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Lynch, J.R.* ; Salik, B.* ; Connerty, P.* ; Vick, B. ; Leung, H.* ; Pijning, A.* ; Jeremias, I. ; Spiekermann, K.* ; Trahair, T.* ; Liu, T.* ; Haber, M.* ; Norris, M.D.* ; Woo, A.J.* ; Hogg, P.* ; Wang, J.* ; Wang, J.Y.*

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

Leukemia 33, 1400-1410 (2019)
Verlagsversion DOI PMC
Free by publisher
Open Access Green möglich sobald Postprint bei der ZB eingereicht worden ist.
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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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter Acute Myeloid-leukemia; Stem-cells; Hormone Receptors; Cancer; Expression; Transcription; Glycolysis; Gene; Phosphorylation; Maintenance
ISSN (print) / ISBN 0887-6924
e-ISSN 1476-5551
Zeitschrift Leukemia
Quellenangaben Band: 33, Heft: 6, Seiten: 1400-1410 Artikelnummer: , Supplement: ,
Verlag Nature Publishing Group
Verlagsort Macmillan Building, 4 Crinan St, London N1 9xw, England
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Research Unit Apoptosis in Hematopoietic Stem Cells (AHS)