RAS-pathway mutation patterns define epigenetic subclasses in juvenile myelomonocytic leukemia

Daniel B. Lipka (), Tania Witte, Reka Toth, Jing Yang, Manuel Wiesenfarth, Peter Nöllke, Alexandra Fischer, David Brocks, Zuguang Gu, Jeongbin Park, Brigitte Strahm, Marcin Wlodarski, Ayami Yoshimi, Rainer Claus, Michael Lübbert, Hauke Busch, Melanie Boerries, Mark Hartmann, Maximilian Schönung, Umut Kilik, Jens Langstein, Justyna A. Wierzbinska, Caroline Pabst, Swati Garg, Albert Catalá, Barbara Moerloose, Michael Dworzak, Henrik Hasle, Franco Locatelli, Riccardo Masetti, Markus Schmugge, Owen Smith, Jan Stary, Marek Ussowicz, Marry M. Heuvel-Eibrink, Yassen Assenov, Matthias Schlesner, Charlotte Niemeyer, Christian Flotho and Christoph Plass ()
Additional contact information
Daniel B. Lipka: German Cancer Research Center (DKFZ), INF 280
Tania Witte: German Cancer Research Center (DKFZ), INF 280
Reka Toth: German Cancer Research Center (DKFZ), INF 280
Jing Yang: German Cancer Research Center (DKFZ), INF 280
Manuel Wiesenfarth: German Cancer Research Center (DKFZ), INF 280
Peter Nöllke: University of Freiburg
Alexandra Fischer: University of Freiburg
David Brocks: German Cancer Research Center (DKFZ), INF 280
Zuguang Gu: German Cancer Research Center (DKFZ), INF 280
Jeongbin Park: German Cancer Research Center (DKFZ), INF 280
Brigitte Strahm: University of Freiburg
Marcin Wlodarski: University of Freiburg
Ayami Yoshimi: University of Freiburg
Rainer Claus: University Medical Center
Michael Lübbert: University Medical Center
Hauke Busch: University of Freiburg
Melanie Boerries: University of Freiburg
Mark Hartmann: German Cancer Research Center (DKFZ), INF 280
Maximilian Schönung: German Cancer Research Center (DKFZ), INF 280
Umut Kilik: German Cancer Research Center (DKFZ), INF 280
Jens Langstein: German Cancer Research Center (DKFZ), INF 280
Justyna A. Wierzbinska: German Cancer Research Center (DKFZ), INF 280
Caroline Pabst: Heidelberg University Hospital
Swati Garg: Heidelberg University Hospital
Albert Catalá: Hospital Sant Joan de Déu
Barbara Moerloose: Ghent University Hospital
Michael Dworzak: Medical University of Vienna
Henrik Hasle: Aarhus University Hospital Skejby
Franco Locatelli: University of Pavia
Riccardo Masetti: University of Bologna
Markus Schmugge: University Children’s Hospital
Owen Smith: Our Lady’s Children’s Hospital Crumlin
Jan Stary: Charles University and University Hospital Motol
Marek Ussowicz: Wroclaw Medical University
Marry M. Heuvel-Eibrink: Princess Maxima Center for Pediatric Oncology
Yassen Assenov: German Cancer Research Center (DKFZ), INF 280
Matthias Schlesner: German Cancer Research Center (DKFZ), INF 280
Charlotte Niemeyer: University of Freiburg
Christian Flotho: University of Freiburg
Christoph Plass: German Cancer Research Center (DKFZ), INF 280

Nature Communications, 2017, vol. 8, issue 1, 1-14

Abstract: Abstract Juvenile myelomonocytic leukemia (JMML) is an aggressive myeloproliferative disorder of early childhood characterized by mutations activating RAS signaling. Established clinical and genetic markers fail to fully recapitulate the clinical and biological heterogeneity of this disease. Here we report DNA methylome analysis and mutation profiling of 167 JMML samples. We identify three JMML subgroups with unique molecular and clinical characteristics. The high methylation group (HM) is characterized by somatic PTPN11 mutations and poor clinical outcome. The low methylation group is enriched for somatic NRAS and CBL mutations, as well as for Noonan patients, and has a good prognosis. The intermediate methylation group (IM) shows enrichment for monosomy 7 and somatic KRAS mutations. Hypermethylation is associated with repressed chromatin, genes regulated by RAS signaling, frequent co-occurrence of RAS pathway mutations and upregulation of DNMT1 and DNMT3B, suggesting a link between activation of the DNA methylation machinery and mutational patterns in JMML.

Date: 2017
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DOI: 10.1038/s41467-017-02177-w

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