Chemotherapy induced signaling from bone marrow stromal cell niches aids survival of leukemia cells leading to disease recurrence

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Authors

• CD Chien
• S Nguyen
• E Jacoby
• H Qin
• TJ Fry

Abstract

Patients with Acute Lympoblastic Leukemia (ALL) that overexpress thymic stromal lymphopoietin receptor (TSLPR) have rates of relapse nearly double the rate of non-overexpressing patients. We hypothesize that TSLPR signaling in bone marrow stromal cell (BMSC) niches is driving relapse of ALL. To study this we developed a syngeneic transplantable model of high TSLPR expressing leukemia (TSLPRhigh). We found an 8-fold difference in the percentage of TSLPRhigh cells in the bone marrow (BM) when compared to parental cells (TSLPRlow) 5 days after implantation into mice. Interestingly, lethality endpoints and cell growth were no different between ALL lines indicating that TSLP does not alter proliferation. From this data we can infer that TSLP/TSLPR signaling is likely to be most critical at early stages of leukemia development when BM stromal niches are intact and not relevant once leukemia burden is high when the normal BM architecture is disrupted. We found that TSLP mRNA and protein were elevated in mice injected with IL-1alpha in the BM and serum respectively. Five days after injecting mice with ALL and IL-1alpha, we observed more TSLPRhigh ALL relative to TLSPRlow ALL implying that IL-1alpha induced TSLP levels to aid early progression of TSLPRhigh ALL. Chemotherapy is known to induce inflammatory cytokines and we found cytarabine was able to dramatically induce IL-1alpha expression from ALL cells while dexamethasone, an anti-inflammatory agent did not. In total, these experiments suggest that chemotherapeutic treatment of ALL could potentially provide an unintended advantage to TSLPR overexpressing ALL at stages of low disease burden.

Scientific Focus Area: Cancer Biology

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