STAT5 Gain-of-Function Mutations Promote Precursor T-Cell Receptor Activation to Drive Immature T-Lymphoblastic Leukemia or Lymphoma

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive immature T-cell cancer. Hotspot mutations in JAK-STAT pathway members IL7R, JAK1 and JAK3 were analyzed in depth, but the role of STAT5A or STAT5B in T-cell development or T-ALL transformation is unclear. Importantly, the driver mutation STAT5BN642H encodes the most frequent activating STAT5 variant in T-ALL and it correlated with disease relapse upon chemotherapy. Here, we show that STAT5BN642H promotes T-ALL-like cancer in mice and transcriptionally upregulates a collection of genes that are involved in T-cell receptor signaling (TCR), even in the absence of surface TCR. Importantly, these genes were also overexpressed in human T-ALL patients. Moreover, T-ALL cells were sensitive to pharmacologic inhibition of STAT3/5 or ZAP70 activity. Collectively, we discovered how hyperactive STAT5 induces and accelerates T-ALL and we suggest therapeutic targeting using selective ZAP70 or STAT5 activity inhibitors in a subgroup of T-ALL patients with prominent IL-7R-JAK1/3-STAT5 activity. Overall design: STAT5B ChIP-seq data from human T-ALL cell lines with high or low STAT5 activation