Abstract 1347: A human-mouse xenograft model to study the role of TSLP in CRLF2d B-ALL

B-cell precursor ALL where genetic defects lead to overexpression of CRLF2 (CRLF2d B-ALL) are high-risk with poor prognosis. CRLFd B-ALL occurs 5 times more frequently among children of Hispanic/Latino ethnicity and is a major contributor to the health disparity in survival of Hispanic children with ALL. CRLF2, together with the IL-7Rα, forms a receptor complex that is activated by the cytokine, TSLP. The JAK-STAT5 pathway is phosphorylated downstream of receptor activation. The activating JAK mutations found in some CRLF2 B-ALL have led to speculation that TSLP stimulation is not a factor in CRLF B-ALL. In preliminary studies to address this question we evaluated the effect of TSLP on two CRLF2d B-ALL cell lines with JAK defects and which have been reported to exhibit constitutive JAK-STAT5 activation. Our data show that TSLP increases STAT5 phosphorylation in both of these cell lines and in primary B-ALL cells that overexpress CRLF2. Our next step was to evaluate the role of TSLP-CRLF2 interaction in vivo in the human-mouse xenograft model. However, mouse TSLP is different from most other cytokines produced in the xenograft in that it is species-specific and does not activate the human TSLP receptor complex that contains CRLF2. Thus, traditional xenograft models do not provide the TSLP-CRLF2 interactions that we believe to be a major factor in CRLF2 B-ALL. To overcome this obstacle we have engineered immune deficient NOD/SCID IL-2Rγ null (NSG) mice to express human TSLP (hTSLP+ mice) as well as control mice that lack the TSLP cytokine (hTSLP- mice). ELISA assays show plasma hTSLP levels in the hTSLP+ mice that approximate the normal range in human plasma. We have used this hTSLP+/− system to expand a sample of primary pre-B ALL cells from a patient that includes clones of CRLF2-HI and CRLF2- B-ALL cells. Preliminary data indicate that the pre-B ALL cells expanded in hTSLP+ mice show higher expression levels of the TSLPR components (CRLF2 and IL-7Rα) than cells expanded in the hTSLP- mice. This data provide evidence that the TSLP produced in this model is active and that it impacts primary pre-B ALL cells. The hTSLP+ mice that we produce will allow for the first time the study of normal and malignant B lymphopoiesis in a model that provides the complex bone marrow architecture of the xenograft while providing the full range of cytokines that are known to act on early B lineage cells (IL-7, FL and TSLP). This model will be particularly important for identifying therapies that can effectively target CRLF2-d B-ALL and reduce cancer health disparities in Hispanic childhood B-ALL. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1347. doi:1538-7445.AM2012-1347