Asxl1 mutation enhances differentiation in CSF3R-mutated myeloproliferative neoplasms [RNA-Seq]

ABSTRACT: Mutations in the epigenetic regulator Additional Sex Combs-Like 1 (ASXL1) are frequently observed in chronic neutrophilic leukemia (CNL). This disease is classically driven by activating mutations in Colony Stimulating Factor 3 Receptor (CSF3R), which promote the overproduction of neutrophils that characterizes this disease. Despite high rates of co-occurrence, the interplay between ASXL1 and CSF3R mutations in hematopoiesis and leukemia development remains poorly understood. Here, we present a new mouse model with both Asxl1Y588X and Csf3rT621I mutations, which recapitulates features of human CNL. Csf3r-mutant mice exhibit an age-associated depletion of hematopoietic stem and progenitor cells, which is reversed by the addition of Asxl1Y588X. This combination of mutations causes an expansion of myeloid-biased stem cells. As the mice age they develop neutrophilia, but leukemia is rare, suggesting additional mutations may be required for transformation. Using models of myeloid differentiation, we find that ASXL1 truncation enhances CSF3RT618I-driven neutrophil differentiation by downregulating MYC programs and activating inflammatory pathways associated with mature myeloid cell production. Moreover, cells with both mutations had increased priming of neutrophil-associated enhancers and reduced priming of enhancers associated with monocytic differentiation. Mutant ASXL1 is known to decrease genome-wide abundance of a repressive histone mark—H2AK119ub. While we see the expected decrease in H2AK119ub in Asxl1-mutant cells, this effect is reversed when CSF3R is also mutated, suggesting a complex interplay between these mutations in regulating chromatin dynamics during hematopoiesis. Our findings highlight context-dependent effects of ASXL1 mutation in myeloid disorders and provide insights into the mechanisms underlying neutrophil differentiation in ASXL1-mutant CNL.

ORGANISM(S): Mus musculus

PROVIDER: GSE266091 | GEO | 2025/01/22

REPOSITORIES: GEO