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Genome-wide CRISPR screen of HoxA9 immortalised R26-CreERT2 Adar1fl/+ and R26-CreERT2 Adar1fl/E861A cells

ABSTRACT: ADAR1 E861A CRISPR knockout pooled library screen

ORGANISM(S): Mus musculus

PROVIDER: GSE233671 | GEO | 2024/11/21

REPOSITORIES: GEO

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Ggnbp2 and Ifih1 knockout in HoxA9 immortalised R26-CreERT2 Adar1fl/E861A myeliod cell line.

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Fractionation of sgControl, sgIfih1 and sgGgnbp2 in HoxA9 immortalized Rosa26-CreERT2 Adar1fl/E861A immortalised myeloid cells.

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Project description: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.

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