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

被引：0

作者：

Wiggers, Caroline R. M. ^{[1
,2
]}

Yuzuguldu, Burak ^{[1
,2
]}

Tadros, Nathanial G. ^{[3
]}

Heavican-Foral, Tayla B. ^{[1
,2
]}

Cho, Eugene Y. ^{[1
]}

Eisenbies, Zachary C. ^{[1
]}

Ozdemir, Merve ^{[1
]}

Kulp, Steffen B. ^{[3
]}

Chae, Yun-Cheol ^{[4
]}

Gutierrez, Alejandro ^{[4
]}

Lohr, Jens G. ^{[2
,3
,5
,6
]}

Knoechel, Birgit ^{[1
,2
,5
,6
,7
]}

机构：

[1] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02215 USA

[2] Harvard Med Sch, Boston, MA 02115 USA

[3] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA

[4] St Jude Childrens Res Hosp, Dept Oncol, Memphis, TN USA

[5] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA

[6] Univ Utah, Huntsman Canc Inst, Salt Lake City, UT 84112 USA

[7] Boston Childrens Hosp, Dept Hematol Oncol, Boston, MA 02115 USA

来源：

SCIENCE ADVANCES | 2025年 / 11卷 / 12期

关键词：

WEB SERVER; TARGET; ACTIVATION; EXPRESSION; LANDSCAPE; EFFICIENT; PROGRAM;

D O I：

10.1126/sciadv.ads8351

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：15

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