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<p>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 <i>Smc3</i>, we paradoxically found that inv(16); <i>Smc3</i><sup>Δ<i>/+</i></sup> mice have a reduced leukemic latency compared to inv(16); <i>Smc3</i><sup><i>+/+</i></sup> 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); <i>Smc3</i><sup>Δ<i>/+</i></sup> 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 <i>Fli1</i> expression and enhanced Fli1 target expression in ST-HSCs. We further show that Fli1 is essential for the maintenance stage of inv(16); <i>Smc3</i><sup>Δ<i>/+</i></sup> 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.</p>

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Cohesin haploinsufficiency and inv(16) cooperate to reinforce Fli1 gene transcriptional programs during acute myeloid leukemia initiation and maintenance

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月27日

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  • Alison E. Meyer,
  • Katelyn E. Heimbruch,
  • Kirthi Pulakanti,
  • Cary Stelloh,
  • Nataly Cruz-Rodriguez,
  • Josiah Murray,
  • Dandan Wang,
  • Lisa Latzko,
  • Sebastian Vosberg,
  • Philipp A. Greif,
  • Lucio H. Castilla,
  • John A. Pulikkan,
  • Subramaniam Malarkannan,
  • Sridhar Rao

摘要

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.