Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
Cancer Program, Broad Institute, Cambridge, Massachusetts, USA.
JCI Insight. 2021 Feb 8;6(3):142149. doi: 10.1172/jci.insight.142149.
The cohesin complex plays an essential role in chromosome maintenance and transcriptional regulation. Recurrent somatic mutations in the cohesin complex are frequent genetic drivers in cancer, including myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). Here, using genetic dependency screens of stromal antigen 2-mutant (STAG2-mutant) AML, we identified DNA damage repair and replication as genetic dependencies in cohesin-mutant cells. We demonstrated increased levels of DNA damage and sensitivity of cohesin-mutant cells to poly(ADP-ribose) polymerase (PARP) inhibition. We developed a mouse model of MDS in which Stag2 mutations arose as clonal secondary lesions in the background of clonal hematopoiesis driven by tet methylcytosine dioxygenase 2 (Tet2) mutations and demonstrated selective depletion of cohesin-mutant cells with PARP inhibition in vivo. Finally, we demonstrated a shift from STAG2- to STAG1-containing cohesin complexes in cohesin-mutant cells, which was associated with longer DNA loop extrusion, more intermixing of chromatin compartments, and increased interaction with PARP and replication protein A complex. Our findings inform the biology and therapeutic opportunities for cohesin-mutant malignancies.
黏连蛋白复合物在染色体维持和转录调控中发挥着重要作用。黏连蛋白复合物中的反复体细胞突变是癌症（包括骨髓增生异常综合征（MDS）和急性髓系白血病（AML））的常见遗传驱动因素。在这里，我们通过基质抗原 2 突变（STAG2 突变）AML 的遗传依赖性筛选，确定了 DNA 损伤修复和复制是黏连蛋白突变细胞的遗传依赖性。我们证明了黏连蛋白突变细胞中 DNA 损伤水平增加，对聚（ADP-核糖）聚合酶（PARP）抑制剂的敏感性增加。我们开发了一种 MDS 的小鼠模型，在该模型中，Stag2 突变作为 Tet 甲基胞嘧啶双加氧酶 2（Tet2）突变驱动的克隆性造血背景下的克隆性二次病变而出现，并在体内证明了 PARP 抑制对黏连蛋白突变细胞的选择性耗竭。最后，我们证明了黏连蛋白突变细胞中 STAG2 到 STAG1 包含的黏连蛋白复合物的转变，这与更长的 DNA 环挤出、染色质区室的更多混合以及与 PARP 和复制蛋白 A 复合物的相互作用增加有关。我们的发现为黏连蛋白突变恶性肿瘤的生物学和治疗机会提供了信息。
