Transcriptome analysis of CD34+ cells from myelodysplastic syndrome patients

Ou, Ruiming; Huang, Jing; Shen, Huijuan; Li, Zhi; Zhu, Yongjian; Zhong, Qi; Zheng, Li; Yao, Mengdong; She, Yanling; Zhou, Shanyao; Chen, Rui; Li, Cheng; Zhang, Qing; Liu, Shuang

doi:10.1016/j.leukres.2017.09.003

Cited by 1 publication

(1 citation statement)

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“…MacroH2A1 and PARP1 activities have been independently implicated in ribosome assembly [35][36][37]. Mutational [38] and transcriptomic [39] approaches have not fully clarified yet the role of del(5q) in MDS pathogenesis; however, CSNK1A1 [40] and RPS14 [41] have been identified as strong promising therapeutic targets. Hematopoietic differences observed in macroH2A1.1 haploinsufficient and macroH2A1.1-deleted mice have been similarly reported in a murine model displaying conditional inactivation of CSNK1A1 [40].…”

Section: Discussionmentioning

confidence: 99%

Deficiency and haploinsufficiency of histone macroH2A1.1 in mice recapitulate hematopoietic defects of human myelodysplastic syndrome

Bereshchenko

Nikulenkov

et al. 2019

Clin Epigenet

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Background: Epigenetic regulation is important in hematopoiesis, but the involvement of histone variants is poorly understood. Myelodysplastic syndromes (MDS) are heterogeneous clonal hematopoietic stem cell (HSC) disorders characterized by ineffective hematopoiesis. MacroH2A1.1 is a histone H2A variant that negatively correlates with the self-renewal capacity of embryonic, adult, and cancer stem cells. MacroH2A1.1 is a target of the frequent U2AF1 S34F mutation in MDS. The role of macroH2A1.1 in hematopoiesis is unclear. Results: MacroH2A1.1 mRNA levels are significantly decreased in patients with low-risk MDS presenting with chromosomal 5q deletion and myeloid cytopenias and tend to be decreased in MDS patients carrying the U2AF1 S34F mutation. Using an innovative mouse allele lacking the macroH2A1.1 alternatively spliced exon, we investigated whether macroH2A1.1 regulates HSC homeostasis and differentiation. The lack of macroH2A1.1 decreased while macroH2A1.1 haploinsufficiency increased HSC frequency upon irradiation. Moreover, bone marrow transplantation experiments showed that both deficiency and haploinsufficiency of macroH2A1.1 resulted in enhanced HSC differentiation along the myeloid lineage. Finally, RNA-sequencing analysis implicated macroH2A1.1-mediated regulation of ribosomal gene expression in HSC homeostasis. Conclusions: Together, our findings suggest a new epigenetic process contributing to hematopoiesis regulation. By combining clinical data with a discrete mutant mouse model and in vitro studies of human and mouse cells, we identify macroH2A1.1 as a key player in the cellular and molecular features of MDS. These data justify the exploration of macroH2A1.1 and associated proteins as therapeutic targets in hematological malignancies.

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