USP22 deficiency leads to myeloid leukemia upon oncogenic Kras activation through a PU.1-dependent mechanism

Ras mutations are commonly observed in Juvenile Myelomonocytic Leukemia (JMML) and Chronic Myelomonocytic Leukemia (CMML). JMML and CMML transform into Acute Myeloid Leukemia (AML) in about 10% and 50% of patients respectively. However, how additional events cooperate with Ras to promote this transformation are largely unknown. We show that absence of the Ubiquitin-Specific-peptidase 22 (USP22), a component of the SAGA chromatin-remodeling complex linked to cancer progression, unexpectedly promotes AML transformation in mice expressing oncogenic Kras G12D/+ . USP22 deficiency in Kras G12D/+ mice resulted in shorter survival compared to control mice. This was due to a block in myeloid cell differentiation leading to the generation of AML. This effect was cell autonomous since mice transplanted with USP22-deficient Kras G12D/+ cells developed an aggressive disease and died rapidly. The transcriptome profile of USP22-deficient Kras G12D/+ progenitors resembled leukemic stem cells and was highly correlated with genes associated with poor prognosis in AML. We show that USP22 functions as a PU.1 deubiquitylase by positively regulating its protein stability and promoting the expression of PU.1 target genes. Reconstitution of PU.1 overexpression in USP22-deficient Kras G12D/+ progenitors rescued their differentiation. Our findings uncovered an unexpected role for USP22 in Ras-induced leukemogenesis and provide further insights into the function of USP22 in carcinogenesis.