Abstract 2372: Inflammatory cytokine induced TSLP from bone marrow niches contributes to relapse of high risk TSLPR overexpressing acute lymphoblastic leukemia
Authors: Christopher D. Chien, Sang Nguyen, Haiying Qin, Terry J. Fry
Journal: Cancer Research (2015)

Abstract Although 5 year survival rates are near 90%, leukemia is the most common cause of death from cancer in children with treatment failure primarily caused by relapse. A subset of acute lymphoblastic leukemia (ALL) patients that have an increased risk of relapse and consequently poorer overall survival have leukemia that overexpresses thymic stromal lymphopoietin receptor (TSLPR/CRLF2). However, it remains unclear what role Thymic Stromal Lymphopoietin (TLSP) signaling may play in increasing the risk of relapse. We hypothesize that TSLP/TSLPR axis may support progression of ALL by providing a signal through overexpressed TSLPR, which would sensitize the leukemia to low levels of the cytokine in bone marrow (BM) niches and promote the survival of the leukemia. We have created a high TSLPR expressing leukemia model (TSLPRhigh) through retroviral transduction of a transplantable syngeneic mouse ALL model (TSLPRlow) in which leukemia progression can be examined. This TSLPRhigh leukemia has expression of TSLPR comparable to what is found on patient derived ALL that naturally overexpress TSLPR and the receptor is functional as we see increased phosphorylation of STAT5 protein in response to TSLP stimulation. When ALL lines were injected into mice, we observed an 8 fold difference in the percentage of TSLPRhigh vs. TSLPRlow ALL in the BM 5 days after injection, where leukemia accounted for less than 4% of the BM corresponding to an early stage of ALL progression, whereas overall leukemia progression was not significantly different. This implies that the TSLP axis is most critical at low leukemic burden when bone marrow niches are intact and not disrupted by high levels of ALL in the BM. TSLPRlow and TSLPRhigh expressing cells show no significant difference in growth rate in vitro or in vivo, however when we treated ALL cells with chemotherapy in the absence or presence of TSLP we found that TSLP signaling significantly decreased the number of apoptotic cells in TSLPRhigh but not TSLPRlow ALL. These data suggest that high TSLPR expression sensitizes leukemia cells to TSLP to promote survival and not growth of ALL. This is significant because we believe that TSLP is likely to be expressed at low levels in the BM under normal circumstances. Interestingly, we have evidence using a nestin positive murine BM stromal cell line and stromal cells derived from fresh murine BM that TSLP mRNA and protein is induced by IL-1α and TNF-α stimulation. We further have found that cytarabine treatment of TSLPRhigh cells leads to induction of both IL-1α and TNF-α suggesting that chemotherapeutic treatment of ALL could potentially provide an unintended advantage to TSLPR overexpressing ALL. Based on this data, we postulate that therapies targeting the TSLP signaling axis in ALL would decrease the risk of relapse in TSLPR overexpressing ALL particularly in the context of standard therapy. Citation Format: Christopher D. Chien, Sang Nguyen, Haiying Qin, Terry J. Fry. Inflammatory cytokine induced TSLP from bone marrow niches contributes to relapse of high risk TSLPR overexpressing acute lymphoblastic leukemia. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2372. doi:10.1158/1538-7445.AM2015-2372