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

Abstract

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.

Keywords: JAK-STAT; JAK2 V617F; hematopoietic stem cells; mouse models; myeloproliferative disorders.

Figure 1. Signaling via the JAK-STAT pathway. (A) Ligand binding induces a conformational change of the cytokine receptor and allows transphosphorylation of JAK proteins. Activated JAKs phosphorylate tyrosine residues in the receptor cytoplasmic domain and provide docking site for STAT proteins. Phosphorylated STATs dissociate from the receptor, dimerize and translocate to the nucleus where they modulate gene expression. (B) In case of the JAK2 V617F, mutant cytosolic tyrosines are constantly phosphorylated, leading to constitutive activation of STAT proteins.

Figure 2. (A) Myeloid blood cell development starts with the hematopoietic stem cell (HSC) that either self-renews or gives rise to a common myeloid progenitor (CMP). The CMP in turn differentiates into more restricted progenitors of the megakaryocyte (MK)-erythroid (E) lineages or granulocyte-monocyte progenitor (GM). These cells give then rise to terminally differentiated erythrocytes, megakaryocytes/platelets, granulocytes (eosinophils, neutrophils and basophils) and monocytes. Cytokines and their receptors control cell proliferation and differentiation during hematopoiesis and ensure the balance between renewal and cell differentiation. (B) Several reports have confirmed that the JAK2 V617F mutation occurs at the level of an HSC. There is, however, still controversy to whether the JAK2 V617F mutant expands the true HSC pool or whether it acts downstream on a more committed progenitor. Further studies are necessary to clarify the exact role of JAK2 V617F on HSC or progenitor expansion. Since the JAK2 V617F mutant only influences myeloid differentiation, we have restricted the schematic to the myeloid lineage.