JMJD1C-mediated metabolic dysregulation contributes to HOXA9-dependent leukemogenesis.

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.

• Authors: 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
• Journal: Leukemia (Leukemia) Vol. 33 Issue 6 Pg. 1400-1410 (06 2019) ISSN: 1476-5551 [Electronic] England
• PMID: 30622285 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Homeodomain Proteins
• homeobox protein HOXA9
• JMJD1C protein, human
• Jumonji Domain-Containing Histone Demethylases
• Oxidoreductases, N-Demethylating

Topics

• Animals
• Gene Expression Regulation, Leukemic
• Glycolysis
• Homeodomain Proteins (genetics, metabolism)
• Humans
• Jumonji Domain-Containing Histone Demethylases (genetics, metabolism)
• Leukemia, Myeloid, Acute (genetics, metabolism, pathology)
• Mice
• Mice, Inbred NOD
• Mice, SCID
• Neoplastic Stem Cells (metabolism, pathology)
• Oxidative Phosphorylation
• Oxidoreductases, N-Demethylating (genetics, metabolism)
• Tumor Cells, Cultured
• Xenograft Model Antitumor Assays