Enhanced FLI1 accessibility mediates STAG2-mutant leukemogenesis
Listed in
This article is not in any list yet, why not save it to one of your lists.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 cells
-
Increased accessibility results in an increased fraction of chromatin-bound FLI1, which overlap with NPM1c targets in STAG2 NPM1c AML cells
-
Stag2 Npm1c co-mutation leads to dysplastic murine AML phenotype arising from myeloid biased progenitors that exhibit increased Fli1 target accessibility
-
In 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.
