Role for MKL1 in megakaryocytic maturation

• Published in: Blood 2009-03, Vol.113 (12), p.2826-2834
• Main Authors: Cheng, Ee-chun, Luo, Qing, Bruscia, Emanuela M., Renda, Matthew J., Troy, James A., Massaro, Stephanie A., Tuck, David, Schulz, Vincent, Mane, Shrikant M., Berliner, Nancy, Sun, Yi, Morris, Stephan W., Qiu, Caihong, Krause, Diane S.
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Blood Cell Count; Bone Marrow - pathology; Cell Differentiation - drug effects; Cell Line, Tumor - drug effects; Cells, Cultured - cytology; Cells, Cultured - drug effects; DNA-Binding Proteins - biosynthesis; DNA-Binding Proteins - genetics; DNA-Binding Proteins - physiology; Gene Expression Profiling; Gene Expression Regulation - drug effects; Hematologic and hematopoietic diseases; Humans; Leukemia, Erythroblastic, Acute - pathology; Medical sciences; Megakaryocytes - cytology; Mice; Mice, Inbred C57BL; Mice, Knockout; Oligonucleotide Array Sequence Analysis; Oncogene Proteins, Fusion - biosynthesis; Oncogene Proteins, Fusion - genetics; Oncogene Proteins, Fusion - physiology; Platelets and Thrombopoiesis; Ploidies; Recombinant Fusion Proteins - physiology; RNA Interference; RNA, Small Interfering - pharmacology; Serum Response Factor - genetics; Serum Response Factor - physiology; Thrombocytopenia - genetics; Thrombocytopenia - pathology; Thrombopoiesis - physiology; Thrombopoietin - blood; Thrombopoietin - pharmacology; Trans-Activators - biosynthesis; Trans-Activators - deficiency; Trans-Activators - genetics; Trans-Activators - physiology
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2008-09-180596

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.