Mutations in <i>CALR</i> observed in myeloproliferative neoplasms (MPN) were recently shown to be pathogenic via their interaction with MPL and the subsequent activation of the Janus Kinase - Signal Transducer and Activator of Transcription (JAK-STAT) pathway.
Newly characterized markers, such as altered expression of polycythemia rubra vera-1 (PRV-1) and the thrombopoietin receptor (c-MPL) as well as deletions on chromosome 20q (del20q) and loss of heterozygosity on chromosome 9p (9pLOH) provide an opportunity to diagnose and identify subpopulations of MPD patients.
Four main molecular types of clonal MPN can be distinguished: JAK2(V617F)-positive ET and PV; JAK2 wild-type ET carrying the MPL(515); mutations in the calreticulin (CALR) gene in JAK2/MPL wild-type ET and MF, and a small proportion of JAK2/MPL/CALR wild-type ET and MF patients.
Somatic mutations in the CALR gene were recently discovered in a substantial proportion of Philadelphia-negative chronic myeloproliferative neoplasm (cMPN) patients lacking JAK2 and MPL mutations.
Molecular genetic assays for the detection of the JAK2 V617F (c.1849G>T) and other pathogenetic mutations within JAK2 exon 12 and MPL exon 10 are part of the routine diagnostic workup for patients presenting with erythrocytosis, thrombocytosis or otherwise suspected to have a myeloproliferative neoplasm.
Somatic mutations in JAK2, MPL and CALR are recurrently identified in most of the cases with Philadelphia chromosome negative myeloproliferative neoplasms (MPNs).
A multiplex snapback primer system was developed for the simultaneous detection of JAK2 V617F and MPLW515L/K mutations in Philadelphia chromosome- (Ph-) negative myeloproliferative neoplasms (MPNs).
As JAK2 V617F, MPLW515L is a novel acquired mutation that induces constitutive cytokine-independent activation of the JAK-STAT pathway in myeloproliferative disorders (MPD).
The thrombopoietin receptor gene (MPL) is expressed in megakaryocytes and exhibits the gain of function point mutation W515K/L in approximately 5% of patients with primary myelofibrosis/idiopathic myelofibrosis (PMF) representing one subtype of the chronic myeloproliferative disorders (myeloproliferative neoplasm).
Recent advances in the biology of MPNs have greatly facilitated their molecular diagnosis since most patients present with mutation(s) in the JAK2, MPL, or CALR genes.
<b>Expert Opinion</b>: Altogether, we believe that MPL is an important, but challenging, therapeutic target in MPNs that requires novel strategies to interrupt the specific conformational changes induced by each mutation or pathologic interaction without compromising the key functions of wild type MPL.
The identification of JAK2/MPL mutations in patients with myeloproliferative neoplasms (MPN) has led to the clinical development of JAK kinase inhibitors, including ruxolitinib.
Therefore, further studies are warranted to elucidate the mechanisms contributing to megakaryopoiesis in CMPD disease entities with decreased c-mpl gene expression.
The thrombopoietin receptor (TpoR, MPL) is one of the major dimeric cytokine receptors that use JAK2 in the myeloid lineage, and was found to be down-modulated in certain MPN patients.
It has recently been shown that mutant CALR constitutively activates the thrombopoietin receptorMPL and, thus, plays a causal role in the development of MPNs.
In >95% of cases, mutations that drive the development of an MPN phenotype occur in a mutually exclusive manner in 1 of 3 genes: <i>JAK2</i>, <i>CALR</i>, or <i>MPL</i> The thrombopoietin receptor, MPL, is the key cytokine receptor in MPN development, and these mutations all activate MPL-JAK-STAT signaling in MPN stem cells.