Leukemia-mutated proteins PHF6 and PHIP form a chromatin complex that represses myeloid leukemia stemness.

Myeloid leukemias are heterogeneous cancers with a diverse mutational landscape. Though many mutated genes fall within common protein complexes, some lack known functional partners and have unclear roles. PHF6 is a poorly-understood chromatin-binding protein with recurrent mutations that confer an unfavorable prognosis in acute and chronic myeloid leukemias. Here, using human knockout and rescue, we show that PHF6 is a transcriptional repressor that binds active chromatin and suppresses a stemness gene program. We dissect nine clinical missense mutations and show that all produce unstable, hypomorphic, or non-functional PHF6 protein. Guided by convergent lines of evidence, we identify PHIP, a newly recognized AML-mutated protein, as a functional partner of PHF6. We show that PHIP loss phenocopies PHF6 loss, and that PHF6 requires PHIP to occupy chromatin and exert downstream transcriptional effects. Our work unifies PHF6 and PHIP, two disparate leukemia-mutated proteins, into a common functional complex that suppresses AML stemness.