A PRC2-Kdm5b axis sustains tumorigenicity of acute myeloid leukemia

Abstract

Acute myeloid leukemias (AMLs) with the NUP98-NSD1 or mixed lineage leukemia (MLL) rearrangement (MLL-r) share transcriptomic profiles associated with stemness-related gene signatures and display poor prognosis. The molecular underpinnings of AML aggressiveness and stemness remain far from clear. Studies with EZH2 enzymatic inhibitors show that polycomb repressive complex 2 (PRC2) is crucial for tumorigenicity in NUP98-NSD1+ AML, whereas transcriptomic analysis reveal that Kdm5b, a lysine demethylase gene carrying “bivalent” chromatin domains, is directly repressed by PRC2. While ectopic expression of Kdm5b suppressed AML growth, its depletion not only promoted tumorigenicity but also attenuated anti-AML effects of PRC2 inhibitors, demonstrating a PRC2–|Kdm5b axis for AML oncogenesis. Integrated RNA sequencing (RNA-seq), chromatin immunoprecipitation followed by sequencing (ChIP-seq), and Cleavage Under Targets & Release Using Nuclease (CUT&RUN) profiling also showed that Kdm5b directly binds and represses AML stemness genes. The anti-AML effect of Kdm5b relies on its chromatin association and/or scaffold functions rather than its demethylase activity. Collectively, this study describes a molecular axis that involves histone modifiers (PRC2–|Kdm5b) for sustaining AML oncogenesis.

Awakening KDM5B to defeat leukemia

“…In PNAS, Ren et al. ( 1 ) report histone demethylase KDM5B (also called JARID1B or PLU1) as a suppressor of acute myeloid leukemia (AML). AML is one of the most frequently diagnosed adult cancers and is the most common type of acute leukemia ( 2 ).…”

“…Ren et al. ( 1 ) show that UNC1999, a dual inhibitor of the histone H3K27 methyltransferases enhancer of zeste homolog 1/2 (EZH1/2), significantly inhibited the clonogenic growth and induced the differentiation and apoptosis of murine AML cells driven by NUP98-NSD1. Consistently, UNC1999 treatment prolonged the survival of mice injected with these AML cells.…”

“…To search for key downstream regulators that become reactivated and account for the antileukemia effect of EZH2 inhibition, Ren et al. ( 1 ) compared overlapping transcriptomic changes of AML cells after treatment with EZH2 inhibitors or down-regulation of embryonic ectoderm development (EED), an essential component of PRC2. Kdm5b was identified as one of the 31 consistently induced genes.…”

“…Kdm5b was identified as one of the 31 consistently induced genes. Chromatin immunoprecipitation sequencing (ChIP-seq) analysis showed that the transcriptional start site of Kdm5b is marked by EZH2, the H3K27me3 repressive mark catalyzed by EZH2, and the H3K4me3 activating mark ( 1 ). These suggest that Kdm5b is a direct target of EZH2 poised for transcriptional activation or repression and could have a tumor-suppressive role in AML.…”

“…In fact, Ren et al. ( 1 ) then demonstrated the tumor suppressor role of Kdm5b in AML through Kdm5b knockdown experiments. Ablation of Kdm5b further enhanced AML clonogenic growth and desensitized AML cells to UNC1999 treatment both in vitro and in vivo.…”