Journal article

Mcl-1 and Bcl-x(L) coordinately regulate megakaryocyte survival

Marlyse A Debrincat, Emma C Josefsson, Chloe James, Katya J Henley, Sarah Ellis, Marion Lebois, Kelly L Betterman, Rachael M Lane, Kelly L Rogers, Michael J White, Andrew W Roberts, Natasha L Harvey, Donald Metcalf, Benjamin T Kile

BLOOD | AMER SOC HEMATOLOGY | Published : 2012

Abstract

Mature megakaryocytes depend on the function of Bcl-x(L), a member of the Bcl-2 family of prosurvival proteins, to proceed safely through the process of platelet shedding. Despite this, loss of Bcl-x(L) does not prevent the growth and maturation of megakaryocytes, suggesting redundancy with other prosurvival proteins. We therefore generated mice with a megakaryocyte-specific deletion of Mcl-1, which is known to be expressed in megakaryocytes. Megakaryopoiesis, platelet production, and platelet lifespan were unperturbed in Mcl-1(Pf4Δ/Pf4Δ) animals. However, treatment with ABT-737, a BH3 mimetic compound that inhibits the prosurvival proteins Bcl-2, Bcl-x(L), and Bcl-w resulted in the complete..

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Grants

Awarded by Australian National Health and Medical Research Council (NHMRC)


Funding Acknowledgements

This work was supported by a Project grant (575535), a Program grant (461219), and an Independent Research Institutes Infrastructure Support Scheme grant (361646) from the Australian National Health and Medical Research Council (NHMRC); Fellowships from the Sylvia and Charles Viertel Foundation (B. T. K.), the Leukemia & Lymphoma Society (E.C.J.), NHMRC/Inserm (C.J.), EMBO (C.J.), NHMRC (A. W. R., B. T. K.); the Cancer Council of Victoria (D. M.) and the National Heart Foundation (N.L.H.); the Australian Cancer Research Fund, and a Victorian State Government Operational Infrastructure Support grant.