<b>Introduction</b>: The abnormally activated JAK-STAT pathway plays a central role in the pathogenesis of BCR/ABL-negative myeloproliferative neoplasms (MPNs), simultaneously providing a theoretical and clinical basis for the development of small-molecule compounds targeting JAK.
Aberrant activation of the JAK/STAT pathway is thought to be the critical event in the pathogenesis of the chronic myeloproliferative neoplasms, polycythemia vera, essential thrombocythemia and primary myelofibrosis.
Although the discovery of mutations in the JAK-STAT pathway is important from a pathogenetic and diagnostic perspective, important questions remain regarding the role of this single disease allele in 3 related but clinically distinct disorders, and the role of additional genetic events in MPD disease pathogenesis.
Although the pathogenesis of primary myelofibrosis (PMF) and other myeloproliferative neoplasms (MPNs) is linked to constitutive activation of the JAK-STAT pathway, JAK inhibitors have neither curative nor MPN-stem cell-eradicating potential, indicating that other targetable mechanisms are contributing to the pathophysiology of MPNs.
As JAK2 V617F, MPL W515L is a novel acquired mutation that induces constitutive cytokine-independent activation of the JAK-STAT pathway in myeloproliferative disorders (MPD).
BCR-ABL-negative myeloproliferative neoplasms (MPNs) are driven by JAK-STAT pathway activation, but epigenetic alterations also play an important pathophysiological role.
Constitutive JAK2 signaling is central to myeloproliferative neoplasm (MPN) pathogenesis and results in activation of STAT, PI3K/AKT, and MEK/ERK signaling.
Discovery in 2006 of mutants of thrombopoietin receptor (TPO-R/MPL) and later on of mutants in negative regulators of JAK-STAT pathway led to the notion that persistent JAK2 activation is a hallmark of MPNs.
Dysregulated signaling of the JAK/STAT pathway is a common feature of chronic myeloproliferative neoplasms (MPN), usually associated with JAK2V617F mutation.
Furthermore, several classes of epigenetic modifiers have also been identified, in patients with MPN, revealing a requirement for mutations in other pathways to cooperate with JAK-STAT pathway mutations in MPN pathogenesis.
Furthermore, the demonstration of distinct STAT staining patterns in molecularly defined MPN suggests that these mutations result in divergent signaling events that may contribute to the biological and prognostic differences in these molecular subsets of MPN.
Many drugs are now under investigations targeting different pathways critical for MPN development, such as the JAK-STAT (JAK2 inhibitors: INCB018424 or ruxolitinib, TG101348 or SAR302503, CYT387, SB1518, CEP701 and LY2784544) and the PI3K/AKT/mTOR (everolimus) pathways, or act through remodeling of chromatin with a key role in epigenetics (givinostat, panobinostat and vorinostat).
Molecularly, this phenotype is mediated by <i>Nol3</i><sup>-/-</sup>-induced JAK-STAT activation and downstream activation of <i>cyclin-dependent kinase 6</i> (<i>Cdk6</i>) and <i>Myc</i><i>Nol3<sup>-/-</sup></i> MPN Thy1<sup>+</sup>LSK cells share significant molecular similarities with primary CD34<sup>+</sup> cells from PMF patients.
Our data indicate that MPN patients, regardless of diagnosis or JAK2 mutational status, are characterized by a distinct gene expression signature with upregulation of JAK-STAT target genes, demonstrating the central importance of the JAK-STAT pathway in MPN pathogenesis.
Our observations reveal that JAK/STAT pathway activation in megakaryocytes induces myeloproliferation and is necessary for MPN maintenance <i>in vivo</i>.