Jang Yoonjeong, Feng Ruopeng, Palmer Lance E, Mayuranathan Thiyagaraj, Yao Yu, Mayberry Kalin, Zhou Sheng, Xu Jian, Gossett Jeffrey M, Kang Guolian, Cheng Yong, Yen Jonathan S, Weiss Mitchell J
Department of Hematology, St. Jude Children's Research Hospital, Memphis, TN.
Center for Stem Cell Research (a unit of inStem, Bengaluru), Christian Medical College Campus, Vellore, India.
Blood Adv. 2025 Jun 10;9(11):2722-2732. doi: 10.1182/bloodadvances.2024015574.
Genetic depletion of the transcriptional repressor BCL11A in red blood cell precursors alleviates β-hemoglobinopathies by inducing the fetal γ-globin genes. However, additional erythroid genes are regulated by BCL11A and the effects of its deficiency on erythropoiesis are insufficiently described. We discovered that Cas9 disruption of the BCL11A intron 2 erythroid enhancer in CD34+ hematopoietic stem and progenitor cells using a clinically approved strategy caused impaired expansion and apoptosis of erythroid precursors in vitro and reduced repopulation of the erythroid compartment after xenotransplantation into immunodeficient mice. Mutant colony-forming unit erythroid cells, proerythroblasts, and basophilic erythroblasts exhibited dysregulation of 94 genes (more than twofold change, false discovery rate < 0.05), 25 of which are likely direct targets of BCL11A. Differentially expressed genes were associated with a range of biological pathways that affect cell expansion and survival. Our findings reveal that BCL11A regulates additional aspects of erythropoiesis beyond γ-globin gene repression, with unknown clinical consequences.
红细胞前体中转录抑制因子BCL11A的基因缺失通过诱导胎儿γ-珠蛋白基因来缓解β-血红蛋白病。然而，其他红系基因也受BCL11A调控，其缺乏对红细胞生成的影响尚未得到充分描述。我们发现，使用临床批准的策略，在CD34+造血干细胞和祖细胞中对BCL11A内含子2红系增强子进行Cas9破坏，会导致体外红系前体细胞的扩增受损和凋亡，并减少异种移植到免疫缺陷小鼠后红系区室的再填充。突变的红细胞集落形成单位细胞、早幼红细胞和嗜碱性成红细胞表现出94个基因的失调（变化超过两倍，错误发现率<0.05），其中25个可能是BCL11A的直接靶点。差异表达基因与一系列影响细胞扩增和存活的生物学途径相关。我们的研究结果表明，BCL11A除了抑制γ-珠蛋白基因外，还调控红细胞生成的其他方面，其临床后果尚不清楚。
