Although JAK2V617F is the most common mutation in BCR-ABL-negative MPNs, approximately 50% of ET and PMF patients are JAK2V617F-negative [
43‐
47]. In 2006,
MPL-W515L was identified by Pikman et al., and
MPL-W515K was discovered several months later [
48,
49]. The frequency rates of
MPL-W515L/K in ET and PMF patients are approximately 1% and 5%, respectively, but they are rarely found in PV patients [
48,
50]. Interestingly, the proportion of the
MPL-W515L mutations is higher than that of
MPL-W515K mutations in MPN patients, although the ratio of homozygous patients is lower for the
MPL-W515L mutation [
51‐
53]. These mutations were identified not only in granulocytes but also in monocytes, B cells, T cells, NK cells, and even haematopoietic stem cells [
54‐
56]. However, increased mutation levels in the myeloid lineage combined with the observation that MPN is a myeloproliferative rather than a lymphoproliferative disorder suggest a proliferative advantage toward the myeloid series induced by
MPL-W515 mutations [
54].
The following aspects clearly indicate the close relationship between
MPL-W515L/K mutations and the pathogenesis of MPNs. 1.
MPL-W515L/K mutations are located in the unique amphipathic KWQFP motif of CD110, which is important for preventing its spontaneous activation [
5]. Thus,
MPL-W515L/K mutations may cause spontaneous activation. In
in vitro assays, several signalling pathways were constitutively phosphorylated and the S phase of the cell cycle was enhanced in
MPL-W515L/K-expressing cell lines; even when deprived of cytokines, cytokine-independent colony formation and higher megakaryocytic cloning efficiency have been reported [
49,
57]. In this process, the cytosolic tyrosine 112 of CD110
MPL-W515 mutants is crucial and represents a potential target for pharmacologic inhibition [
58].
2. In
in vivo assays, the analysis of tumourigenesis induction capacity of
MPL- W515L/K mutants in nude mice revealed a clinical phenomenon similar to that observed with ET and PMF and showed atypical megakaryocytic hyperplasia, splenomegaly and thrombocytosis [
49,
57,
59].
3. Currently,
MPL-W515L/K mutations have not been observed in normal individuals, and several studies have indicated that MPN patients with
MPL-W515L/K mutations present with older age, lower haemoglobin levels and higher platelet counts. However, the relationship between mutation and complications, such as thrombosis, remains unclear [
51,
53,
60].
4. Two
MPL-W515L mutation-positive PMF patients were treated with allogeneic stem cell transplantation (allo)-SCT, and the
MPL-W515L mutation was not detected after allo-SCT and mutation status remained negative for a long follow-up period, which is in line with the absence of clinical or molecular relapse [
61]. This observation suggests that the
MPL-W515L mutation could be used as a minimal residual disease marker and shows that
MPL-W515L plays a pathogenic role in MPN.
5. As mentioned above,
MPL-W515L/K mutations may cause spontaneous signal transduction, including that of the JAK-STAT/Crkl pathway. Moreover, various small molecule JAK kinase inhibitors not only inhibit spontaneous activation, thereby reducing the colony-forming capacity of cells with
MPL-W515L/K mutation in
in vitro assays, but also effectively relieve the symptoms observed in a
MPL-W515L murine model of MPN [
59,
62]. Additionally, JAK kinase inhibitors display therapeutic value for MPN patients with
MPL-W515L/K mutations [
63‐
65]. These observations confirm the status of
MPL-W515L/K in MPNs.
The
MPL-W515L mutation has also been identified in RARS-t and AML patient samples. Currently, RARS-t patients harbouring the
MPL-W515L mutation are rare [
66‐
68]. However, the mutation rate of
MPL-W515L has been found to be as high as 25% in acute megakaryoblastic leukaemia (AMKL) with myelofibrosis, which is a subtype of AML [
69]. The
MPL-W515L mutation may also be involved in the pathogenesis of RARS-t and AML; however, as reports on this topic are sparse, the function of the mutation in these two diseases remains uncertain.