Fig. 5

Therapeutic targeting of mutant ASXL1 in myeloid malignancies. Mutated ASXL1 (MT-ASXL1) stabilizes BAP1, resulting in a hyperactive MT-ASXL1/BAP1 complex that demonstrates increased localization to leukemogenic loci and subsequent reduction of repressive H2AK119Ub1 and H3K27me3. Targeting BAP1 decreases MT-ASXL1/BAP1 complex leukemogenicity. MT-ASXL1/BAP1 complex also deubiquinates and stabilizes AKT, resulting in enhanced signaling through AKT/mTOR pathway, leading to HSC/HPC dysfunction, clonal hematopoiesis of indeterminate potential (CHIP), and increased risk of leukemogenesis. Pharmacologic inhibition of mTOR (i.e., rapamycin) abrogates abnormal hematopoiesis. MT-ASXL1 gains interaction with bromodomain-containing protein 4 (BRD4) leading to aberrant acetylation of H3 (e.g., H3K27 and H3K122Ac), marks associated with open chromatin and active transcription, leading to leukemogenic gene activation and HSC/HPC dysfunction. BET bromodomain inhibitors (BETis) reduce the levels of H3K122Ac and H3K27Ac and normalize HSC/HPC functions