USP22 is a novel vulnerability regulating MEIS1 protein abundance and gene transcription in KMT2Ar acute leukemia

The resulting KMT2A fusion proteins dysregulate gene expression, leading to an upregulation of leukemogenic transcription factors such as HOXA9 and MEIS1, which drives leukemic transformation. Although Menin inhibitors are proving to be promising new therapeutics for patients with KMT2A-rearranged (KMT2Ar) acute leukemia, resistance mechanisms have already been described and new therapeutic approaches for this patient subgroup must be identified.

Here, a genome-wide CRISPR/Cas9 screen in a KMT2Ar B-cell acute lymphoblastic leukemia (ALL) cell line identified the deubiquitinase USP22 as a novel regulator of MEIS1 protein stability. USP22 is a member of the Spt-Ada-Gcn5 acetyltransferase (SAGA) multiprotein complex, which has crucial functions in shaping the chromatin landscape and modulating transcription. Genetic depletion of USP22 impaired cellular growth and proliferation in KMT2Ar acute leukemia models.