Human ASXL1-mutant hematopoiesis is driven by a truncated protein associated with aberrant de-ubiquitination of H2AK119.

Mutations in additional sex combs like 1 (ASXL1) confer poor prognosis both in myeloid malignancies and in pre-malignant clonal hematopoiesis (CH). However, the mechanisms by which these mutations contribute to disease initiation remain unresolved and mutation-specific targeting has remained elusive. To address this, we developed a human disease model that recapitulates the disease trajectory from ASXL1-mutant CH to lethal myeloid malignancy. We demonstrate that mutations in ASXL1 lead to the expression of a functional, truncated protein and determine that truncated ASXL1 leads to global redistribution of the repressive chromatin mark H2AK119Ub, increased transposase-accessible chromatin, and activation of both myeloid and stem cell gene expression programs. Finally, we demonstrate that H2AK119Ub levels are tied to truncated ASXL1 expression levels and leverage this observation to demonstrate that inhibition of the PRC1 complex might be an ASXL1-mutant specific therapeutic vulnerability both in pre-malignant CH and myeloid malignancy.