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PMID: 19136660 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Role for MKL1 in megakaryocytic maturation.

Blood ·Vol. 113 ·No. 12 ·2009-03-19 ·Pages 2826-34

Cheng EC, Luo Q, Bruscia EM, Renda MJ, Troy JA, Massaro SA, Tuck D, Schulz V, Mane SM, Berliner N, Sun Y, Morris SW, Qiu C, Krause DS

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.

MeSH Terms
Animals Blood Cell Count Bone Marrow/pathology Cell Differentiation/drug effects Cell Line, Tumor/drug effects Cells, Cultured/cytology,drug effects DNA-Binding Proteins/biosynthesis,genetics,physiology Gene Expression Profiling Gene Expression Regulation/drug effects Humans Leukemia, Erythroblastic, Acute/pathology Megakaryocytes/cytology Mice Mice, Inbred C57BL Mice, Knockout Oligonucleotide Array Sequence Analysis Oncogene Proteins, Fusion/biosynthesis,genetics,physiology Ploidies RNA Interference RNA, Small Interfering/pharmacology Recombinant Fusion Proteins/physiology Serum Response Factor/genetics,physiology Thrombocytopenia/genetics,pathology Thrombopoiesis/physiology Thrombopoietin/blood,pharmacology Trans-Activators/biosynthesis,deficiency,genetics,physiology
Chemicals
DNA-Binding Proteins MRTFA protein, human Mrtfa protein, mouse Oncogene Proteins, Fusion RNA, Small Interfering Recombinant Fusion Proteins Serum Response Factor Trans-Activators Thrombopoietin
Authors & Affiliations
14 authors, click to expand affiliations / ORCID
Cheng Ee-Chun
Department of Laboratory Medicine, Yale University, New Haven, CT 06520-8073, USA.
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
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Article Info
Journal
Blood
Abbr.
Blood
ISSN
1528-0020
DOI
10.1182/blood-2008-09-180596
Published
2009-03-19
Epub
2009-00-09
Pages
2826-34
Language
English
Region
United States
NLM ID
7603509
PMCID
PMC2661865
Subset
IM
Grants
NHLBI NIH HHS · T32-HL07262 · United States
NIDDK NIH HHS · P30 DK072442 · United States
NIDDK NIH HHS · T32-DK07556 · United States
NHLBI NIH HHS · HL63357 · United States
NCI NIH HHS · CA21765 · United States
NIDDK NIH HHS · T32 DK007556 · United States
NHLBI NIH HHS · T32 HL007262 · United States
NIDDK NIH HHS · R01 DK086267 · United States
NCI NIH HHS · P30 CA021765 · United States
NHLBI NIH HHS · P01 HL063357 · United States
NHLBI NIH HHS · N01-HV-28 186 · United States
NIDDK NIH HHS · DK072442 · United States
External Links
PubMed source DOI: 10.1182/blood-2008-09-180596 PMC Full Text View journal details
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