This review focusses on the role of JAK2 and the JAK/STAT pathway in MPN and LPN, whether there is a role for the genetic background in the occurrence of both MPN and LPN, and whether there is a role for cytoreductive drugs in the occurrence of both MPN and LPN.
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.
While JAK-STAT pathway activation has been shown to be central to the pathogenesis of the MPN phenotype, the mechanism by which mutant CALR alters cellular function to result in myeloid proliferation remains unclear.
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.
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.
BCR-ABL-negative myeloproliferative neoplasms (MPNs) are driven by JAK-STAT pathway activation, but epigenetic alterations also play an important pathophysiological role.
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.
Such complexities undermine the value of JAK-STAT as a robust drug target in MPN and partly explain the hitherto lack of histologic or molecular remissions associated with currently available JAK inhibitors.
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.
Constitutive JAK2 signaling is central to myeloproliferative neoplasm (MPN) pathogenesis and results in activation of STAT, PI3K/AKT, and MEK/ERK signaling.
Our observations reveal that JAK/STAT pathway activation in megakaryocytes induces myeloproliferation and is necessary for MPN maintenance <i>in vivo</i>.
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).
The discovery of JAK2V617F and other JAK-STAT-activating mutations in BCR-ABL1-negative myeloproliferative neoplasms (MPN) has led to the development of small-molecule ATP-mimetics that inhibit wild-type and mutant JAK.
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.
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.