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Nat Commun. 2015 May 22;6:7091. doi: 10.1038/ncomms8091.

Dissecting the role of aberrant DNA methylation in human leukaemia.

Author information

1
1] Harvard Medical School, Boston, Massachusetts 02115, USA [2] Harvard Stem Cell Institute, Harvard University, Cambridge, Massachusetts 02138, USA.
2
Max Plank Institute for Informatics, Saarbrücken 117599, Germany.
3
Cancer Science Institute, National University of Singapore, Singapore 66123, Singapore.
4
1] Harvard Medical School, Boston, Massachusetts 02115, USA [2] Harvard Stem Cell Institute, Harvard University, Cambridge, Massachusetts 02138, USA [3] Institute of Biomedical Technologies, National Research Council (CNR), Pisa 56124, Italy.
5
Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna 40126, Italy.
6
Netherlands Cancer Institute, Amsterdam 1066, The Netherlands.
7
Section of Hematology/Oncology and the Comprehensive Cancer Center, University of Chicago, Chicago, Illinois 60637, USA.
8
University of Michigan, Department of Pathology, Ann Arbor, Michigan 48109-2200, USA.
9
1] Max Plank Institute for Informatics, Saarbrücken 117599, Germany [2] CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna 1090, Austria [3] Department of Laboratory Medicine, Medical University of Vienna, Vienna 1090, Austria.
10
1] Harvard Medical School, Boston, Massachusetts 02115, USA [2] Harvard Stem Cell Institute, Harvard University, Cambridge, Massachusetts 02138, USA [3] Cancer Science Institute, National University of Singapore, Singapore 66123, Singapore.

Abstract

Chronic myeloid leukaemia (CML) is a myeloproliferative disorder characterized by the genetic translocation t(9;22)(q34;q11.2) encoding for the BCR-ABL fusion oncogene. However, many molecular mechanisms of the disease progression still remain poorly understood. A growing body of evidence suggests that the epigenetic abnormalities are involved in tyrosine kinase resistance in CML, leading to leukaemic clone escape and disease propagation. Here we show that, by applying cellular reprogramming to primary CML cells, aberrant DNA methylation contributes to the disease evolution. Importantly, using a BCR-ABL inducible murine model, we demonstrate that a single oncogenic lesion triggers DNA methylation changes, which in turn act as a precipitating event in leukaemia progression.

PMID:
25997600
PMCID:
PMC4443494
DOI:
10.1038/ncomms8091
[Indexed for MEDLINE]
Free PMC Article

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