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

ABSTRACT: Core binding factor (CBF) acute myeloid leukemias most commonly harbor the translocations t(8;21) or inv(16). Cohesin mutations are less commonly observed in inv(16) than in t(8;21), suggesting that they may negatively impact leukemic initiation or maintenance in this setting. We used a mouse model of inv(16) with haploinsufficiency of the cohesin subunit Smc3 and paradoxically found that inv(16);Smc3D/+ mice have a reduced leukemic latency compared to inv(16);Smc3+/+ mice, suggesting a role for cohesin loss in leukemic initiation or maintenance. Given the known role of cohesin haploinsufficiency in altering chromatin accessibility, we demonstrated an increase in chromatin accessibility in inv(16);Smc3 D/+ HSPCs prior to leukemia development, with an enrichment for Fli1 DNA binding motifs. We also observe an increase in Fli1 expression and enhanced Fli1 target expression in the most primitive hematopoietic stem cells using scRNA-seq, linking enhanced Fli1 activity in the inv(16);Smc3D/+ setting to leukemic initiation consistent with elevated RAS activity, which is common in inv(16) AML. We further show that Fli1 is essential for the maintenance stage of inv(16);Smc3D/+ AML. Our data demonstrate that cohesin loss drives both leukemic initiation and maintenance in inv(16) AML, identifying Fli1 as a previously unrecognized therapeutic vulnerability.

ORGANISM(S): Mus musculus

PROVIDER: GSE329080 | GEO | 2026/07/16

REPOSITORIES: GEO

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	GSE329080_MACS2Peaks.xlsx	Xlsx

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Project description:Background: Gene expression profiling has shown its ability to identify with high accuracy low cytogenetic risk acute myeloid leukemia such as acute promyelocytic leukemia and leukemias with t(8;21) or inv(16). The aim of this gene expression profiling study was to evaluate to what extent suboptimal samples with low leukemic blast load (range, 2-59%) and/or poor quality control criteria could also be correctly identified. Methods: Specific signatures were first defined so that all 71 acute promyelocytic leukemia, leukemia with t(8;21) or inv(16)-AML as well as cytogenetically normal acute myeloid leukemia samples with at least 60% blasts and good quality control criteria were correctly classified (training set). The classifiers were then evaluated for their ability to assign to the expected class 111 samples considered as suboptimal because of a low leukemic blast load (n=101) and/or poor quality control criteria (n=10) (test set). Results: With 10-marker classifiers, all training set samples as well as 97 of the 101 test samples with a low blast load, and all 10 samples with poor quality control criteria were correctly classified. Regarding test set samples, the overall error rate of the class prediction was below 4 percent, even though the leukemic blast load was as low as 2%. Sensitivity, specificity, negative and positive predictive values of the class assignments ranged from 91% to 100%. Of note, for acute promyelocytic leukemia and leukemias with t(8;21) or inv(16), the confidence level of the class assignment was influenced by the leukemic blast load. Conclusion: Gene expression profiling and a supervised method requiring 10-marker classifiers enable the identification of favorable cytogenetic risk acute myeloid leukemia even when samples contain low leukemic blast loads or display poor quality control criterion. Specific signatures were first defined so that all 71 acute promyelocytic leukemia, leukemia with t(8;21) or inv(16)-AML as well as cytogenetically normal acute myeloid leukemia samples with at least 60% blasts and good quality control criteria were correctly classified (training set). The classifiers were then evaluated for their ability to assign to the expected class 111 samples considered as suboptimal because of a low leukemic blast load (n=101) and/or poor quality control criteria (n=10) (test set).

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

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