The thrombopoietin receptor, MPL, is critical for development of a JAK2V617F-induced myeloproliferative neoplasm

The most frequent contributing factor in Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs) is the acquisition of a V617F mutation in Janus kinase 2 (JAK2) in hematopoietic stem cells (HSCs). Recent evidence has demonstrated that to drive MPN transformation, JAK2V(617)F needs to directly associate with a functional homodimeric type I cytokine receptor, suggesting that, although acquiring JAK2V(617)F may promote disease, there are additional cellular components necessary for MPN development. Here we show that loss of the thrombopoietin (TPO) receptor (MPL) significantly ameliorates MPN development in JAK2V(617)F(+) transgenic mice, whereas loss of TPO only mildly affects the disease phenotype. Specifically, compared with JAK2V(617)F(+) mice, JAK2V(617)F(+) Mpl(-/-) mice exhibited reduced thrombocythemia, neutrophilia, splenomegaly, and neoplastic stem cell pool. The importance of MPL is highlighted as JAK2V(617)FMpl(+/-) mice displayed a significantly reduced MPN phenotype, indicating that Mpl level may have a substantial effect on MPN development and severity. Splenomegaly and the increased neoplastic stem cell pool were retained in JAK2V(617)F(+)Tpo(-/-) mice, although thrombocytos is was reduced compared with JAK2V(617)F(+) mice. These results demonstrate that Mpl expression, but not Tpo, is fundamental in the development of JAK2V(617)F(+) MPNs, highlighting an entirely novel target for therapeutic intervention.