Abstract
The H3K27 demethylases UTX and JMJD3 have opposing roles in regulating NOTCH1-induced T-ALL growth.
Major finding: The H3K27 demethylases UTX and JMJD3 have opposing roles in regulating NOTCH1-induced T-ALL growth.
Mechanism: JMJD3 interacts with NOTCH1 to regulate oncogenic genes, whereas UTX is a tumor suppressor.
Impact: The small-molecule inhibitor GSKJ4 blocks JMJD3 activity and may be a novel therapeutic for T-ALL.
T-cell acute lymphoblastic leukemia (T-ALL) has a 25% relapse rate and an overall poor prognosis. Although drugs that target epigenetic factors have been approved for the treatment of hematopoietic disorders, they are not currently used to treat T-ALL. Recent studies have implicated histone 3 lysine 27 (H3K27) methyltransferase complexes as tumor suppressors in T-ALL; however, the role of the H3K27 demethylases lysine (K)-specific demethylase 6A (KDM6A, also known as UTX) and lysine (K)-specific demethylase 6B (KDM6B, also known as JMJD3) in T-ALL progression is unknown. Ntziachristos, Tsirigos, and colleagues found that JMJD3 expression was elevated in murine NOTCH1-induced T-ALL cells compared with untransformed T cells and was regulated by NOTCH1 and the NF-κB pathway. JMJD3 binding to the promoters of oncogenic NOTCH1 target genes was associated with co-occupancy with NOTCH1 and activating histone marks. Furthermore, JMJD3 interacted directly with the NOTCH1 transcriptional complex, suggesting that it plays a key role in regulating oncogenic programs in T-ALL. Both knockdown of JMJD3 in human T-ALL cells and Jmjd3 knockout in mouse models resulted in reduced leukemic cell viability and improved survival rates. In contrast, silencing of UTX resulted in enhanced T-ALL cell proliferation and shorter tumor latency, whereas UTX overexpression stimulated apoptosis and inhibited tumor cell growth in vitro, suggesting that this enzyme may function as a tumor suppressor. Further studies demonstrated that UTX positively regulated tumor suppressor genes, and that deletions and mutations in UTX were found in patients with T-ALL. Importantly, the small-molecule inhibitor GSKJ4 induced cell-cycle arrest and apoptosis in human T-ALL cells and resulted in a similar gene expression and epigenetic profile as JMJD3-silenced cells, suggesting that it mainly acts by inhibiting JMJD3 demethylase activity. These results identify contrasting functions for the H3K27 demethylases JMJD3 and UTX in T-ALL, and support further studies of GSKJ4 as a potential targeted therapy for T-ALL.
Note: Research Watch is written by Cancer Discovery Science Writers. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://CDnews.aacrjournals.org.