STAT5 antagonism of B cell superenhancer networks initiates progenitor B cell leukemia and predicts patient survival (HEM1P.222)

Abstract

Abstract B cell Acute Lymphoblastic Leukemia (B-ALL) arises from the transformation of progenitor B cells. The transcription factor STAT5 is required for transformation but how STAT5 mediates this effect is unclear. Previous studies suggested that STAT5 only acts to promote survival of progenitor B cells. However, other roles for STAT5 in B cell development and B-ALL have not been explored. Here we show 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 Ikzf1. Using microarray analysis and ChIP-Seq we demonstrate that STAT5 disrupts the function of superenhancer binding transcription factor networks that normally promote B cell development. STAT5 versus NFkB or IKAROS binding to these enhancers largely had opposing effects on target gene expression. The antagonism between STAT5 and IKAROS or NFκB 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 had more aggressive disease characterized by shorter remission and decreased survival. Thus, our studies illustrate how modest perturbations in two opposing transcriptional programs can have dramatic consequences for B cell development and transformation and how the degree of antagonism between these transcriptional programs ultimately predicts patient outcome to therapy.