Targeting the EIF2AK1 Signaling Pathway Rescues Red Blood Cell Production in SF3B1-Mutant Myelodysplastic Syndromes With Ringed Sideroblasts.
Targeting the EIF2AK1 Signaling Pathway Rescues Red Blood Cell Production in SF3B1-Mutant Myelodysplastic Syndromes With Ringed Sideroblasts.
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DOI：
10.1158/2643-3230.bcd-21-0220
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发表时间：
2022-11-02
影响因子：
11.2
通讯作者：
中科院分区：
文献类型：
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作者：
SF3B1突变的MDS-RS与红系祖细胞上调EIF2AK1相关的血红素缺乏反应和自噬基因有关。靶向EIF2AK1可缓解异常的祖细胞表型。SF3B1突变发生在20%的骨髓增生异常综合征(MDS)患者中，是一种特殊的MDS亚型的特征，即MDS伴环状铁粒母细胞(MDS-RS)，其特征是红系前体细胞在骨髓中聚集，主要影响老年人群。在这里，使用单细胞技术和对原始SF3B1突变MDS-RS样本的功能验证研究表明，SF3B1突变导致EIF2AK1途径激活，以应对血红素缺乏，靶向这一途径拯救了异常的红系分化，并使MDS-RS红细胞能够成熟。这些数据支持EIF2AK1抑制剂的开发，以克服红细胞产生受损的SF3B1突变MDS-RS患者的输血依赖。MDS-RS的特征是明显的贫血。MDS-RS患者死于红细胞短缺和铁超载的副作用，这是因为他们经常需要输血。我们的研究对开发治疗方法以实现持久的血液学反应具有重要意义。本文在本期特写中重点介绍，第476页
SF3B1-mutant MDS-RS is associated with buildup of erythroid progenitor cells upregulating EIF2AK1-associated heme deficiency response and autophagy genes. Targeting EIF2AK1 relieves the dysregulated progenitor phenotype. SF3B1 mutations, which occur in 20% of patients with myelodysplastic syndromes (MDS), are the hallmarks of a specific MDS subtype, MDS with ringed sideroblasts (MDS-RS), which is characterized by the accumulation of erythroid precursors in the bone marrow and primarily affects the elderly population. Here, using single-cell technologies and functional validation studies of primary SF3B1-mutant MDS-RS samples, we show that SF3B1 mutations lead to the activation of the EIF2AK1 pathway in response to heme deficiency and that targeting this pathway rescues aberrant erythroid differentiation and enables the red blood cell maturation of MDS-RS erythroblasts. These data support the development of EIF2AK1 inhibitors to overcome transfusion dependency in patients with SF3B1-mutant MDS-RS with impaired red blood cell production. MDS-RS are characterized by significant anemia. Patients with MDS-RS die from a shortage of red blood cells and the side effects of iron overload due to their constant need for transfusions. Our study has implications for the development of therapies to achieve long-lasting hematologic responses. This article is highlighted in the In This Issue feature, p. 476
具有SF3B1突变的髓样肿瘤的克隆轨迹和细胞动力学。
影响因子：
11.4
作者：
Awada H;Kerr CM;Durmaz A;Adema V;Gurnari C;Pagliuca S;Zawit M;Kongkiatkamon S;Rogers HJ;Saunthararajah Y;Sekeres MA;Carraway H;Maciejewski JP;Visconte V
通讯作者：
Visconte V