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Additional sex combs-like 1(ASXL1)interacts with BRCAI-associated protein 1(BAP1)deubiquitinase to oppose the polycomb repressive complex 1(PRC1)-mediated histone H2A ubiquitylation.Germline BAP1 mutations are found in a spectrum of human malignan-cies,while ASXL1 mutations recurrently occur in mye-loid neoplasm and are associated with poor prognosis.Nearly all ASXL1 mutations are heterozygous frameshift or nonsense mutations in the middle or to a less extent the C-terminal region,resulting in the production of C-terminally truncated mutant ASXL1 proteins.How ASXL1 regulates specific target genes and how the C-terminal truncation of ASXL1 promotes leukemogen-esis are unclear.Here,we report that ASXL1 interacts with forkhead transcription factors FOXK1 and FOXK2 to regulate a subset of FOXK1/K2 target genes.We show that the C-terminally truncated mutant ASXL1 proteins are expressed at much higher levels than the wild-type protein in ASXL1 heterozygous leukemia cells,and lose the ability to interact with FOXK1/K2.Specific deletion of the mutant allele eliminates the expression of C-termi-nally truncated ASXL1 and increases the association of wild-type ASXL1 with BAP1,thereby restoring the expression of BAP1-ASXL1-FOXK1/K2 target genes,particularly those involved in glucose metabolism,oxy-gen sensing,and JAK-STAT3 signaling pathways.In addition to FOXK1/K2,we also identify other DNA-bind-ing transcription regulators including transcription fac-tors(TFs)which interact with wild-type ASXL1,but not C-terminally truncated mutant.Our results suggest that ASXL1 mutations result in neomorphic alleles that con-tribute to leukemogenesis at least in part through dom-inantly inhibiting the wild-type ASXL1 from interacting with BAP1 and thereby impairing the function of ASXL1-BAP1-TF in regulating target genes and leukemia cell growth.