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Differential in vivo roles of Mpl cytoplasmic tyrosine residues in murine hematopoiesis and myeloproliferative disease

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posted on 2024-06-06, 04:12 authored by K Behrens, M Kauppi, EM Viney, AJ Kueh, CD Hyland, TA Willson, L Salleh, CA de Graaf, JJ Babon, Marco HeroldMarco Herold, NA Nicola, WS Alexander
Thrombopoietin (Tpo), which binds to its specific receptor, the Mpl protein, is the major cytokine regulator of megakaryopoiesis and circulating platelet number. Tpo binding to Mpl triggers activation of Janus kinase 2 (Jak2) and phosphorylation of the receptor, as well as activation of several intracellular signalling cascades that mediate cellular responses. Three tyrosine (Y) residues in the C-terminal region of the Mpl intracellular domain have been implicated as sites of phosphorylation required for regulation of major Tpo-stimulated signalling pathways: Mpl-Y565, Mpl-Y599 and Mpl-Y604. Here, we have introduced mutations in the mouse germline and report a consistent physiological requirement for Mpl-Y599, mutation of which resulted in thrombocytopenia, deficient megakaryopoiesis, low hematopoietic stem cell (HSC) number and function, and attenuated responses to myelosuppression. We further show that in models of myeloproliferative neoplasms (MPN), where Mpl is required for pathogenesis, thrombocytosis was dependent on intact Mpl-Y599. In contrast, Mpl-Y565 was required for negative regulation of Tpo responses; mutation of this residue resulted in excess megakaryopoiesis at steady-state and in response to myelosuppression, and exacerbated thrombocytosis associated with MPN. (Figure presented.).


This work was supported by the Australian National Health and Medical Research Council (NHMRC) (Project Grants 1122999, 1159658, 1186575 and 1145728, program grant 1113577, Fellowship 1156095 to MJH, Fellowship 1121755 to JJB, Investigator grant 1173342 to WSA and Independent Research Institutes Infrastructure Support Scheme grants), the Cancer Council of Victoria (project grant 1147328 and 2021 Grant In Aid to MJH), the Medical Research Future Fund (grant MRF2008972) the Australian Cancer Research Fund, and the Victorian State Government Operational Infrastructure Support scheme. KB received a fellowship (341020624) from the Deutsche Forschungsgemeinschaft. The generation of CRISPR/Cas9 modified mice used in this study was supported by Phenomics Australia and the Australian Government through the National Collaborative Research Infrastructure Strategy program.


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11p. (p. 1342-1352)


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