2. Academic Validation
  3. Genome-wide CRISPR screen identifies IRF1 and TFAP4 as transcriptional regulators of Galectin-9 in T cell acute lymphoblastic leukemia

Genome-wide CRISPR screen identifies IRF1 and TFAP4 as transcriptional regulators of Galectin-9 in T cell acute lymphoblastic leukemia

  • Sci Adv. 2025 Mar 21;11(12):eads8351. doi: 10.1126/sciadv.ads8351.
Caroline R M Wiggers 1 2,  Burak Yüzügüldü 1 2,  Nathanial G Tadros 3,  Tayla B Heavican-Foral 1 2,  Eugene Y Cho 1,  Zachary C Eisenbies 1,  Merve Ozdemir 1,  Steffen B Kulp 3,  Yun-Cheol Chae 4,  Alejandro Gutierrez 4,  Jens G Lohr 2 3 5 6,  Birgit Knoechel 1 2 5 6 7
Affiliations

Affiliations

  • 1 Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • 2 Harvard Medical School, Boston, MA, USA.
  • 3 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • 4 Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN, USA.
  • 5 Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • 6 Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.
  • 7 Department of Hematology/Oncology, Boston Children's Hospital, Boston, MA, USA.
PMID: 40106574 DOI: 10.1126/sciadv.ads8351
Abstract

Galectin-9 is overexpressed in a variety of cancers and associated with worse clinical outcome in some cancers. However, the regulators driving Galectin-9 expression are unknown. Here, we defined the transcriptional regulators and epigenetic circuitry of Galectin-9 in pediatric T cell acute lymphoblastic leukemia (T-ALL), as an example of a disease with strong Galectin-9 expression, in which higher expression was associated with lower overall survival. By performing a genome-wide CRISPR screen, we identified the transcription factors IRF1 and TFAP4 as key regulators for Galectin-9 expression by binding its regulatory elements. Whereas IRF1 was observed exclusively on the promoter, TFAP4 binding was detected at an enhancer solely in T-ALL cells associated with higher Galectin-9 levels. Together, our results show that IRF1 is responsible and indispensable for Galectin-9 expression and TFAP4 further fine-tunes its expression. Our approach, a flow-based genome-wide CRISPR screen complemented by transcription factor binding and enhancer mapping, creates innovative opportunities for understanding and manipulating epigenetic transcriptional regulation in Cancer.

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