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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
Leukemia, 06/2019, Letnik: 33, Številka: 6Journal Article
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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JCR | SNIP | JCR | SNIP | JCR | SNIP | JCR | SNIP |
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