Polycomb factor PHF19 affects AML initiation, patient prognosis, and survival

Acute myeloid leukemia (AML) is marked by unchecked expansion of undifferentiated myeloid cells. Although oncogenic fusions such as MLL-AF9 can initiate disease, the early steps of leukemogenesis and the role of cell-intrinsic regulators remain unclear. We previously showed that the Polycomb-associated factor Phf19 is required for hematopoietic stem cell (HSC) maintenance and state control in mice and that its loss (Phf19^KO) impairs HSC function. To define Phf19's role in transformation, we expressed MLL-AF9 in Phf19^KO hematopoietic cells and performed integrated multiomic analyses. Phf19 deletion promoted acquisition of stemlike features and reduced responsiveness to differentiation-inducing AML therapies. Molecular and functional consequences of Phf19 loss paralleled those observed in the datasets of patients with AML. From these data, we derived a prognostic signature-PHFScore-which reveals previously unrecognized AML survival-correlating genes that robustly stratify patients across distinct cellular origins and leukemogenic stages, underscoring Phf19's key role in AML biology and prognosis.