Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
Curr Opin Hematol. 2021 Mar 1;28(2):73-79. doi: 10.1097/MOH.0000000000000632.
Mutations in components of the spliceosome are the most common acquired lesions in myelodysplastic syndromes (MDS) and are frequently identified in other myeloid malignancies with a high rate of progression to acute myeloid leukemia (AML) including chronic myelomonocytic leukemia and primary myelofibrosis. The only curative option for these disorders remains allogeneic stem-cell transplantation, which is associated with high morbidity and mortality in these patients. The purpose of this review is to highlight the recent therapeutic developments and strategies being pursued for clinical benefit in splicing factor mutant myeloid malignancies.
Cells harboring splicing factor mutations have increased aberrant splicing leading to R-loop formation and cell cycle stalling that create dependencies on Checkpoint kinase 1 (CHK1) activation and canonical splicing maintained by protein arginine methyltransferase activity. Both targeting of the spliceosome and targeting of the downstream consequences of splicing factor mutation expression show promise as selective strategies for the treatment of splicing factor-mutant myeloid malignancies.
An improved understanding of the therapeutic vulnerabilities in splicing factor-mutant MDS and AML has led to the development of clinical trials of small molecule inhibitors that target the spliceosome, ataxia telangectasia and Rad3 related (ATR)-CHK1 pathway, and methylation of splicing components.
目的综述：剪接体成分的突变是骨髓增生异常综合征（MDS）中最常见的获得性病变，并且经常在其他向急性髓系白血病（AML）进展率高的髓系恶性肿瘤中被识别，包括慢性髓单核细胞白血病和原发性骨髓纤维化。这些疾病唯一的治愈方法仍然是异基因造血干细胞移植，但在这些患者中，这种方法与高发病率和死亡率相关。本文的目的是强调最近在剪接因子突变的髓系恶性肿瘤中为获得临床获益而进行的治疗进展和策略。
最近的发现：携带剪接因子突变的细胞中存在更多的异常剪接，导致 R 环形成和细胞周期停滞，从而产生对检查点激酶 1（CHK1）激活和蛋白精氨酸甲基转移酶活性维持的经典剪接的依赖性。靶向剪接体和靶向剪接因子突变表达的下游后果都显示出作为治疗剪接因子突变的髓系恶性肿瘤的选择性策略的潜力。
总结：对剪接因子突变的 MDS 和 AML 的治疗弱点的理解的提高，导致了靶向剪接体、共济失调毛细血管扩张症和 Rad3 相关（ATR）-CHK1 途径以及剪接成分甲基化的小分子抑制剂的临床试验的发展。
