JMJD1C-mediated metabolic dysregulation contributes to HOXA9-dependent leukemogenesis

Jennifer R. Lynch, Basit Salik, Patrick Connerty, Binje Vick, Halina Leung, Aster Pijning, Irmela Jeremias, Karsten Spiekermann, Toby Trahair, Tao Liu, Michelle Haber, Murray D. Norris, Andrew J. Woo, Philip Hogg, Jianlong Wang, Jenny Y. Wang

Research output: Contribution to journalArticlepeer-review

27 Scopus citations

Abstract

Abnormal metabolism is a fundamental hallmark of cancer and represents a therapeutic opportunity, yet its regulation by oncogenes remains poorly understood. Here, we uncover that JMJD1C, a jumonji C (JmjC)-containing H3K9 demethylase, is a critical regulator of aberrant metabolic processes in homeobox A9 (HOXA9)-dependent acute myeloid leukemia (AML). JMJD1C overexpression increases in vivo cell proliferation and tumorigenicity through demethylase-independent upregulation of a glycolytic and oxidative program, which sustains leukemic cell bioenergetics and contributes to an aggressive AML phenotype in vivo. Targeting JMJD1C-mediated metabolism via pharmacologic inhibition of glycolysis and oxidative phosphorylation led to ATP depletion, induced necrosis/apoptosis and decreased tumor growth in vivo in leukemias co-expressing JMJD1C and HOXA9. The anti-metabolic therapy effectively diminished AML stem/progenitor cells and reduced tumor burden in a primary AML patient-derived xenograft. Our data establish a direct link between drug responses and endogenous expression of JMJD1C and HOXA9 in human AML cell line- and patient-derived xenografts. These findings demonstrate a previously unappreciated role for JMJD1C in counteracting adverse metabolic changes and retaining the metabolic integrity during tumorigenesis, which can be exploited therapeutically.

Original languageEnglish
Pages (from-to)1400-1410
Number of pages11
JournalLeukemia
Volume33
Issue number6
DOIs
StatePublished - 1 Jun 2019

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