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

Abstract

Glucocorticoids (GCs) are the cornerstone of acute lymphoblastic leukemia (ALL) therapy. Although 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 10 primary mouse T-lineage acute lymphoblastic leukemias (T-ALLs) initiated by retroviral insertional mutagenesis with GC dexamethasone (DEX). Multiple distinct relapsed clones from 1 such leukemia (T-ALL 8633) exhibited discrete retroviral integrations that upregulated Jdp2 expression. This leukemia harbored a Kdm6a mutation. In the human T-ALL cell line CCRF-CEM, enforced JDP2 overexpression conferred GC resistance, whereas KDM6A inactivation unexpectedly enhanced GC sensitivity. In the context of KDM6A knockout, JDP2 overexpression induced profound GC resistance, counteracting the sensitization conferred by KDM6A loss. These resistant "double mutant" cells with combined KDM6A loss and JDP2 overexpression exhibited decreased NR3C1 mRNA and GR protein upregulation upon DEX exposure. Analysis of paired samples from 2 patients with KDM6A-mutant T-ALL in a relapsed pediatric ALL cohort revealed a somatic NR3C1 mutation at relapse in 1 patient and a markedly elevated JDP2 expression in the other. Together, these data implicate JDP2 overexpression as a mechanism of adaptive GC resistance in T-ALL, which functionally interacts with KDM6A inactivation.

• Authors: Anya L Levinson, Karensa Tjoa, Benjamin Huang, Lauren K Meyer, Mi-Ok Kim, Samuel W Brady, Jinghui Zhang, Kevin Shannon, Anica M Wandler
• Journal: Blood advances (Blood Adv) Vol. 7 Issue 14 Pg. 3479-3484 (07 25 2023) ISSN: 2473-9537 [Electronic] United States
• PMID: 36897249 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.

Chemical References

• Glucocorticoids
• Dexamethasone
• Receptors, Glucocorticoid
• JDP2 protein, human
• Repressor Proteins

Topics

• Child
• Humans
• Mice
• Animals
• Glucocorticoids (pharmacology, therapeutic use)
• Dexamethasone (pharmacology)
• Precursor T-Cell Lymphoblastic Leukemia-Lymphoma (drug therapy, genetics, metabolism)
• Receptors, Glucocorticoid (genetics)
• Precursor Cell Lymphoblastic Leukemia-Lymphoma (metabolism)
• Recurrence
• Repressor Proteins