 783, 10.1182/blood-2009-12-257063

Mullally, 2010, Physiologic Jak2V617F expression causes a lethal myeloproliferative neoplasm with differential effects on hematopoietic stem and progenitor cells., Cancer Cell, 17, 584, 10.1016/j.ccr.2010.05.015

Li, 2010, JAK2 V617F impairs hematopoietic stem cell function in a conditional knockin mouse model of JAK2 V617F-positive essential thrombocythemia., Blood, 116, 1528, 10.1182/blood-2009-12-259747

Santos, 2010, Phase 2 study of CEP-701, an orally available JAK2 inhibitor, in patients with primary or post-polycythemia vera/essential thrombocythemia myelofibrosis., Blood, 115, 1131, 10.1182/blood-2009-10-246363

Pardanani, 2011, Safety and efficacy of TG101348, a selective JAK2 inhibitor, in myelofibrosis., J Clin Oncol, 29, 789, 10.1200/JCO.2010.32.8021

Funakoshi-Tago, 2010, STAT5 activation is critical for the transformation mediated by myeloproliferative disorder-associated JAK2 V617F mutant., J Biol Chem, 285, 5296, 10.1074/jbc.M109.040733

Cui, 2004, Inactivation of Stat5 in mouse mammary epithelium during pregnancy reveals distinct functions in cell proliferation, survival, and differentiation., Mol Cell Biol, 24, 8037, 10.1128/MCB.24.18.8037-8047.2004

Kühn, 1995, Inducible gene targeting in mice., Science, 269, 1427, 10.1126/science.7660125

Mohi, 2005, Prognostic, therapeutic and mechnistic implications of a mouse model of leukemia evoked by Shp2 (PTPN11) mutations., Cancer Cell, 7, 179, 10.1016/j.ccr.2005.01.010

Pronk, 2007, Elucidation of the phenotypic, functional, and molecular topography of a myeloerythroid progenitor cell hierarchy., Cell Stem Cell, 1, 428, 10.1016/j.stem.2007.07.005

Prchal, 1974, Letter: Bone-marrow responses in polycythemia vera., N Engl J Med, 290, 1382, 10.1056/NEJM197406132902419

Zhu, 2008, Hematopoietic-specific Stat5-null mice display microcytic hypochromic anemia associated with reduced transferrin receptor gene expression., Blood, 112, 2071, 10.1182/blood-2007-12-127480

Levine, 2008, Myeloproliferative disorders., Blood, 112, 2190, 10.1182/blood-2008-03-077966

Druker, 2008, Translation of the Philadelphia chromosome into therapy for CML., Blood, 112, 4808, 10.1182/blood-2008-07-077958

Braun, 2008, Targeting Ras in myeloid leukemias., Clin Cancer Res, 14, 2249, 10.1158/1078-0432.CCR-07-1005

Li, 1999, The P190, P210, and P230 forms of the BCR/ABL oncogene induce a similar chronic myeloid leukemia-like syndrome in mice but have different lymphoid leukemogenic activity., J Exp Med, 189, 1399, 10.1084/jem.189.9.1399

Braun, 2004, Somatic activation of oncogenic Kras in hematopoietic cells initiates a rapidly fatal myeloproliferative disorder., Proc Natl Acad Sci U S A, 101, 597, 10.1073/pnas.0307203101

Chan, 2004, Conditional expression of oncogenic K-ras from its endogenous promoter induces a myeloproliferative disease., J Clin Invest, 113, 528, 10.1172/JCI20476

Sattler, 2002, Critical role for Gab2 in transformation by BCR/ABL., Cancer Cell, 1, 479, 10.1016/S1535-6108(02)00074-0

Zou, 2011, Differential biologic activity of disease-associated JAK2 mutants., FEBS Lett, 585, 1007, 10.1016/j.febslet.2011.02.032

O'Farrell, 1998, IL-10 inhibits macrophage activation and proliferation by distinct signaling mechanisms: evidence for Stat3-dependent and -independent pathways., EMBO J, 17, 1006, 10.1093/emboj/17.4.1006

Oh, 2002, Overexpression of a dominant negative form of STAT3 selectively impairs hematopoietic stem cell activity., Oncogene, 21, 4778, 10.1038/sj.onc.1205592

Zhang, 2011, SHP2 tyrosine phosphatase stimulates CEBPA gene expression to mediate cytokine-dependent granulopoiesis., Blood, 118, 2266, 10.1182/blood-2011-01-331157

de Boer, 2003, Transgenic mice with hematopoietic and lymphoid specific expression of Cre., Eur J Immunol, 33, 314, 10.1002/immu.200310005

Georgiades, 2002, VavCre transgenic mice: a tool for mutagenesis in hematopoietic and endothelial lineages., Genesis, 34, 251, 10.1002/gene.10161

Teglund, 1998, Stat5a and Stat5b proteins have essential and nonessential, or redundant, roles in cytokine responses., Cell, 93, 841, 10.1016/S0092-8674(00)81444-0

Socolovsky, 1999, Fetal anemia and apoptosis of red cell progenitors in Stat5a−/−5b−/− mice: a direct role for Stat5 in Bcl-X(L) induction., Cell, 98, 181, 10.1016/S0092-8674(00)81013-2

Hoelbl, 2010, Stat5 is indispensable for the maintenance of bcr/abl-positive leukaemia., EMBO Mol Med, 2, 98, 10.1002/emmm.201000062

Wang, 2009, Conditional deletion of STAT5 in adult mouse hematopoietic stem cells causes loss of quiescence and permits efficient nonablative stem cell replacement., Blood, 113, 4856, 10.1182/blood-2008-09-181107

Ye, 2006, STAT5 signaling is required for the efficient induction and maintenance of CML in mice., Blood, 107, 4917, 10.1182/blood-2005-10-4110

Hoelbl, 2006, Clarifying the role of Stat5 in lymphoid development and Abelson-induced transformation., Blood, 107, 4898, 10.1182/blood-2005-09-3596

Garcon, 2006, Constitutive activation of STAT5 and Bcl-xL overexpression can induce endogenous erythroid colony formation in human primary cells., Blood, 108, 1551, 10.1182/blood-2005-10-009514

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Blood

Tập 119 Số 15

3539-3549

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