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Systematic characterization of the HOXA9 downstream targets in MLL-r leukemia by noncoding CRISPR screens

Author

Listed:
  • Shaela Wright

    (St. Jude Children’s Research Hospital)

  • Xujie Zhao

    (St. Jude Children’s Research Hospital
    Advanced Institute for Life and Health, Southeast University)

  • Wojciech Rosikiewicz

    (St. Jude Children’s Research Hospital)

  • Shelby Mryncza

    (Rhodes College)

  • Judith Hyle

    (St. Jude Children’s Research Hospital)

  • Wenjie Qi

    (St. Jude Children’s Research Hospital)

  • Zhenling Liu

    (St. Jude Children’s Research Hospital)

  • Siqi Yi

    (St. Jude Children’s Research Hospital)

  • Yong Cheng

    (St. Jude Children’s Research Hospital)

  • Beisi Xu

    (St. Jude Children’s Research Hospital)

  • Chunliang Li

    (St. Jude Children’s Research Hospital)

Abstract

Accumulating evidence indicates that HOXA9 dysregulation is necessary and sufficient for leukemic transformation and maintenance. However, it remains largely unknown how HOXA9, as a homeobox transcriptional factor, binds to noncoding regulatory sequences and controls the downstream genes. Here, we conduct dropout CRISPR screens against 229 HOXA9-bound peaks identified by ChIP-seq. Integrative data analysis identifies reproducible noncoding hits, including those located in the distal enhancer of FLT3 and intron of CDK6. The Cas9-editing and dCas9-KRAB silencing of the HOXA9-bound sites significantly reduce corresponding gene transcription and impair cell proliferation in vitro, and in vivo by transplantation into NSG female mice. In addition, RNA-seq, Q-PCR analysis, chromatin accessibility change, and chromatin conformation evaluation uncover the noncoding regulation mechanism of HOXA9 and its functional downstream genes. In summary, our work improves our understanding of how HOXA9-associated transcription programs reconstruct the regulatory network specifying MLL-r dependency.

Suggested Citation

  • Shaela Wright & Xujie Zhao & Wojciech Rosikiewicz & Shelby Mryncza & Judith Hyle & Wenjie Qi & Zhenling Liu & Siqi Yi & Yong Cheng & Beisi Xu & Chunliang Li, 2023. "Systematic characterization of the HOXA9 downstream targets in MLL-r leukemia by noncoding CRISPR screens," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-43264-5
    DOI: 10.1038/s41467-023-43264-5
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