University of Minnesota Ph.D. dissertation. August 2015. Major: Microbiology, Immunology and Cancer Biology. Advisor: Michael Farrar. 1 computer file (PDF); viii, 119 pages.B cell Acute Lymphoblastic Leukemia (B-ALL) arises from transformation of progenitor B cells. The transcription factor STAT5 plays a critical role in B-ALL, as high STAT5 activation is correlated with poor patient survival. How STAT5 mediates this effect is unclear. Previous studies suggested that STAT5 simply promotes the survival of progenitor B cells. However, other roles for STAT5 in B-ALL have not been explored. This study demonstrates that STAT5 activation drives leukemia in cooperation with defects in a linear signaling pathway emanating from the pre-BCR, including Blnk, Btk, Prkcb, Nfkb1, and Ikaros. Using microarray analysis and chromatin immunoprecipitation followed by high throughput sequencing (ChIP-seq), we demonstrate that STAT5 antagonizes NFκB and IKAROS by opposing regulation of shared target genes. High levels of STAT5 binding was enriched at super-enhancers that are typically associated with an opposing network of B cell transcription factors including PAX5, EBF1, PU.1, IRF4, or IKAROS. The antagonism between STAT5 and NFκB or IKAROS has direct clinical relevance as the balance between these transcription factors affects patient outcome. Patients with high ratios of active STAT5 to NFκB or IKAROS have more aggressive disease characterized by decreased survival. Our studies illustrate how modest perturbations in two opposing transcriptional programs have dramatic consequences for B cell transformation, and that the degree of antagonism between these transcriptional programs correlates with patient survival
