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 Blood, 5 November 2009, Vol. 114, No. 19, pp. 4221-4232.
Prepublished online as a Blood First Edition Paper on September 1, 2009; DOI 10.1182/blood-2009-03-209932.

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PLATELETS AND THROMBOPOIESIS

MAL/SRF complex is involved in platelet formation and megakaryocyte migration by regulating MYL9 (MLC2) and MMP9

Laure Gilles13, Dominique Bluteau13, Siham Boukour13, Yunhua Chang13, Yanyan Zhang13, Thomas Robert2,3, Philippe Dessen24, Najet Debili13, Olivier A. Bernard5, William Vainchenker13, and Hana Raslova13

1 Inserm, U790, Villejuif; 2 Université Paris XI, Villejuif; 3 Institut Gustave Roussy, IFR54, Villejuif; 4 Centre National de la Recherche Scientifique, FRE2939, Villejuif; and 5 Inserm, Hôpital Necker, Paris, France

Megakaryoblastic leukemia 1 (MAL) is a transcriptional coactivator of serum response factor (SRF). In acute megakaryoblastic leukemia, the MAL gene is translocated and fused with the gene encoding one twenty-two (OTT). Herein, we show that MAL expression increases during the late differentiation steps of neonate and adult human megakaryopoiesis and localized into the nucleus after Rho GTPase activation by adhesion on collagen I or convulxin. MAL knockdown in megakaryocyte progenitors reduced the percentage of cells forming filopodia, lamellipodia, and stress fibers after adhesion on the same substrates, and reduced proplatelet formation. MAL repression led to dysmorphic megakaryocytes with disorganized demarcation membranes and {alpha} granules heterogeneously scattered in the cytoplasm. Gene expression profiling revealed a marked decrease in metalloproteinase 9 (MMP-9) and MYL9 expression after MAL inhibition. Luciferase assays in HEK293T cells and chromatin immunoprecipitation in primary megakaryocytes showed that the MAL/SRF complex directly regulates MYL9 and MMP9 in vitro. Megakaryocyte migration in response to stromal cell–derived factor 1, through Matrigel was considerably decreased after MAL knockdown, implicating MMP9 in migration. Finally, the use of a shRNA to decrease MYL9 expression showed that MYL9 was involved in proplatelet formation. MAL/SRF complex is thus involved in platelet formation and megakaryocyte migration by regulating MYL9 and MMP9.


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Related Article in Blood Online:

MAL: not just a leukemia inducer
Katya Ravid
Blood 2009 114: 3977-3978. [Full Text] [PDF]



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K. Ravid
MAL: not just a leukemia inducer
Blood, November 5, 2009; 114(19): 3977 - 3978.
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