Identification of direct target genes of NUP98-KDM5A reveals regulatory gene networks in Acute Myeloid Leukemia

Oncogenic Nucleoporin 98 (NUP98) fusion proteins are recurrently found in pediatric acute myeloid leukemia (AML) with poor prognosis, but the molecular mechanisms of NUP98-fusion-driven leukemogenesis are unclear. We aimed to characterize transcriptional programs that govern the development and maintenance of NUP98-KDM5A-driven AML. A genome-scale CRISPR/Cas9 loss-of-function screen identified 4105 genes that were essential in NUP98-KDM5A-driven murine AML cells. To study direct transcriptional effects of NUP98-fusion-dependent gene regulation we developed a model for ligand-induced degradation of NUP98-KDM5A. Nascent RNA-seq upon fusion protein degradation identified 45 direct NUP98-KDM5A target genes, of which 12 were classified as essential for NUP98-KDM5A AML growth. RNA-seq analysis upon RNAi-induced knockdown revealed that a small subset of the 12 NUP98-KDM5A target genes was able to recapitulate global patterns of NUP98-KDM5A-induced gene deregulation. Further investigation of the interplay between core members of the NUP98-KDM5A effector network will lead to a better understanding of aberrant gene expression in NUP98-fusion AML and might identify novel therapeutic targets.

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Artikel online veröffentlicht:
17. Mai 2022