Abstract 1308

Megakaryocytes (MK) are unique mammalian cells that undergo polyploidization during differentiation, which leads to an increase in cell size and protein production that precedes platelet production. The molecular basis of MK polyploidization, denoted endomitosis, which is strongly altered in hematological malignancies and various other disease states, remain poorly understood. Recent evidence demonstrates that endomitosis is a consequence of a late failure in cytokinesis, associated with a contractile ring defect. Here, we demonstrate that the myosin non-muscle IIB heavy chain (MYH10) is expressed in immature human and mouse megakaryocytes and its expression is repressed during differentiation. In immature MK, MYH10 is specifically localized in the contractile ring while MYH9 is mainly present in the cytoplasm suggesting that they occupy two different functions during MK differentiation. Importantly, MYH10 down-modulation by shRNA or by addition of a chemical inhibitor blebbistatin, increases polyploidization by inhibiting the return of 4N cells to 2N. Conversely, re-expression of MYH10 in MKs prevents polyploidization and the transition of 2N cells to 4N cells. Furthermore, we demonstrated that RUNX1 directly repress the transcription of MYH10. In vitro and in vivo RUNX1 invalidation inhibits MK polyploidization and increases expression of MYH10. Accordingly, in patients with a germline mutation of RUNX1 (FPD/AML), MYH10 is still expressed in platelets. Altogether ours results demonstrated that the RUNX1-mediated silencing of MYH10 is needed for the switch from mitosis to endomitosis linking thus polyploidization with MK differentiation.

Disclosures:

No relevant conflicts of interest to declare.

Author notes

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Asterisk with author names denotes non-ASH members.

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