Language
English
Publication Date
10-30-2025
Journal
Experimental Hematology
DOI
10.1016/j.exphem.2025.105287
PMID
41173205
Abstract
Cohesin gene mutations occur in many malignancies, including acute myeloid leukemia (AML). Loss-of-function mutations in the four major cohesin complex genes (RAD21, SMC3, SMC1a, and STAG2) occur across most major genetic subtypes of AML but are notably absent in AML harboring CBFB::MYH11, suggesting that cohesin mutations yield distinct biological outcomes dependent on the genetic AML driver. We hypothesized that CBFB::MYH11-expressing leukemias would be dependent on intact cohesin genes given their near-mutual exclusivity. To investigate this, we combined either germline or inducible heterozygous deletions in cohesin genes Smc3 or Rad21, respectively, with an inducible murine model of Cbfb::MYH11 AML. This approach allowed us to evaluate the effects of cohesin haploinsufficiency on leukemia development, chromatin accessibility, and transcriptional output. We demonstrated that intact cohesin function is dispensable for Cbfb::MYH11-driven leukemia. Instead, Cbfb::MYH11 expression is the primary driver of the transcriptional program in transformed leukemic cells. Furthermore, we observed differential effects of Rad21 and Smc3 deletion on leukemia development and secondary engraftment despite only minor differences in gene expression. These results demonstrate that cohesin mutations are not only tolerated in Cbfb::MYH11-expressing cells, but they also likely do not confer a strong selective advantage and are therefore not preferentially selected for during clonal evolution of this leukemia.
Published Open-Access
yes
Recommended Citation
Conneely, Shannon E; Quezada, Alexis; Kurtz, Kristen J; et al., "Cohesin Haploinsufficiency Is Tolerated in Cbfb::MYH11-Driven Murine Acute Myeloid Leukemia" (2025). Faculty and Staff Publications. 4845.
https://digitalcommons.library.tmc.edu/baylor_docs/4845
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