Recurrent mutations in multiple components of the cohesin complex in myeloid neoplasms

Abstract

Cohesin is a multimeric protein complex that is involved in the cohesion of sister chromatids, post-replicative DNA repair and transcriptional regulation. Here we report recurrent mutations and deletions involving multiple components of the cohesin complex, including STAG2, RAD21, SMC1A and SMC3, in different myeloid neoplasms. These mutations and deletions were mostly mutually exclusive and occurred in 12.1% (19/157) of acute myeloid leukemia, 8.0% (18/224) of myelodysplastic syndromes, 10.2% (9/88) of chronic myelomonocytic leukemia, 6.3% (4/64) of chronic myelogenous leukemia and 1.3% (1/77) of classical myeloproliferative neoplasms. Cohesin-mutated leukemic cells showed reduced amounts of chromatin-bound cohesin components, suggesting a substantial loss of cohesin binding sites on chromatin. The growth of leukemic cell lines harboring a mutation in RAD21 (Kasumi-1 cells) or having severely reduced expression of RAD21 and STAG2 (MOLM-13 cells) was suppressed by forced expression of wild-type RAD21 and wild-type RAD21 and STAG2, respectively. These findings suggest a role for compromised cohesin functions in myeloid leukemogenesis.

Chromosome Dynamics during Mitosis

“…Such trends will undoubtedly continue in the years to come. It will also be important to determine to what extent mutations or misregulation of cohesin and condensin subunits might contribute to human cancers (Ham et al 2007;Balbás-Martínez et al 2013;Guo et al 2013;Kon et al 2013;Solomon et al 2013). Third, and, finally, all issues described above need to be addressed, also, from an evolutionary point of view.…”

Loss of STAG2 causes aneuploidy in normal human bladder cells

“…Similarly, somatic mutation of STAG2 is rare in acute leukemias (Chung et al, 2012) and neuroblastoma tumors (Djos et al, 2013). In contrast, in myeloid neoplasms, recurrent mutations and deletions have been detected in another study (Kon et al, 2013). Although there is dispute concerning the mutation of STAG2 in other carcinomas, it is reported by many scientists that there is a frequent mutation of STAG2 in bladder cancer (Solomon et al, 2011(Solomon et al, , 2013Balbás-Martínez et al, 2013).…”

Epigenetic alterations in acute myeloid leukemias

“…Up to now, frequent mutations in cohesin subunits have been reported in MDS, chronic myelomonocytic leukemia, chronic myelogenous leukemia, and myeloproliferative neoplasms. Even though cohesin has a well-recognized role in sister chromatid segregation, myeloid malignancies with cohesin mutations have an aneuploid ratio that is similar to that in leukemias with other mutations [97]; thus, how altered function of cohesin is involved in AML and other malignant transformations has not been well elucidated. One of the proposed mechanisms by which cohesin plays a role in leukemia transformation is through its impact on the global genomic architecture.…”