Session: 614. Acute Lymphoblastic Leukemia: Therapy, excluding Transplantation: Poster III
Hematology Disease Topics & Pathways:
Biological, Therapies, Biological Processes, Clinically relevant, signal transduction
Objective. The objective of the proposed research was to evaluate potential mechanisms of TSLP’s anti-leukemia effects.
Research Design/Methods. TSLP dose response studies were performed and flow cytometry was used to evaluate the effect of TSLP on CRLF2 signaling, surface expression of TSLP receptor components (IL-7Ra and CRLF2) and expression of the Suppressor of Cytokine Signaling (SOCS) proteins in CRLF2 B-ALL cell lines (MUTZ5 and CALL-4) and CRLF2 B-ALL cells from Hispanic pediatric patients. Whole genome microarray was used to evaluate TSLP effects on SOCS gene expression in patient samples.
Results. CRLF2 B-ALL cell lines cultured with TSLP showed a dose-dependent loss in the ability to induce phosphorylation of STAT5 and S6 (downstream of PI3/AKT/mTOR) following TSLP stimulation. This loss was correlated with a complete loss of surface IL-7Ra, and maintained for 24-48 hours following a pulse of high-dose, but not low-dose, hTSLP. The loss of surface CRLF2 was minimal. The loss of signaling and surface IL-7Ra could be prolonged if high-dose hTSLP levels were maintained. Similarly, preliminary studies of CRLF2 B-ALL cells from pediatric patients showed a loss of surface IL-7Ra following culture with high-dose TSLP. A potential mechanism for the effects of high-dose TSLP are the suppressor of cytokine signaling (SOCS) genes. These genes encode a family of proteins (SOCS1-7 and CISH) that regulate cytokine signaling via negative feedback through multiple mechanisms including ubiquitin-mediated cytokine receptor degradation. Whole genome microarray showed that SOCS1, SOCS2, SOCS3 and CISH mRNA are upregulated in patient CRLF2 B-ALL cells cultured with high-dose TSLP. Flow cytometry analysis showed that high-dose TSLP upregulates SOCS1 and SOCS3 proteins in CRLF2 B-ALL cell lines and in patient samples.
Conclusion. These data provide evidence that TSLP exerts anti-leukemia effects by shutting down CRLF2-mediated signals and that these effects are at least partially mediated by the loss of the IL-7Ra component, and potentially through SOCS family proteins. These studies identify the human TSLP cytokine as a potential biologic therapy to treat CRLF2 B-ALL. Supported in part by 1R01CA209829 (KJP and SD), 1R43CA224723 (XM and KJP), ASH HONORS Award 2018-2019 (WBW), and Alpha Omega Alpha Carolyn L. Kuckein Student Research Fellowship 2018-2019 (WBW).
Disclosures: Coats: Elf Zone, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees. Meng: Elf Zone, Inc.: Employment. Dovat: Elf Zone, Inc.: Membership on an entity's Board of Directors or advisory committees. Payne: Elf Zone, Inc.: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees.
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