High-Dose TSLP Induces Co-Receptor Internalization and Signal Shutdown in Ph-like B-ALL with Overexpression of CRLF2

Background. Approximately half of all Ph-like B cell acute lymphoblastic leukemia is characterized by overexpression of CRLF2 (CRLF2 B-ALL). CRLF2 B-ALL is associated with high rates of relapse and is more prevalent in Hispanic children with Native American ancestry. CRLF2, together with the IL-7 receptor alpha (IL-7Ra), comprises a receptor complex that is activated by the cytokine, TSLP. Receptor activation by TSLP induces JAK2/STAT5 and PI3/AKT/mTOR signals that promote survival and proliferation of leukemia cells. To study the role of TSLP in CRLF2 B-ALL, we developed a patient-derived xenograft (PDX) model of CRLF2 B-ALL that allows us to vary circulating levels of human TSLP (hTSLP) in a physiologic environment. We generated PDX from patients' CRLF2 B-ALL cells and compared leukemia burden in mice with varying levels of hTSLP. CRLF2 B-ALL cells grew robustly in PDX models with hTSLP levels at or below levels present in pediatric cancer patients (~10 pg/mL). In contrast, CRLF2 B-ALL cells were essentially eliminated in PDXs with hTSLP at high physiological levels (40-140 pg/mL). These data suggest that high physiologic levels of TSLP exert a potent anti-leukemia effect in Ph-like B-ALL with overexpression of CRLF2.