GFI1 Cooperates with IKZF1/IKAROS to Activate Gene Expression in T-cell Acute Lymphoblastic Leukemia

Abstract

Abstract 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. GFI1 variants deficient in LSD1 binding fail to activate NOTCH3, but conversely, small molecules that disrupt the SNAG—LSD1 interaction while leaving the SNAG primary structure intact stimulate NOTCH3 expression. These results identify a noncanonical transcriptional control mechanism in T-ALL which supports GFI1-mediated transactivation in partnership with IKAROS and suggest competition between LSD1-containing repressive complexes and others favoring transactivation. Implications: Combinatorial diversity and cooperation between DNA binding proteins and complexes assembled by them can direct context-dependent transcriptional outputs to control cell fate and may offer new insights for therapeutic targeting in cancer.