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 journalArticle

3 Citations (Scopus)

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
Publication statusE-pub ahead of print - 8 Jan 2019

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Homeobox Genes
Acute Myeloid Leukemia
Heterografts
Stem Cells
Oxidative Phosphorylation
Glycolysis
Myeloid Cells
Tumor Burden
Oncogenes
Energy Metabolism
Neoplasms
Carcinogenesis
Leukemia
Necrosis
Up-Regulation
Adenosine Triphosphate
Cell Proliferation
Apoptosis
Phenotype
Cell Line

Cite this

Lynch, J. R., Salik, B., Connerty, P., Vick, B., Leung, H., Pijning, A., ... Wang, J. Y. (2019). JMJD1C-mediated metabolic dysregulation contributes to HOXA9-dependent leukemogenesis. Leukemia, 33(6), 1400-1410. https://doi.org/10.1038/s41375-018-0354-z
Lynch, Jennifer R ; Salik, Basit ; Connerty, Patrick ; Vick, Binje ; Leung, Halina ; Pijning, Aster ; Jeremias, Irmela ; Spiekermann, Karsten ; Trahair, Toby ; Liu, Tao ; Haber, Michelle ; Norris, Murray D ; Woo, Andrew J ; Hogg, Philip ; Wang, Jianlong ; Wang, Jenny Y. / JMJD1C-mediated metabolic dysregulation contributes to HOXA9-dependent leukemogenesis. In: Leukemia. 2019 ; Vol. 33, No. 6. pp. 1400-1410.
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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.",
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Lynch, JR, Salik, B, Connerty, P, Vick, B, Leung, H, Pijning, A, Jeremias, I, Spiekermann, K, Trahair, T, Liu, T, Haber, M, Norris, MD, Woo, AJ, Hogg, P, Wang, J & Wang, JY 2019, 'JMJD1C-mediated metabolic dysregulation contributes to HOXA9-dependent leukemogenesis' Leukemia, vol. 33, no. 6, pp. 1400-1410. https://doi.org/10.1038/s41375-018-0354-z

JMJD1C-mediated metabolic dysregulation contributes to HOXA9-dependent leukemogenesis. / Lynch, Jennifer R; Salik, Basit; Connerty, Patrick; Vick, Binje; Leung, Halina; Pijning, Aster; Jeremias, Irmela; Spiekermann, Karsten; Trahair, Toby; Liu, Tao; Haber, Michelle; Norris, Murray D; Woo, Andrew J; Hogg, Philip; Wang, Jianlong; Wang, Jenny Y.

In: Leukemia, Vol. 33, No. 6, 08.01.2019, p. 1400-1410.

Research output: Contribution to journalArticle

TY - JOUR

T1 - JMJD1C-mediated metabolic dysregulation contributes to HOXA9-dependent leukemogenesis

AU - Lynch, Jennifer R

AU - Salik, Basit

AU - Connerty, Patrick

AU - Vick, Binje

AU - Leung, Halina

AU - Pijning, Aster

AU - Jeremias, Irmela

AU - Spiekermann, Karsten

AU - Trahair, Toby

AU - Liu, Tao

AU - Haber, Michelle

AU - Norris, Murray D

AU - Woo, Andrew J

AU - Hogg, Philip

AU - Wang, Jianlong

AU - Wang, Jenny Y

PY - 2019/1/8

Y1 - 2019/1/8

N2 - 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.

AB - 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.

U2 - 10.1038/s41375-018-0354-z

DO - 10.1038/s41375-018-0354-z

M3 - Article

VL - 33

SP - 1400

EP - 1410

JO - Leukemia

JF - Leukemia

SN - 0887-6924

IS - 6

ER -

Lynch JR, Salik B, Connerty P, Vick B, Leung H, Pijning A et al. JMJD1C-mediated metabolic dysregulation contributes to HOXA9-dependent leukemogenesis. Leukemia. 2019 Jan 8;33(6):1400-1410. https://doi.org/10.1038/s41375-018-0354-z