Acute myeloid leukemia (AML) is characterized by uncontrolled proliferation of myeloid progenitors accompanied by a differentiation arrest. This aggressive bone marrow malignancy is a heterogeneous disease with the types of mutations and co-mutations playing a major role in determining the disease prognosis, risk, and patient outcome. PHF6 is one such leukemia-mutated protein, and while its molecular role is unclear, Phf6 loss from the hematopoietic system increases HSC self-renewal without malignant transformation. To understand the consequences of this phenotype in myeloid leukemias, we introduce Phf6 conditional knockout in two leukemia mouse models of chronic and acute myeloid leukemia. We observe that Phf6 loss in Flt3-ITD-driven mouse chronic myelomonocytic leukemia (CMML) converts CMML into overt AML with reduced survival. The conversion of the myeloid-biased chronic disease to the acute stem-like disease is evident through the transformation of myeloid dysplasia in infiltrated organs to sheets of blasts on AML transformation. We also show that in Hoxa9-driven AML model Phf6 loss increases the aggressiveness of leukemia over successive transplantations, by increasing the percentage and stemness-signature of its leukemia initiating cells (LIC-enriched or LIC-e). Finally, to understand the molecular mechanism of PHF6 in AML, we use genomic knockout and rescue of PHF6 in the THP-1 human monocytic leukemia cell line and the ER-HoxB8 mouse GMP cell line. We show that PHF6 is a transcriptional repressor and suppresses a stemness gene network. We also show that hematopoietic PHF6 missense mutations, which are currently clinically classified as variants, produce unstable or non-functional protein and contribute to the pathogenesis of the disease. Additionally, we present a novel finding backed by multiple lines of evidence showing the mechanistic and functional convergence between PHF6 and the newly identified AML-mutated protein PHIP. Through RNA-Seq and flow cytometry, we show that PHIP loss phenocopies PHF6 loss in both cell lines. We also showed that PHF6 requires PHIP to interact with the chromatin and perform its transcriptional function. In conclusion, our work highlights the regulatory function of PHF6 in leukemia stemness and unifies the molecular function of two disparate leukemia-mutated proteins, PHF6 and PHIP.