Role for MKL1 in megakaryocytic maturation

Abstract

Megakaryoblastic leukemia 1 (MKL1), identified as part of the t(1;22) translocation specific to acute megakaryoblastic leukemia, is highly expressed in differentiated muscle cells and promotes muscle differentiation by activating serum response factor (SRF). Here we show that Mkl1 expression is up-regulated during murine megakaryocytic differentiation and that enforced overexpression of MKL1 enhances megakaryocytic differentiation.When the human erythroleukemia (HEL) cell line is induced to differentiate with 12-O-tetradecanoylphorbol 13-acetate, overexpression of MKL1 results in an increased number of megakaryocytes with a concurrent increase in ploidy. MKL1 overexpression also promotes megakaryocytic differentiation of primary human CD34 ؉ cells cultured in the presence of thrombopoietin. The effect of MKL1 is abrogated when SRF is knocked down, suggesting that MKL1 acts through SRF. Consistent with these findings in human cells, knockout of Mkl1 in mice leads to reduced platelet counts in peripheral blood, and reduced ploidy in bone marrow megakaryocytes. In conclusion, MKL1 promotes physiologic maturation of human and murine megakaryocytes.

Whole exome sequencing identifies genetic variants in inherited thrombocytopenia with secondary qualitative function defects

“…[30][31][32] Recently, the first case of a homozygous mutation in MKL1 in a patient with severe immunodeficiency and no hematologic malignancies was reported. 33 One interesting phenotypic presentation of the affected individual was an intermittent mild thrombocytopenia with low platelet counts in whole blood of between 50x10 9 /L and 150x10 9 /L.…”

Serum response factor is an essential transcription factor in megakaryocytic maturation

“…After 4 days, the cells were fractionated on a 3% discontinuous bovine serum albumin (BSA; Sigma-Aldrich) gradient as described. 21 The fully mature polyploid megakaryocytes are mainly in the pellet below the 3% BSA fraction. For some assays, murine BM was lineage-depleted (lin Ϫ ) with the BD IMag Mouse Hematopoietic Progenitor (Stem) Cell Enrichment Set, according to the manufacturer's protocol (BD Biosciences).…”

The serum response factor (SRF)/megakaryocytic acute leukemia (MAL) network participates in megakaryocyte development

“…1,2 The human MAL gene is fused to the OTT/ RBM15 gene in acute megakaryoblastic leukemia (AMKL) 3,4 and a contribution of Mal activity to the late steps of murine and human megakaryopoiesis has been reported. 5,6 Although the lack of Srf results in major cellular defects and embryonic lethality (reviewed in Miano et al 7 ), Mal germ line deficiency results in a limited myoepithelial cells phenotype 8,9 probably because of the redundancies of Mrtf proteins.…”