Myeloproliferative neoplasms and the JAK/STAT signaling pathway: an overview

Abstract

Myeloproliferative neoplasms are caused by a clonal proliferation of a hematopoietic progenitor. First described in 1951 as ‘Myeloproliferative Diseases’ and reevaluated by the World Health Organization classification system in 2011, myeloproliferative neoplasms include polycythemia vera, essential thrombocythemia and primary myelofibrosis in a subgroup called breakpoint cluster region-Abelson fusion oncogene-negative neoplasms. According to World Health Organization regarding diagnosis criteria for myeloproliferative neoplasms, the presence of the JAK2 V617F mutation is considered the most important criterion in the diagnosis of breakpoint cluster region-Abelson fusion oncogene-negative neoplasms and is thus used as a clonal marker. The V617F mutation in the Janus kinase 2 (JAK2) gene produces an altered protein that constitutively activates the Janus kinase/signal transducers and activators of transcription pathway and other pathways downstream as a result of signal transducers and activators of transcription which are subsequently phosphorylated. This affects the expression of genes involved in the regulation of apoptosis and regulatory proteins and modifies the proliferation rate of hematopoietic stem cells.

Cancer stem cell signaling pathways

“…Aberrant JAK/STAT signaling has also been observed in myeloproliferative malignancies. [ 30 ] Isolation and analysis of CSCs from patients with acute myeloid leukemia (AML) identified constitutive activation of JAK/STAT signaling. In vitro studies indicated that the growth and survival of these CSCs were reduced when treated with a JAK1/2 inhibitor.…”

Regulation of normal and leukemic stem cells through cytokine signaling and the microenvironment

“…The constitutive activation of the JAK/STAT pathway drives leukemogenic potential as observed in BCR/ABL + CML, BCR/ABL − myeloproliferative neoplasms and is even associated with poor prognosis of AML LSCs [84][85][86]. Janus kinases (JAKs), cytoplasmically associated with cytokine receptors are phosphorylated at their tyrosine residues and are activated when cytokines and growth factors bind to their receptors.…”

“…Mutated and constitutively active JAK, cause the phosphorylation and dimerization of STATs that are transcription factors regulating genes important for cell survival and proliferation. There have been significant advances in targeting these pathways in leukemia and solid tumors [84,87]. Interestingly, tyrosine-unphosphorylated STAT5 (uSTAT5) represses megakaryocytic transcriptional program in the absence of thrombopoietin (THPO) and restricted the access of ERG, a transcriptional factor to its target genes, proving the role of cytokine in megakaryocytic differentiation [87].…”

Gene expression profiling of CD34(+) cells from patients with myeloproliferative neoplasms

“…The role of JAK-STAT signaling in hematopoiesis has been demonstrated in mice with a germline deletion of JAK2 , leading to embryonic lethal effects due to disrupted erythropoiesis ( 18 ). Mutations in the pseudokinase domain of JAK2 results in an uninhibited phosphorylation of the tyrosine kinase and constitutive activation of the JAK-STAT pathway, which is central to the pathogenesis of MPNs that possess this gain-of-function mutation ( 19 ). JAK2 mutations are reported in ~95% of PVs, 50–60% of ETs and 50–60% of PMFs, which led to the investigation of differing phenotypes resulting from the same genetic aberration ( 7 ).…”