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  • Title: c-Mpl-del, a c-Mpl alternative splicing isoform, promotes AMKL progression and chemoresistance.
    Author: Li F, Xiong Y, Yang M, Chen P, Zhang J, Wang Q, Xu M, Wang Y, He Z, Zhao X, Huang J, Gu X, Zhang L, Sun R, Sun X, Li J, Ou J, Xu T, Huang X, Cao Y, Xu XR, Karakas D, Li J, Ni H, Zhang Q.
    Journal: Cell Death Dis; 2022 Oct 13; 13(10):869. PubMed ID: 36229456.
    Abstract:
    Acute megakaryocytic leukemia (AMKL) is a clinically heterogeneous subtype of acute myeloid leukemia characterized by unrestricted megakaryoblast proliferation and poor prognosis. Thrombopoietin receptor c-Mpl is a primary regulator of megakaryopoeisis and a potent mitogenic receptor. Aberrant c-Mpl signaling has been implicated in a myriad of myeloid proliferative disorders, some of which can lead to AMKL, however, the role of c-Mpl in AMKL progression remains largely unexplored. Here, we identified increased expression of a c-Mpl alternative splicing isoform, c-Mpl-del, in AMKL patients. We found that c-Mpl-del expression was associated with enhanced AMKL cell proliferation and chemoresistance, and decreased survival in xenografted mice, while c-Mpl-del knockdown attenuated proliferation and restored apoptosis. Interestingly, we observed that c-Mpl-del exhibits preferential utilization of phosphorylated c-Mpl-del C-terminus Y607 and biased activation of PI3K/AKT pathway, which culminated in upregulation of GATA1 and downregulation of DDIT3-related apoptotic responses conducive to AMKL chemoresistance and proliferation. Thus, this study elucidates the critical roles of c-Mpl alternative splicing in AMKL progression and drug resistance, which may have important diagnostic and therapeutic implications for leukemia accelerated by c-Mpl-del overexpression.
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