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Aberrant  HOXA9  expression is a hallmark of most aggressive acute leukemias, notably those with KMT2A (MLL) gene rearrangements.  HOXA9  overexpression not only predicts poor diagnosis and outcome but also plays a critical role in leukemia transformation and maintenance. However, our current understanding of  HOXA9  regulation in leukemia is limited, hindering development of therapeutic strategies. Here, we generated the  HOXA9-mCherry  knock-in reporter cell lines to dissect  HOXA9  regulation. By utilizing the reporter and CRISPR/Cas9 screens, we identified transcription factors controlling  HOXA9  expression, including a novel regulator, USF2, whose depletion significantly down-regulated  HOXA9  expression and impaired MLLr leukemia cell proliferation. Ectopic expression of Hoxa9 rescued impaired leukemia cell proliferation upon USF2 loss. Cut and Run analysis revealed the direct occupancy of USF2 at  HOXA9  promoter in MLLr leukemia cells. Collectively, the  HOXA9  reporter facilitated the functional interrogation of the  HOXA9  regulome and has advanced our understanding of the molecular regulation network in  HOXA9 -driven leukemia.

Functional interrogation of HOXA9 regulome in MLLr leukemia via reporter-based CRISPR/Cas9 screen