biostudies-literatureSun WHHS | National Institutes of HealthAmerican Cancer SocietyAlex's Lemonade Stand Foundation for Childhood CancerNIAID NIH HHSNCI NIH HHSNIGMS NIH HHS501-514https://www.ebi.ac.uk/biostudies/studies/S-EPMC8983472biostudies-literatureUnknown20(4)Growth factor independence-1 (GFI1) is a transcriptional repressor and master regulator of normal and malignant hematopoiesis. Repression by GFI1 is attributable to recruitment of LSD1-containing protein complexes via its SNAG domain. However, the full complement of GFI1 partners in transcriptional control is not known. We show that in T-acute lymphoblastic leukemia (ALL) cells, GFI1 and IKAROS are transcriptional partners that co-occupy regulatory regions of hallmark T-cell development genes. Transcriptional profiling reveals a subset of genes directly transactivated through the GFI1-IKAROS partnership. Among these is NOTCH3, a key factor in T-ALL pathogenesis. Surprisingly, NOTCH3 expression by GFI1 and IKAROS requires the GFI1 SNAG domain but occurs independent of SNAG-LSD1 binding. GFIMolecular cancer research : MCRGFI1 Cooperates with IKZF1/IKAROS to Activate Gene Expression in T-cell Acute Lymphoblastic Leukemia.PMC8983472P30 CA042014R01CA201235R01AI100873R01 GM122778R01 AI100873R01GM122778R01 CA201235P30CA042014Cairns BREngel MEGuo JTantin DBareyan DPoeschla ASun WCasey MJMcClellan DfalseGFI1 Cooperates with IKZF1/IKAROS to Activate Gene Expression in T-cell Acute Lymphoblastic Leukemia.Growth factor independence-1 (GFI1) is a transcriptional repressor and master regulator of normal and malignant hematopoiesis. Repression by GFI1 is attributable to recruitment of LSD1-containing protein complexes via its SNAG domain. However, the full complement of GFI1 partners in transcriptional control is not known. We show that in T-acute lymphoblastic leukemia (ALL) cells, GFI1 and IKAROS are transcriptional partners that co-occupy regulatory regions of hallmark T-cell development genes. Transcriptional profiling reveals a subset of genes directly transactivated through the GFI1-IKAROS partnership. Among these is NOTCH3, a key factor in T-ALL pathogenesis. Surprisingly, NOTCH3 expression by GFI1 and IKAROS requires the GFI1 SNAG domain but occurs independent of SNAG-LSD1 binding. GFI2022-01-01T00:00:00Z2022 Apr2026-06-01T02:23:22.409Z2025-04-05T20:47:40.604ZS-EPMC89834723498059510.1158/1541-7786.MCR-21-035210.1158/1541-7786.mcr-21-0352