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miR-181c regulates MCL1 and cell survival in GATA2 deficient cells.
Wang, Weixin; Chen, Rui; Droll, Stephenie; Barber, Emily; Saleh, Layla; Corrigan-Cummins, Meghan; Trick, Megan; Anastas, Vollter; Hawk, Nga Voong; Zhao, Zhen; Vinh, Donald C; Hsu, Amy; Hickstein, Dennis D; Holland, Steven M; Calvo, Katherine R.
Afiliación
  • Wang W; Department of Laboratory Medicine, National Institutes of Health (NIH) Clinical Center, Bethesda, Maryland, USA.
  • Chen R; Department of Laboratory Medicine, Beijing Tong-Ren Hospital, Capital Medical University, Beijing, China.
  • Droll S; Department of Laboratory Medicine, National Institutes of Health (NIH) Clinical Center, Bethesda, Maryland, USA.
  • Barber E; Department of Laboratory Medicine, National Institutes of Health (NIH) Clinical Center, Bethesda, Maryland, USA.
  • Saleh L; Department of Laboratory Medicine, National Institutes of Health (NIH) Clinical Center, Bethesda, Maryland, USA.
  • Corrigan-Cummins M; Hematology Section, Clinical Pathology Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt.
  • Trick M; Department of Laboratory Medicine, National Institutes of Health (NIH) Clinical Center, Bethesda, Maryland, USA.
  • Anastas V; Department of Laboratory Medicine, National Institutes of Health (NIH) Clinical Center, Bethesda, Maryland, USA.
  • Hawk NV; Department of Laboratory Medicine, National Institutes of Health (NIH) Clinical Center, Bethesda, Maryland, USA.
  • Zhao Z; Experimental Transplantation and Immunology Branch, National Cancer Institute (NCI), NIH, Bethesda, Maryland, USA.
  • Vinh DC; Department of Laboratory Medicine, National Institutes of Health (NIH) Clinical Center, Bethesda, Maryland, USA.
  • Hsu A; Department of Pathology & Laboratory Medicine, Weill Cornell Medical College, New York, New York, USA.
  • Hickstein DD; Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD, USA.
  • Holland SM; Division of Infectious Diseases, McGill University Health Centre, Montreal, Canada.
  • Calvo KR; Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD, USA.
J Leukoc Biol ; 111(4): 805-816, 2022 04.
Article en En | MEDLINE | ID: mdl-34270823
GATA2 is a transcription factor critical for hematopoiesis. Germline mutations in GATA binding protein 2 (GATA2) led to haploinsufficiency, severe cytopenias of multiple cell lineages, susceptibility to infections and strong propensity to develop myelodysplastic syndrome, and acute myeloid leukemia. Mechanisms of progressive cytopenias remain unclear. MicroRNA (miRNA) represents a unique mechanism of post-transcriptional gene regulation. In this study, miRNA profiles were evaluated and eight miRNAs were found to be differentially expressed (≥2-fold, P ≤ 0.05) in patient-derived cell lines (N = 13) in comparison to controls (N = 10). miR-9, miR-181a-2-3p, miR-181c, miR-181c-3p, miR-486-3p, and miR-582 showed increased expression, whereas miR-223 and miR-424-3p showed decreased expression. Cell death assays indicated that miR-181c potently induces cell death in lymphoid (Ly-8 and SP-53) and myeloid (HL-60) cell lines. miR-181c was predicted to target myeloid cell leukemia (MCL)1, which was confirmed by transfection assays, resulting in significantly reduced MCL1 mRNA and decreased live cell numbers. Bone marrow analysis of 34 GATA2 patients showed significantly decreased cellularity, CD34-positive cells, monocytes, dendritic cells, NK cells, B cells, and B cell precursors in comparison to healthy controls (N = 29; P < 0.001 for each), which was accompanied by decreased levels of MCL1 (P < 0.05). GATA2 expression led to significant repression of miR-181c expression in transfection experiments. Conversely, knockdown of GATA2 led to increased miR-181c expression. These findings indicate that miR-181c expression is increased and MCL1 levels decreased in GATA2 deficiency cells, and that GATA2 represses miR-181c transcription. Increased miR-181c may contribute to elevated cell death and cytopenia in GATA2 deficiency potentially through down-regulation of MCL1.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: MicroARNs / Proteína 1 de la Secuencia de Leucemia de Células Mieloides / Deficiencia GATA2 Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: J Leukoc Biol Año: 2022 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: MicroARNs / Proteína 1 de la Secuencia de Leucemia de Células Mieloides / Deficiencia GATA2 Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: J Leukoc Biol Año: 2022 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido