<i>ARID5B</i> Influences Antimetabolite Drug Sensitivity and Prognosis of Acute Lymphoblastic Leukemia.

Abstract

Treatment outcomes for childhood acute lymphoblastic leukemia (ALL) have improved steadily, but a significant proportion of patients still experience relapse due to drug resistance, which is partly explained by inherited and/or somatic genetic alternations. Recently, we and others have identified genetic variants in the <i>ARID5B</i> gene associated with susceptibility to ALL and also with relapse. In this study, we sought to characterize the molecular pathway by which ARID5B affects antileukemic drug response in patients with ALL. We analyzed association of ARID5B expression in primary human ALL blasts with molecular subtypes and treatment outcome. Subsequent mechanistic studies were performed in ALL cell lines by manipulating <i>ARID5B</i> expression isogenically, in which we evaluated drug sensitivity, metabolism, and molecular signaling events. <i>ARID5B</i> expression varied substantially by ALL subtype, with the highest level being observed in hyperdiploid ALL. Lower <i>ARID5B</i> expression at diagnosis was associated with the risk of ALL relapse, and further reduction was noted at ALL relapse. In isogenic ALL cell models <i>in vitro</i>, <i>ARID5B</i> knockdown led to resistance specific to antimetabolite drugs (i.e., 6-mercaptopurine and methotrexate), without significantly affecting sensitivity to other antileukemic agents. <i>ARID5B</i> downregulation significantly inhibited ALL cell proliferation and caused partial cell-cycle arrest. At the molecular level, the cell-cycle checkpoint regulator p21 (encoded by <i>CDKN1A</i>) was most consistently modulated by ARID5B, plausibly as its direct transcription regulation target. Our data indicate that ARID5B is an important molecular determinant of antimetabolite drug sensitivity in ALL, in part, through p21-mediated effects on cell-cycle progression.