Opposing effects of KDM6A and JDP2 on glucocorticoid sensitivity in T-ALL

Abstract

Glucocorticoids (GCs) are a cornerstone of acute lymphoblastic leukemia (ALL) therapy. While mutations in NR3C1, which encodes the GC receptor (GR), and other genes involved in GC signaling occur at relapse, additional mechanisms of adaptive GC resistance are uncertain. We transplanted and treated ten primary mouse T-lineage acute lymphoblastic leukemias (T-ALLs) initiated by retroviral insertional mutagenesis with the GC dexamethasone (DEX). Multiple, distinct relapsed clones from one such leukemia (T-ALL 8633) exhibited discrete retroviral integrations that up-regulated Jdp2 expression. This leukemia harbored a Kdm6a mutation. In the human T-ALL cell line CCRF-CEM, enforced JDP2 over-expression conferred GC resistance, while KDM6A inactivation unexpectedly enhanced GC sensitivity. In the context of KDM6A knock-out, JDP2 over-expression induced profound GC resistance, counteracting the sensitization conferred by KDM6A loss. These resistant "double mutant" cells with combined KDM6A loss and JDP2 over-expression exhibited decreased NR3C1 mRNA and GR protein up-regulation upon DEX exposure. Analysis of paired samples from two KDM6A-mutant T-ALL patients in a relapsed pediatric ALL cohort revealed a somatic NR3C1 mutation at relapse in one and markedly elevated JDP2 expression in another. Together, these data implicate JDP2 over-expression as a mechanism of adaptive GC resistance in T-ALL that functionally interacts with KDM6A inactivation.