Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 111, Issue 33, Pages 12133-12138Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1412944111
Keywords
histone chaperones; leukemogenesis; hematopoiesis; oncogenes; PML nuclear bodies
Categories
Funding
- Deutsche Forschungsgemeinschaft [STE 1003/2-1, STE 1003/3-1]
- Else-Kroner-Fresenius Stiftung [2012_A287]
- European Union [FP7-IRG 256220]
- Fordergemeinschaft Kinderkrebs-Zentrum Hamburg e.V.
- Heinrich Pette Institute
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In most acute promyelocytic leukemia (APL) cases, translocons produce a promyelocytic leukemia protein-retinoic acid receptor a (PML-RAR alpha) fusion gene. Although expression of the human PML fusion in mice promotes leukemia, its efficiency is rather low. Unexpectedly, we find that simply replacing the human PML fusion with its mouse counterpart results in a murine PML-RAR alpha (mPR) hybrid protein that is transformed into a significantly more leukemogenic oncoprotein. Using this more potent isoform, we show that mPR promotes immortalization by preventing cellular senescence, impeding up-regulation of both the p21 and p19(ARF) cell-cycle regulators. This induction coincides with a loss of the cancer-associated ATRX/Daxx-histone H3.3 predisposition complex and suggests inhibition of senescence as a targetable mechanism in APL therapy.
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