Suppressors and activators of JAK-STAT signaling at diagnosis and relapse of acute lymphoblastic leukemia in Down syndrome

Significance Children with Down syndrome are at increased risk for B-cell acute lymphoblastic leukemia (DS-ALL), often expressing cytokine receptor-like factor 2 (CRLF2). Here we studied matched diagnosis and relapse DS-ALLs to understand the pathogenesis of relapse. We confirm that enhanced JAK-STAT signaling frequently “drives” CRLF2 pos DS-ALL at diagnosis, but discovered that clones with JAK mutations are unstable, suggesting that they also endowed the transformed cells with vulnerabilities. We find USP9X loss in up to 25% of CRLF2 pos ALLs, and demonstrate that its ablation decreases the toxic effect of JAK2 hypersignaling. Thus, in CRLF2 pos ALLs JAK-STAT signaling is often buffered by loss of USP9X. These results have therapeutic implications because they suggest that ALL cells can tolerate a limited range of JAK-STAT signaling.