The inhibitor of MyoD Family A (I-MFA) regulates megakaryocyte lineage commitment and terminal differentiation

IF 2.1 4区 医学 Q3 HEMATOLOGY Blood Cells Molecules and Diseases Pub Date : 2023-09-01 DOI:10.1016/j.bcmd.2023.102760
Jeremy S. Houser , Maulin Patel , Kyle Wright , Marta Onopiuk , Leonidas Tsiokas , Mary Beth Humphrey
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Abstract

Hematopoiesis and lineage commitment are regulated by several conserved cell-intrinsic signaling pathways, including MAPKs and β-catenin/TCF/LEF. The Inhibitor of MyoD Family A (I-MFA), a transcriptional repressor and tumor suppressor gene, interacts with these pathways and is dysregulated in chronic and acute myeloid leukemias, suggesting it may play a role in development and differentiation during hematopoiesis. To study this, immune cell populations in the bone marrow (BM) and periphery were analyzed in mice lacking Mdfi, encoding I-MFA (I-MFA−/−), and wild type (WT) controls. I-MFA−/− mice had reduced spleen and BM cellularity, with significant hyposplenism, compared to WT mice. In blood, total red blood cells and platelet counts were significantly reduced in I-MFA−/− mice, accompanied by a reduction in megakaryocyte (MK)/erythrocyte progenitor cells and an increase in myeloid progenitors in BM compared to WT mice. The K562 cell line exhibits PMA-induced MK differentiation, and shRNA knockdown of I-MFA resulted in reduced differentiation compared to control, with an increase and prolongation in phospho-JNK and phospho-ERK signaling. Overexpression of I-MFA promoted MK differentiation. These results suggest I-MFA plays a cell-intrinsic role in the response to differentiation signals, an effect that can be explored in the context of hematological cancers or other blood proliferative disorders.

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MyoD家族A抑制剂(I-MFA)调节巨核细胞谱系承诺和终末分化。
造血和谱系承诺由几种保守的细胞内在信号通路调节,包括MAPKs和β-连环蛋白/TCF/LEF。MyoD家族A抑制剂(I-MFA)是一种转录抑制因子和肿瘤抑制基因,与这些途径相互作用,在慢性和急性髓系白血病中失调,这表明它可能在造血过程中的发育和分化中发挥作用。为了研究这一点,在缺乏Mdfi、编码I-MFA(I-MFA-/-)和野生型(WT)对照的小鼠中分析了骨髓(BM)和外周的免疫细胞群。与WT小鼠相比,I-MFA-/-小鼠的脾脏和骨髓细胞减少,脾功能明显不足。在血液中,I-MFA-/-小鼠的总红细胞和血小板计数显著降低,与WT小鼠相比,BM中的巨核细胞(MK)/红细胞祖细胞减少,骨髓祖细胞增加。K562细胞系表现出PMA诱导的MK分化,与对照相比,I-MFA的shRNA敲低导致分化减少,磷酸化JNK和磷酸化ERK信号增加和延长。I-MFA的过表达促进了MK的分化。这些结果表明,I-MFA在对分化信号的反应中起着细胞固有的作用,这种作用可以在血液学癌症或其他血液增殖性疾病的背景下进行探索。
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来源期刊
CiteScore
4.90
自引率
0.00%
发文量
42
审稿时长
14 days
期刊介绍: Blood Cells, Molecules & Diseases emphasizes not only blood cells, but also covers the molecular basis of hematologic disease and studies of the diseases themselves. This is an invaluable resource to all those interested in the study of hematology, cell biology, immunology, and human genetics.
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