MAL/SRF complex is involved in platelet formation and megakaryocyte migration by regulating MYL9 (MLC2) and MMP9
MAL/SRF complex is involved in platelet formation and megakaryocyte migration by regulating MYL9 (MLC2) and MMP9
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DOI：
10.1182/blood-2009-03-209932
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发表时间：
2009-11-05
期刊：
影响因子：
20.3
通讯作者：
Raslova, Hana
中科院分区：
文献类型：
--
作者：
Gilles, Laure;Bluteau, Dominique;Raslova, Hana
巨核细胞白血病1（MAL）是一种血清反应因子（SRF）的转录共激活因子。在急性巨核细胞白血病中，MAL基因易位并与编码1 - 22（OTT）的基因融合。在此，我们发现，MAL表达增加，在新生儿和成人巨核细胞生成的晚期分化步骤，并定位到细胞核后，RhoGTdR激活粘附在胶原蛋白I或惊厥。MAL敲低巨核细胞祖细胞减少了细胞的百分比形成丝状伪足，板状伪足，应力纤维后，粘附在相同的基板上，并减少前血小板的形成。MAL抑制导致畸形巨核细胞，其分界膜紊乱，α颗粒不均匀地分散在细胞质中。基因表达谱显示MAL抑制后金属蛋白酶9（MMP-9）和MYL 9表达显著降低。HEK 293 T细胞中的荧光素酶测定和原代巨核细胞中的染色质免疫沉淀显示MAL/SRF复合物在体外直接调节MYL 9和MMP 9。MAL敲低后，巨核细胞通过基质胶对基质细胞衍生因子1的迁移反应显著降低，这表明MMP 9参与了迁移。最后，使用shRNA降低MYL 9表达表明MYL 9参与前血小板形成。因此，MAL/SRF复合物通过调节MYL 9和MMP 9参与血小板形成和巨核细胞迁移。（血。2009; 114：4221-4232）
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 RhoGTPase 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. (Blood. 2009; 114:4221-4232)