Enhanced FLI1 accessibility mediates STAG2-mutant leukemogenesis

Abstract

Transcription factors (TFs) influencing cell fate can be dysregulated in cancer. FLI1 is crucial for hematopoietic stem/progenitor cell (HSPC) function, with STAG2 regulating FLI1 target accessibility. STAG2 depletion enhances HSPC self-renewal, but its role in leukemic transformation is unclear. We uncovered that STAG2 loss maintains FLI1 target accessibility in murine HSPCs and enhances FLI1 binding in NPM1c leukemia. In our Stag2/Npm1c/+ murine model, myeloid-biased HSPCs with increased FLI1 accessibility are reservoirs for transformation, leading to a fully penetrant leukemia. STAG2 deleted NPM1c cell lines exhibit increased chromatin accessibility and chromatin-looping of key stem and leukemia genes including FLI1-target genes CD34 and MEN1. Similarly, enrichment for a CD34+ immunophenotype was observed in co-mutant leukemia patients. STAG2 deficient cells show increased chromatin-bound MENIN and increased sensitivity to MENIN inhibition. Our findings demonstrate that altered chromatin architecture can co-opt oncogenic TF signaling, such as FLI1, as a hallmark of leukemogenesis.

Key findings: Loss of STAG2 results in aberrant increased accessibility at FLI1 targets in mouse and human hematopoietic stem and progenitor cellsIncreased accessibility results in an increased fraction of chromatin-bound FLI1, which overlap with NPM1c targets in STAG2 NPM1c AML cellsStag2 Npm1c co-mutation leads to dysplastic murine AML phenotype arising from myeloid biased progenitors that exhibit increased Fli1 target accessibilityIn addition to higher chromatin-bound FLI1, co-mutant cells have higher chromatin-bound MENIN, including at the HOXA cluster, rendering cells highly sensitive to MENIN inhibition.

Statement of significance: Here, we identify enhanced FLI1 chromatin accessibility as a driver of stemness and leukemic transformation in STAG2 mutant leukemia. Through comprehensive in vivo and in vitro modeling, we demonstrate that altered chromatin architecture can co-opt oncogenic TF activity, like FLI1, to drive divergent leukemia development and therapeutic response.