Acute lymphoblastic leukemias (ALL) positive for () translocation, which constitute 60% of all infant ALL cases, have a poor prognosis even after allogeneic hematopoietic stem cell transplantation (allo-HSCT). This poor prognosis is due to one of two factors, either resistance to TNFα, which mediates a graft-versus-leukemia (GVL) response after allo-HSCT, or immune resistance due to upregulated expression of the immune escape factor S100A6. Here, we report an immune stimulatory effect against -positive ALL cells by treatment with the anti-allergy drug amlexanox, which we found to inhibit S100A6 expression in the presence of TNF-α. In -positive transgenic (Tg) mice, amlexanox enhanced tumor immunity and lowered the penetrance of leukemia development. Similarly, in a NOD/SCID mouse model of human -positive ALL, amlexanox broadened GVL responses and extended survival. Our findings show how amlexanox degrades the resistance of -positive ALL to TNFα by downregulating S100A6 expression, with immediate potential implications for improving clinical management of -positive ALL. .
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