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| Home > Publications database > Cohesin haploinsufficiency and inv(16) cooperate to reinforce Fli1 gene transcriptional programs during acute myeloid leukemia initiation and maintenance. |
| Home > Publications database > Cohesin haploinsufficiency and inv(16) cooperate to reinforce Fli1 gene transcriptional programs during acute myeloid leukemia initiation and maintenance. |
| Journal Article | DKFZ-2026-01876 |
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2026
Springer Nature
London
Abstract: Core binding factor (CBF) acute myeloid leukemias typically harbor the translocations t(8;21) or inv(16). As cohesin mutations are less commonly observed with inv(16) than with t(8;21), we hypothesized that they may negatively impact inv(16)-driven AML. Using a mouse model of inv(16) with haploinsufficiency of the cohesin subunit Smc3, we paradoxically found that inv(16); Smc3Δ/+ mice have a reduced leukemic latency compared to inv(16); Smc3+/+ mice, disproving our initial hypothesis and instead suggesting a role for cohesin loss in enhancing inv(16)-driven disease. Consistent with the known role of cohesin haploinsufficiency in altering chromatin accessibility, we demonstrated an increase in chromatin accessibility in inv(16); Smc3Δ/+ hematopoietic stem and progenitor cells (HSPCs) prior to leukemia development, with an enrichment for Fli1 DNA binding motifs. Through scRNA-seq on pre-leukemic HSPCs, we observe an increase in Fli1 expression and enhanced Fli1 target expression in ST-HSCs. We further show that Fli1 is essential for the maintenance stage of inv(16); Smc3Δ/+ AML. Our data demonstrate a role for cohesin loss in enhancing the aggressiveness of inv(16)-driven AML and identify Fli1 as a previously unrecognized therapeutic vulnerability in cohesin-mutated AML.
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