JDP2 overexpression

The peptide-mediated antiproliferative effect initiated erythrocyte differentiation in K562 cells and increased G0/G1 cells across multiple cell line models. We also found that many of the antiproliferative peptides identified in this study, including JDP2;bZIP_1, did not require a nuclear localization signal to function, a potential benefit for delivering these peptides in therapeutic applications.

We transplanted and treated ten primary mouse T-lineage acute lymphoblastic leukemias (T-ALLs) initiated by retroviral insertional mutagenesis with the GC dexamethasone (DEX)...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.

In an unbiased in vivo screen to discover GC resistance mechanisms, we transplanted and treated 10 primary mouse T-ALLs initiated by retroviral insertional mutagenesis with the GC dexamethasone (DEX) (Wandler et al., 2020). We also unexpectedly found that KDM6A inactivation sensitizes T-ALL cells to GC treatment and hypothesize that this results in strong selective pressure for the outgrowth of GC-resistant clones due to JDP2 over-expression and other mechanisms. The FDA-approved BCL-2 inhibitor venetoclax and H3K27me3 inhibition are rational therapeutic approaches for potentially overcoming adaptive GC resistance in relapsed patients with KDM6A-mutant T-ALL.