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

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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.
Keywords
ISLAND METHYLATOR PHENOTYPE, CHRONIC LYMPHOCYTIC-LEUKEMIA, STEM-CELL, TRANSPLANTATION, CIS-REGULATORY ELEMENTS, NERVE SHEATH TUMORS, DNA, METHYLATION, MYELODYSPLASTIC SYNDROMES, MOLECULAR CLASSIFICATION, SOMATIC MUTATIONS, EPITHELIAL-CELLS

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MLA
Lipka, Daniel B, Tania Witte, Reka Toth, et al. “RAS-pathway Mutation Patterns Define Epigenetic Subclasses in Juvenile Myelomonocytic Leukemia.” NATURE COMMUNICATIONS 8 (2017): n. pag. Print.
APA
Lipka, D. B., Witte, T., Toth, R., Yang, J., Wiesenfarth, M., Noellke, P., Fischer, A., et al. (2017). RAS-pathway mutation patterns define epigenetic subclasses in juvenile myelomonocytic leukemia. NATURE COMMUNICATIONS, 8.
Chicago author-date
Lipka, Daniel B, Tania Witte, Reka Toth, Jing Yang, Manuel Wiesenfarth, Peter Noellke, Alexandra Fischer, et al. 2017. “RAS-pathway Mutation Patterns Define Epigenetic Subclasses in Juvenile Myelomonocytic Leukemia.” Nature Communications 8.
Chicago author-date (all authors)
Lipka, Daniel B, Tania Witte, Reka Toth, Jing Yang, Manuel Wiesenfarth, Peter Noellke, Alexandra Fischer, David Brocks, Zuguang Gu, Jeongbin Park, Brigitte Strahm, Marcin Wlodarski, Ayami Yoshimi, Rainer Claus, Michael Luebbert, Hauke Busch, Melanie Boerries, Mark Hartmann, Maximilian Schoenung, Umut Kilik, Jens Langstein, Justyna A Wierzbinska, Caroline Pabst, Swati Garg, Albert Catala, Barbara De Moerloose, Michael Dworzak, Henrik Hasle, Franco Locatelli, Riccardo Masetti, Markus Schmugge, Owen Smith, Jan Stary, Marek Ussowicz, Marry M van den Heuvel-Eibrink, Yassen Assenov, Matthias Schlesner, Charlotte Niemeyer, Christian Flotho, and Christoph Plass. 2017. “RAS-pathway Mutation Patterns Define Epigenetic Subclasses in Juvenile Myelomonocytic Leukemia.” Nature Communications 8.
Vancouver
1.
Lipka DB, Witte T, Toth R, Yang J, Wiesenfarth M, Noellke P, et al. RAS-pathway mutation patterns define epigenetic subclasses in juvenile myelomonocytic leukemia. NATURE COMMUNICATIONS. 2017;8.
IEEE
[1]
D. B. Lipka et al., “RAS-pathway mutation patterns define epigenetic subclasses in juvenile myelomonocytic leukemia,” NATURE COMMUNICATIONS, vol. 8, 2017.
@article{8554844,
  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.},
  articleno    = {2126},
  author       = {Lipka, Daniel B and Witte, Tania and Toth, Reka and Yang, Jing and Wiesenfarth, Manuel and Noellke, Peter and Fischer, Alexandra and Brocks, David and Gu, Zuguang and Park, Jeongbin and Strahm, Brigitte and Wlodarski, Marcin and Yoshimi, Ayami and Claus, Rainer and Luebbert, Michael and Busch, Hauke and Boerries, Melanie and Hartmann, Mark and Schoenung, Maximilian and Kilik, Umut and Langstein, Jens and Wierzbinska, Justyna A and Pabst, Caroline and Garg, Swati and Catala, Albert and De Moerloose, Barbara and Dworzak, Michael and Hasle, Henrik and Locatelli, Franco and Masetti, Riccardo and Schmugge, Markus and Smith, Owen and Stary, Jan and Ussowicz, Marek and van den Heuvel-Eibrink, Marry M and Assenov, Yassen and Schlesner, Matthias and Niemeyer, Charlotte and Flotho, Christian and Plass, Christoph},
  issn         = {2041-1723},
  journal      = {NATURE COMMUNICATIONS},
  keywords     = {ISLAND METHYLATOR PHENOTYPE,CHRONIC LYMPHOCYTIC-LEUKEMIA,STEM-CELL,TRANSPLANTATION,CIS-REGULATORY ELEMENTS,NERVE SHEATH TUMORS,DNA,METHYLATION,MYELODYSPLASTIC SYNDROMES,MOLECULAR CLASSIFICATION,SOMATIC MUTATIONS,EPITHELIAL-CELLS},
  language     = {eng},
  pages        = {14},
  title        = {RAS-pathway mutation patterns define epigenetic subclasses in juvenile myelomonocytic leukemia},
  url          = {http://dx.doi.org/10.1038/s41467-017-02177-w},
  volume       = {8},
  year         = {2017},
}

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