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

Abstract

Key Points MPL is essential for the development of JAK2V617F-positive myeloproliferative neoplasms in vivo. Ablation or reduction of Mpl significantly reduces the pool of neoplastic hematopoietic stem cells.

Calreticulin mutants in mice induce an MPL-dependent thrombocytosis with frequent progression to myelofibrosis

“…In both cases, MPL but not TPO is indispensable, TPO only increasing the disease phenotype. 19 Moreover, in the companion article, the requirement of MPL and of JAK2 in the TPO-independent growth of primary megakaryocyte progenitors from human patients was confirmed using specific short hairpin RNAs. 18 Elucidating the mechanism of action of CALR mutants has profound implications for the therapy of CALR-positive patients.…”

Genetic basis and molecular pathophysiology of classical myeloproliferative neoplasms

“…However, in all models, MPL activation plays a central role by its role on HSCs and on megakaryocytes (MKs). 19,51,61 MK hyperplasia plays a central role in the pathogenesis of MPNs not only by increasing platelet production, but also by serving as a niche for HSCs, by remodeling bone marrow leading to MF and also by inducing neo-osteogenesis (Figure 3). However, in none of the models did mice develop a PMF, whereas they did develop secondary MF (post-ET or post-PV); no leukemic transformation is observed during Figure 4.…”

A thrombopoietin receptor antagonist is capable of depleting myelofibrosis hematopoietic stem and progenitor cells

“…A growing number of reports have highlighted the role of enhanced TPO/MPL signaling in the development and progression of MF and other MPNs, [10][11][12][13][14][15][16][17][18][19] suggesting that disrupting the association of TPO with its receptor might provide a means of depleting MF HSCs. Using in vitro HPC assays and in vivo HSC assays, we have examined the effects of a TPORA, LCP4, on primary MF HSCs/HPCs.…”