Amlexanox Downregulates S100A6 to Sensitize <i>KMT2A/AFF1</i>-Positive Acute Lymphoblastic Leukemia to TNFα Treatment

Abstract

Acute lymphoblastic leukemias (ALL) positive for <i>KMT2A/AFF1</i> (<i>MLL/AF4</i>) 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 <i>KMT2A/AFF1</i>-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 <i>KMT2A/AFF1</i>-positive transgenic (Tg) mice, amlexanox enhanced tumor immunity and lowered the penetrance of leukemia development. Similarly, in a NOD/SCID mouse model of human <i>KMT2A/AFF1</i>-positive ALL, amlexanox broadened GVL responses and extended survival. Our findings show how amlexanox degrades the resistance of <i>KMT2A/AFF1</i>-positive ALL to TNFα by downregulating S100A6 expression, with immediate potential implications for improving clinical management of <i>KMT2A/AFF1</i>-positive ALL. <i>Cancer Res; 77(16); 4426-33. ©2017 AACR</i>.