The JAK-STAT pathway and hematopoietic stem cells from the JAK2 V617F perspective

Janus kinases (JAKs) are non-receptor tyrosine kinases essential for activation of signaling mediated by cytokine receptors that lack catalytic activity, including receptors for erythropoietin, thrombopoietin, most interleukins and interferon. Upon hormone binding, JAKs phosphorylate tyrosine residues in the receptor cytoplasmic domains and in JAKs themselves leading to recruitment and activation of downstream signaling proteins such as signal transducer and activator of transcription (STAT). The JAK-STAT pathway is important for functional hematopoiesis and several activating mutations in JAK proteins have recently been described as underlying cause of blood disorders. One of the best studied examples is the JAK2 V617F mutant which is found in 95% of polycythemia vera patients and 50% of patients suffering from essential thrombocythemia and primary myelofibrosis. Much effort has been made to understand how the JAK2 V617F affects hematopoietic stem cell (HSC) renewal and lineage differentiation, since convincing evidence has been provided to support the notion that the mutation is acquired at the HSC level. We discuss several in vivo models that support contrary conclusions with respect to the advantage given to HSCs by JAK2 V617F. Moreover, we provide the current knowledge about STAT5 activation and its link to HSC expansion as well as amplification of the erythroid compartment. Evidence for both JAK2 V617F mutated HSCs exhibiting skewed differentiation potential and for amplification occurring after erythroid commitment has been provided, and we will discuss whether this evidence is relevant for the disease.

[1]  D. Yan,et al.  Critical requirement for Stat5 in a mouse model of polycythemia vera. , 2012, Blood.

[2]  L. Hennighausen,et al.  Essential role for Stat5a/b in myeloproliferative neoplasms induced by BCR-ABL1 and JAK2(V617F) in mice. , 2009, Blood.

[3]  A. Green,et al.  Effects of the JAK2 mutation on the hematopoietic stem and progenitor compartment in human myeloproliferative neoplasms. , 2011, Blood.

[4]  R. Hoffman,et al.  The renaissance of interferon therapy for the treatment of myeloid malignancies. , 2011, Blood.

[5]  D. Kent,et al.  Mouse models of myeloproliferative neoplasms: JAK of all grades , 2011, Disease Models & Mechanisms.

[6]  E. Vellenga,et al.  Identification of HIF2alpha as an important STAT5 target gene in human hematopoietic stem cells. , 2011, Blood.

[7]  J. Spivak,et al.  Disease burden at the progenitor level is a feature of primary myelofibrosis: a multivariable analysis of 164 JAK2 V617F-positive myeloproliferative neoplasm patients. , 2011, Experimental hematology.

[8]  E. Dermitzakis,et al.  Distinct clinical phenotypes associated with JAK2V617F reflect differential STAT1 signaling. , 2010, Cancer cell.

[9]  W. Vainchenker,et al.  Myeloproliferative neoplasm induced by constitutive expression of JAK2V617F in knock-in mice. , 2010, Blood.

[10]  C. Pecquet,et al.  miR-28 is a thrombopoietin receptor targeting microRNA detected in a fraction of myeloproliferative neoplasm patient platelets. , 2010, Blood.

[11]  Stefan N. Constantinescu,et al.  JAK2 V617F Constitutive Activation Requires JH2 Residue F595: A Pseudokinase Domain Target for Specific Inhibitors , 2010, PloS one.

[12]  Michael G. Kharas,et al.  Physiological Jak2V617F expression causes a lethal myeloproliferative neoplasm with differential effects on hematopoietic stem and progenitor cells. , 2010, Cancer cell.

[13]  Nathan C Boles,et al.  Quiescent hematopoietic stem cells are activated by IFNγ in response to chronic infection , 2010, Nature.

[14]  E. Pronier,et al.  Clonal analysis of erythroid progenitors suggests that pegylated interferon α-2a treatment targets JAK2V617F clones without affecting TET2 mutant cells , 2010, Leukemia.

[15]  Nathan C Boles,et al.  Distinct hematopoietic stem cell subtypes are differentially regulated by TGF-beta1. , 2010, Cell stem cell.

[16]  A. Trumpp,et al.  Awakening dormant haematopoietic stem cells , 2010, Nature Reviews Immunology.

[17]  S. Fiering,et al.  Conditional expression of heterozygous or homozygous Jak2V617F from its endogenous promoter induces a polycythemia vera-like disease. , 2009, Blood.

[18]  J. Soulier,et al.  Mutation in TET2 in myeloid cancers. , 2009, The New England journal of medicine.

[19]  J. Godbold,et al.  Human CD34+ cells are capable of generating normal and JAK2V617F positive endothelial like cells in vivo. , 2009, Blood cells, molecules & diseases.

[20]  David R. Liu,et al.  Conversion of 5-Methylcytosine to 5- Hydroxymethylcytosine in Mammalian DNA by the MLL Partner TET1 , 2009 .

[21]  Andreas Trumpp,et al.  IFNα activates dormant haematopoietic stem cells in vivo , 2009, Nature.

[22]  W. Vainchenker,et al.  The hematopoietic stem cell compartment of JAK2V617F-positive myeloproliferative disorders is a reflection of disease heterogeneity. , 2008, Blood.

[23]  E. Vellenga,et al.  Maximal STAT5-Induced Proliferation and Self-Renewal at Intermediate STAT5 Activity Levels , 2008, Molecular and Cellular Biology.

[24]  E. Vellenga,et al.  Downregulation of Signal Transducer and Activator of Transcription 5 (STAT5) in CD34+ Cells Promotes Megakaryocytic Development, Whereas Activation of STAT5 Drives Erythropoiesis , 2008, Stem cells.

[25]  M. Tomasson,et al.  The Jak2V617F oncogene associated with myeloproliferative diseases requires a functional FERM domain for transformation and for expression of the Myc and Pim proto-oncogenes. , 2008, Blood.

[26]  R. Tiedt,et al.  Ratio of mutant JAK2-V617F to wild-type Jak2 determines the MPD phenotypes in transgenic mice. , 2007, Blood.

[27]  Qingshan Li,et al.  Transgenic expression of JAK2V617F causes myeloproliferative disorders in mice. , 2007, Blood.

[28]  K. Takenaka,et al.  Development of ET, primary myelofibrosis and PV in mice expressing JAK2 V617F , 2008, Leukemia.

[29]  R. Hoffman,et al.  Behavior of CD34+ cells isolated from patients with polycythemia vera in NOD/SCID mice. , 2007, Experimental hematology.

[30]  T. Cenci,et al.  Different STAT-3 and STAT-5 phosphorylation discriminates among Ph-negative chronic myeloproliferative diseases and is independent of the V617F JAK-2 mutation. , 2007, Blood.

[31]  R. Hoffman,et al.  The expression of CXCR4 is down-regulated on the CD34+ cells of patients with myelofibrosis with myeloid metaplasia. , 2007, Blood cells, molecules & diseases.

[32]  G. Schreiber,et al.  The receptor of the type I interferon family. , 2007, Current topics in microbiology and immunology.

[33]  W. Vainchenker,et al.  Evidence that the JAK2 G1849T (V617F) mutation occurs in a lymphomyeloid progenitor in polycythemia vera and idiopathic myelofibrosis. , 2007, Blood.

[34]  R. V. van Etten,et al.  Molecular Pathogenesis and Therapy of Polycythemia Induced in Mice by JAK2 V617F , 2006, PloS one.

[35]  W. Vainchenker,et al.  JAK2V617F expression in murine hematopoietic cells leads to MPD mimicking human PV with secondary myelofibrosis. , 2006, Blood.

[36]  R. Levine,et al.  Expression of Jak2V617F causes a polycythemia vera-like disease with associated myelofibrosis in a murine bone marrow transplant model. , 2006, Blood.

[37]  I. Weissman,et al.  The JAK2 V617F mutation occurs in hematopoietic stem cells in polycythemia vera and predisposes toward erythroid differentiation. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[38]  E. Vellenga,et al.  STAT5-induced self-renewal and impaired myelopoiesis of human hematopoietic stem/progenitor cells involves down-modulation of C/EBPalpha. , 2005, Blood.

[39]  H. Lodish,et al.  Expression of a homodimeric type I cytokine receptor is required for JAK2V617F-mediated transformation. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[40]  S. Constantinescu,et al.  JAK1 and Tyk2 Activation by the Homologous Polycythemia Vera JAK2 V617F Mutation , 2005, Journal of Biological Chemistry.

[41]  D. Oscier,et al.  Widespread occurrence of the JAK2 V617F mutation in chronic myeloproliferative disorders. , 2005, Blood.

[42]  Qingshan Li,et al.  Identification of an Acquired JAK2 Mutation in Polycythemia Vera* , 2005, Journal of Biological Chemistry.

[43]  K. Boyd,et al.  Transgenic mice with pancellular enhanced green fluorescent protein expression in primitive hematopoietic cells and all blood cell progeny , 2005, Genesis.

[44]  Stefan N. Constantinescu,et al.  A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera , 2005, Nature.

[45]  Mario Cazzola,et al.  A gain-of-function mutation of JAK2 in myeloproliferative disorders. , 2005, The New England journal of medicine.

[46]  V. Moucadel,et al.  Differential STAT5 Signaling by Ligand-dependent and Constitutively Active Cytokine Receptors* , 2005, Journal of Biological Chemistry.

[47]  Sandra A. Moore,et al.  Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis. , 2005, Cancer cell.

[48]  P. Campbell,et al.  Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders , 2005, The Lancet.

[49]  Giovanni Morrone,et al.  Constitutive Activation of STAT5A Promotes Human Hematopoietic Stem Cell Self-Renewal and Erythroid Differentiation , 2004, The Journal of experimental medicine.

[50]  Mauno Vihinen,et al.  Autoinhibition of Jak2 tyrosine kinase is dependent on specific regions in its pseudokinase domain. , 2003, Molecular biology of the cell.

[51]  M. McMahon,et al.  Identification and Characterization of a Constitutively Active STAT5 Mutant That Promotes Cell Proliferation , 2022 .

[52]  M. Barbacid,et al.  vav, a novel human oncogene derived from a locus ubiquitously expressed in hematopoietic cells. , 1989, The EMBO journal.

[53]  P. Fialkow,et al.  Clonal origin of human tumors. , 1979, Annual review of medicine.

[54]  W. Dameshek.  Editorial: Some Speculations on the Myeloproliferative Syndromes , 1951 .

[55]  W. Dameshek.  Some speculations on the myeloproliferative syndromes. , 1951, Blood.