Epigenetic reactivation of the tumor suppressor ZBTB7A by KDM4 inhibition in human acute myeloid leukemia.

Authors

• Alexander Arnuk, The Jackson LaboratoryFollow
• Cuijuan Han, The Jackson LaboratoryFollow
• Abimbola Eunice Lawal, The Jackson LaboratoryFollow
• Bofei Wang
• Sadik Karma, The Jackson LaboratoryFollow
• Zhiping Zhang
• Mhd Yousuf Yassouf
• Sakthi Harini Rajendran, The Jackson LaboratoryFollow
• Harshpreet Chandok, The Jackson LaboratoryFollow
• Madeline L Eller
• Sogand Sajedi
• Meryl McKenna, The Jackson Laboratory
• Eve Herman, The Jackson LaboratoryFollow
• Louisa Hagen, The Jackson Laboratory
• Bettina Nadorp
• Zengshuo Mo
• Hector Orellana, The Jackson Laboratory
• Aristotelis Tsirigos
• Pedro Miura
• Hussein A Abbas
• Iannis Aifantis
• Eric Wang, The Jackson LaboratoryFollow

Document Type

Article

Publication Date

2-25-2026

Original Citation

Arnuk A, Han C, Lawal A, Wang B, Karma S, Zhang Z, Yassouf M, Rajendran S, Chandok H, Eller M, Sajedi S, McKenna M, Herman E, Hagen L, Nadorp B, Mo Z, Orellana H, Tsirigos A, Miura P, Abbas H, Aifantis I, Wang E. Epigenetic reactivation of the tumor suppressor ZBTB7A by KDM4 inhibition in human acute myeloid leukemia. Sci Transl Med. 2026;18(838):eady2936.

Keywords

JGM, SS1

JAX Source

Sci Transl Med. 2026;18(838):eady2936.

ISSN

1946-6242

PMID

41739902

DOI

https://doi.org/10.1126/scitranslmed.ady2936

Grant

This work was supported by the Jackson Laboratory Cancer Center (JAXCC) New Investigator Award (P30CA034196 to E.W.), JAX start-up funds, JAX cancer center Fast Forward Award, JAX Cancer Center Innovation Pilot Award (P30CA034196), American Society of Hematology (ASH) Scholar Award, Leukemia Research Foundation (LRF), and Butler Family Foundation to E.W; the JAXCC Brooks Scholar Award to A.A.; the American Society of Hematology (ASH) Scholar Award to S.K.; the American Heart Association (AHA) Fellowship to S.H.R.;

Abstract

Inactivation of tumor suppressor genes (TSGs) imparts a cellular fitness in cancers, including in acute myeloid leukemia (AML). The detection of silenced TSGs without direct mutations presents challenges in designing targeted cancer treatments, yet it also opens a therapeutic opportunity to restore their function. In this study, we identified the transcriptional repressor ZBTB7A as a TSG that is down-regulated in samples from patients with AML and is associated with poor survival outcomes. Loss of ZBTB7A amplifies TNF signaling, driving a dysfunctional inflammatory state that accelerates AML progression in vivo. Mechanistically, the mRNA decay factor ZFP36L2 binds to the 3′ untranslated region (3′UTR) of ZBTB7A, promoting its transcript degradation in human AML cells. To identify therapeutic targets, we developed a CRISPR-based screening approach coupled with fluorescence in situ hybridization and flow cytometry (FISH-Flow), pinpointing the KDM4 family of histone demethylases as a vulnerability to restore ZBTB7A function. Pharmacologic inhibition of KDM4 up-regulated ZBTB7A expression, promoted terminal differentiation in patient-derived xenograft models, and demonstrated broad antileukemic efficacy across AML subtypes as well as preserved normal hematopoiesis. These findings reveal regulatory mechanisms of ZBTB7A and support epigenetic therapy as a promising strategy to reactivate its tumor suppressor function in hematologic cancers.