SF3B1 deficiency impairs human erythropoiesis via activation of p53 pathway: Implications for understanding of ineffective erythropoiesis in MDS

Yumin Huang, John Hale, Yaomei Wang, Wei Li, Shijie Zhang, Jieying Zhang, Huizhi Zhao, Xinhua Guo, Jing Liu, Hongxia Yan, Karina Yazdanbakhsh, Gang Huang, Christopher D. Hillyer, Narla Mohandas, Lixiang Chen, Ling Sun, Xiuli An

Producción científica: Articlerevisión exhaustiva

30 Citas (Scopus)

Resumen

Background: SF3B1 is a core component of splicing machinery. Mutations in SF3B1 are frequently found in myelodysplastic syndromes (MDS), particularly in patients with refractory anemia with ringed sideroblasts (RARS), characterized by isolated anemia. SF3B1 mutations have been implicated in the pathophysiology of RARS; however, the physiological function of SF3B1 in erythropoiesis remains unknown. Methods: shRNA-mediated approach was used to knockdown SF3B1 in human CD34+ cells. The effects of SF3B1 knockdown on human erythroid cell differentiation, cell cycle, and apoptosis were assessed by flow cytometry. RNA-seq, qRT-PCR, and western blot analyses were used to define the mechanisms of phenotypes following knockdown of SF3B1. Results: We document that SF3B1 knockdown in human CD34+ cells leads to increased apoptosis and cell cycle arrest of early-stage erythroid cells and generation of abnormally nucleated late-stage erythroblasts. RNA-seq analysis of SF3B1-knockdown erythroid progenitor CFU-E cells revealed altered splicing of an E3 ligase Makorin Ring Finger Protein 1 (MKRN1) and subsequent activation of p53 pathway. Importantly, ectopic expression of MKRN1 rescued SF3B1-knockdown-induced alterations. Decreased expression of genes involved in mitosis/cytokinesis pathway including polo-like kinase 1 (PLK1) was noted in SF3B1-knockdown polychromatic and orthochromatic erythroblasts comparing to control cells. Pharmacologic inhibition of PLK1 also led to generation of abnormally nucleated erythroblasts. Conclusions: These findings enabled us to identify novel roles for SF3B1 in human erythropoiesis and provided new insights into its role in regulating normal erythropoiesis. Furthermore, these findings have implications for improved understanding of ineffective erythropoiesis in MDS patients with SF3B1 mutations.

Idioma originalEnglish (US)
Número de artículo19
PublicaciónJournal of Hematology and Oncology
Volumen11
N.º1
DOI
EstadoPublished - feb 12 2018
Publicado de forma externa

ASJC Scopus subject areas

  • Molecular Biology
  • Hematology
  • Oncology
  • Cancer Research

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