Cohesin haploinsufficiency is tolerated in Cbfb::MYH11-driven murine acute myeloid leukemia.

Cohesin Haploinsufficiency Promotes Reduced Latency in Inv(16) Acute Myeloid Leukemia

Combinatorial Genetic Uncovers DOCK1/RAC2 As Specific Targets for the Treatment of NPM1;Cohesin Mutated AML

Genomic Landscape of Pediatric CBF-AML By SNP-Array Karyotyping and Extensive Mutational Analysis

The prognostic impact of cohesin mutations in patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) is controversial. In patients with AML and MDS who underwent next-generation sequencing at the authors' center during 2017-2023, the authors assessed the landscape of cohesin mutations and the impact of co-occurring mutations on overall survival (OS) and compared outcomes between patients with cohesin mutations and those with wild-type (WT) cohesin genes. The study included 83 patients, 36 with cohesin mutations (STAG2, n=28; SMC1A, n=7; SMC3, n=3; co-expression of cohesin mutations, n=2) and 47 with WT cohesin genes. Of the 36 patients with cohesin mutations, 17 (47%) had AML (six de novo and 11 secondary), and 19 (53%) had MDS. Patients who had STAG2 mutations had better median OS than patients who had only SMC1A and SMC3 mutations (26 vs. 10 months; p=.043). SRSF2 mutation was the most frequent co-occurring mutation (n=12; 33%) and was associated with worse median OS than WT SRSF2 (13 vs. 43 months; p=.016). Seven patients (19%) with cohesin mutations underwent hematopoietic transplantation; their median OS was 70 months. Compared with the WT cohesin group, patients who had cohesin mutations were more likely to have adverse-risk AML (82% vs. 53%). The median OS was similar among patients with adverse-risk AML in the cohesin-mutation and WT cohesin groups (10 vs. 14 months, respectively; p=.9). The current study provides insight into the prognostic impact of cohesin mutations and co-occurring mutations in patients with myeloid malignancies.

The Clinical and Prognostic Influence Of Mutations In The Cohesin Complex In Acute Myeloid Leukemia

Subunit-Specific Analysis of Cohesin-Mutant Myeloid Malignancies Reveals Distinct Ontogeny and Outcomes

Genetic alterations of the cohesin complex genes in myeloid malignancies

Cohesin Complex Mutations Impair Differentiation of Human Hematopoietic Stem and Progenitor Cells

Cohesin Haploinsufficiency Drives Leukemic Initiation through Fli1 Upregulation in Inv(16) AML

e19007 Background: Mutations in the genes STAG1, STAG2, SMC1A, SMC3, and RAD21 which are part of the cohesin complex are recurrent in myelodysplastic syndrome and acute myeloid leukemia. The cohesin complex is involved in sister chromatid attachment during cell division and in DNA loop formation bringing enhancers and genes together. Prognosis and treatment efficacy for this subgroup has not been well studied in MDS or AML. We evaluated the treatment outcomes of a subgroup with cohesin mutations from a database of MDS and AML patients at the University of Massachusetts. Methods: We performed a retrospective analysis of adult patients with a new diagnosis of AML and/or MDS from 2015-2019 in the University of Massachusetts Leukemia Registry. Fisher’s exact test was used to compare initial response to treatment via induction chemotherapy or hypomethylating agents. Kaplan-Meier curves for overall survival were compared using the log-rank test. We considered < 5% blasts by morphology to be complete remission (regardless of hematologic recovery). Four patients who did not undergo treatment were excluded from treatment and survival analysis. Results: A total of 19 patients had mutations in a cohesin complex gene with one patient having mutations in both STAG2 and SMC1A. The cohesin complex mutation frequency was 9.95% (19 out of 191 patients) with STAG2 representing 70% of the mutations. First-line induction chemotherapy resulted in an improved rate of complete remission 83.3% compared to hypomethylating agents 0% (p = 0.002). For AML patients alone, there was improvement in complete response rate for induction chemotherapy vs. hypomethylating agents (p = 0.048). There was no overall survival benefit for induction chemotherapy compared to hypomethylating agents (44.4% vs 41.7% probability of survival at 2 years) with p = 0.87. Excluding the MDS patients, there was still no difference in overall survival with p = 0.63. Conclusions: In this retrospective analysis of cohesin complex-mutant MDS and AML, induction chemotherapy resulted in significantly improved complete remission rates compared to hypomethylating agents. There was no overall survival benefit. We also found one patient with simultaneous mutations in two cohesin genes while cohesin mutations were previously reported to be mutually exclusive. Further work looking at additional samples may be able to show induction chemotherapy is the treatment of choice for cohesin mutant AML.[Table: see text]

Characteristics and Clinical Outcomes of Patients with Myeloid Malignancies and Cohesin Mutations

Prognostic Impacts and Dynamic Changes of Cohesin Complex Gene Mutations in De Novo Acute Myeloid Leukemia

Impact of cohesin complex gene mutations on clinical outcomes in Acute Myeloid Leukemia

A subset of myeloid progenitors drives leukemogenesis in familial CEBPA-mutated acute myeloid leukaemia

Altered Hematopoietic Cell Gene Expression Identifies Patients at Risk for Development of Therapy-Related Leukemia (t-MDS/AML)