STAT5 Gain-of-Function Variants Promote Precursor T-Cell Receptor Activation to Drive T-Cell Acute Lymphoblastic Leukemia

Abstract

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. However, the role of STAT5A or STAT5B mutations promoting their hyperactivation is poorly understood in the context of T-cell cancer initiation and acute leukemia progression. Importantly, the driver mutation STAT5BN642H encodes the most frequent activating STAT5 variant in T-ALL associated with poor prognosis. Here, we show that hyperactive STAT5 promotes early T-cell progenitor (ETP)-ALL-like cancer in mice and upregulated genes involved in T-cell receptor signaling (TCR), even in absence of surface TCR promoting. Importantly, these genes were also overexpressed in human T-ALL and other STAT5-dependent T-cell cancers. Moreover, human T-ALL cells were sensitive to pharmacologic inhibition by dual STAT3/5 degraders or ZAP70 tyrosine kinase blockers. Thus, we define STAT5 target genes in T-ALL that promote pre-TCR signaling mimicry. We propose therapeutic targeting using selective ZAP70 or STAT3/5 inhibitors in a subgroup of T-ALL patients with prominent IL-7R-JAK1/3-STAT5 activity.

ADGRE5-centered Tsurv model in T cells recognizes responders to neoadjuvant cancer immunotherapy

“…Astonishingly, only one replication of H9RET retained activation of ADGRE5, H9RETR and the control groups all failed, while IL32 remained strongly enriched under both conditions, which indicated that the regulation of STAT5 by ADGRE5 was stricter than that by IL32. Nevertheless, IL2-mediated STAT5 activation provides indirect evidence to some extent, and we further reanalyzed DEGs from Tobias et al They constructed the "gain-of-function" mutations STAT5A N642H and STAT5B S710F in CD8 + T cells via CRISPR/Cas9 and performed bulk RNA-seq on wild-type CD8 + T cells (97). Again, ADGRE5 was upregulated in STAT5 N642H and STAT5 S710F cells (Figure 3L), further confirming the positive regulatory effect of STAT5 on ADGRE5.…”