JMJD1C-mediated metabolic dysregulation contributes to HOXA9-dependent leukemogenesis

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

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Item Type: Article
Status: Published
Official URL: https://doi.org/10.1038/s41375-018-0354-z
Journal or Publication Title: Leukemia
Volume: 33
Number: 6
Page Range: pp. 1400-1410
Date: 2019
Divisions: ACRF Centenary Cancer Research Centre
Depositing User: General Admin
Identification Number: 10.1038/s41375-018-0354-z
ISSN: 0887-6924
Date Deposited: 21 Dec 2020 22:51
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.

Creators:
Creators
Email
Lynch, Jennifer R.
UNSPECIFIED
Salik, Basit
UNSPECIFIED
Connerty, Patrick
UNSPECIFIED
Vick, Binje
UNSPECIFIED
Leung, Halina
UNSPECIFIED
Pijning, Aster
UNSPECIFIED
Jeremias, Irmela
UNSPECIFIED
Spiekermann, Karsten
UNSPECIFIED
Trahair, Toby
UNSPECIFIED
Liu, Tao
UNSPECIFIED
Haber, Michelle
UNSPECIFIED
Norris, Murray D.
UNSPECIFIED
Woo, Andrew J.
UNSPECIFIED
Hogg, Philip
UNSPECIFIED
Wang, Jianlong
UNSPECIFIED
Wang, Jenny Y.
UNSPECIFIED
Last Modified: 21 Dec 2020 22:51
URI: https://eprints.centenary.org.au/id/eprint/212

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