Abstract
BackgroundMyeloproliferative neoplasms (MPN) are a group of blood cancers that boost normal blood cell production in the bone marrow. Abnormal mutations in stem cells were found accompanying with the occurrence of MPN. It has been shown that MPL mutations (MPL W515L or MPL W515K) were involved in patients with MPN. Since tyrosine residues 625 and 630 mediate normal MPL signaling, whether them affect MPL W515L-induced myeloproliferative neoplasms (MPNs) is unknown.ResultsIn this study, we further tested their functions in MPL W515L-induced myeloproliferative neoplasms (MPNs) by substituting either or both of them with phenylalanine in MPL W515L (termed as MPL515/625, MPL515/630 and MPL515/625/630, respectively). In vitro, MPL515/630 but not MPL515/625 or MPL515/625/630 retained the ability to induce TPO-independent proliferation and increase colony-forming unit megakaryocytes (CFU-Mk). Accordingly, differential activation of the downstream signaling by four mutants was observed and constitutively active STAT5 or AKT instead of STAT3 partially compensated MPL515/625/630 function. Further support this, STAT5-deficiency impaired MPL W515L-induced CFU-Mk expansion. In vivo, MPL515/630 but not MPL515/625 or MPL515/625/630 induced typical features of MPNs with high WBC and platelet counts, splenomegaly, hepatomegaly and hypercellularity in the bone marrow. Surprisingly, MPL515/625 also caused hypercellularity of bone marrow and splenomegaly without any other significant features. We also observed differential effects of the four mutants on progenitors, myeloid cells and megakaryocytes.ConclusionsOur studies have revealed distinct features of tyrosine sites 625 and 630 in mediating MPL W515L-induced megakaryocyte hyperproliferation and MPNs. Our study also suggests that MPL cytosolic phosphorylated Y625 and flanking amino acids could become targets for pharmacologic inhibition in MPNs.Electronic supplementary materialThe online version of this article (doi:10.1186/s13578-016-0097-3) contains supplementary material, which is available to authorized users.
Highlights
Myeloproliferative neoplasms (MPN) are a group of blood cancers that boost normal blood cell production in the bone marrow
Tyrosine 625 plays a critical role in MPL W515L‐induced hyperproliferation of megakaryocytes Previously, we observed that overexpression of janus kinase 2 (JAK2) V617F or MPL W515L conferred TPO-independent growth in G1ME cells [26]
Tyrosine sites 625 and 630 are known to mediate normal MPL signaling by docking signal transducer and activator of transcription 3 (STAT3) and signal transducer and activator of transcription 5 (STAT5) [25, 29]
Summary
Myeloproliferative neoplasms (MPN) are a group of blood cancers that boost normal blood cell production in the bone marrow. JAK2 and MPL mutations are associated with BCR-ABL negative myeloproliferative neoplasms (MPNs) including polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF) [1,2,3]. These mutations caused activation of JAK2, cytokine independent growth of human blood cells, and induced MPNs in mouse models [4,5,6,7]. Besides developing new types of JAK2 inhibitor, other downstream signaling pathways activated by these mutants were proposed to be potential targets for MPNs therapy. JAK2 and MPL mutations primarily activate JAK/ STAT, PI3K/AKT and MAPK/ERK signaling pathways. Its role in typical MPNs with JAK2 or MPL mutations had not been addressed
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