STAT5 is abnormally activated in patients with acute lymphoblastic leukemia, and increased STAT5 activation synergizes with PAX5 and EBF1 to induce disease.

The transcription factor STAT5 plays a critical role in B cell acute lymphoblastic leukemia (B-ALL). How STAT5 mediates this effect is unclear. Here we demonstrate that STAT5 activation cooperates with defects in the pre-BCR signaling components encoded by Blnk, Btk, Prkcb, Nfkb1, and Ikzf1 to initiate B-ALL. STAT5 antagonizes NF-κB and IKAROS by opposing regulation of shared target genes. STAT5 binding was enriched at super-enhancers, which were associated with an opposing network of transcription factors, including PAX5, EBF1, PU.1, IRF4, and IKAROS. Patients with high ratios of active STAT5 to NF-κB or IKAROS have more aggressive disease. Our studies illustrate that an imbalance of two opposing transcriptional programs drive B-ALL, and suggest that restoring the balance of these pathways may inhibit B-ALL.

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The transcription factor signal transducer and activator of transcription 5 (STAT5) is activated by a number of cytokine and growth hormone receptors and plays a key role in the development and function of many organ systems. In this review, we focus on recent discoveries about the role of STAT5 in the development and function of B and T lymphocytes. Of particular interest is the growing appreciation for the function of STAT5 as a transcriptional repressor. Finally, we discuss recent discoveries about the role of STAT5 in transformation of B and T lymphocytes.

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Mice expressing a constitutively active form of STAT5b (Stat5b-CA mice) develop pre-B leukemia with low frequency (~1-2%). Microarray analysis of these leukemias shows decreased expression of genes involved in pre-BCR signaling. Stat5b-CA mice crossed to mice with defects in a coherent signaling pathway downstream of the pre-BCR involving BLNK, BTK, or PKCβ developed pre-B leukemia in > 75% of progeny. These leukemias exhibited reduced expression of a subset of NFκB target genes, which was important for transformation as Stat5b-CA x Nfkb1-/- mice also developed pre-B leukemia. Our results point to an unexpected role for NFκB1 as a tumor suppressor in pre-B cells. Microarrary analysis revealed that STAT5 activation resulted in reduced expression of several NFκB and FOXO target genes, thereby antagonizing these tumor suppressor pathways. To examine this regulation in further detail, we performed ChIP-seq analysis, which showed that STAT5 binds 38% of NFκB target genes that are expressed in pre-B cells. We also observed binding of STAT5 to several FOXO targets including: Foxo1, Cdkn1a, Cdkn2d, Blnk, Vegfa, Cxcr4, Bim, and Dgka. We have validated STAT5 binding to the FOXO targets Foxo1 and Cdkn2d and the NFκB targets Nfkb1, Rel, Irf4, Irf8, Ikzf1, and Ikzf3 by ChIP-qPCR. Our findings demonstrate that STAT5 activation antagonizes the pre-BCR-dependent NFκB and FOXO tumor suppressor pathways that limit pre-B cell proliferation and promote pre-B cell differentiation.