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 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; Christoph Plass

doi:10.1038/s41467-017-02177-w

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 KilikJens Langstein, Justyna A. Wierzbinska, Caroline Pabst, Swati Garg, Albert Catalá, 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, Christoph Plass

^*Corresponding author for this work

Research output: Contribution to journal › Article › Research › peer-review

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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.

Original language	English
Article number	2126
Journal	Nature Communications
Volume	8
Issue number	1
DOIs	https://doi.org/10.1038/s41467-017-02177-w
Publication status	Published - 1 Dec 2017
Externally published	Yes

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Lipka, D. B., Witte, T., Toth, R., Yang, J., Wiesenfarth, M., Nöllke, P., Fischer, A., Brocks, D., Gu, Z., Park, J., Strahm, B., Wlodarski, M., Yoshimi, A., Claus, R., Lübbert, M., Busch, H., Boerries, M., Hartmann, M., Schönung, M., ... Plass, C. (2017). RAS-pathway mutation patterns define epigenetic subclasses in juvenile myelomonocytic leukemia. Nature Communications, 8(1), [2126]. https://doi.org/10.1038/s41467-017-02177-w

@article{e9b2dc40eab4459fbeac97a96a7c1ec5,

title = "RAS-pathway mutation patterns define epigenetic subclasses in juvenile myelomonocytic leukemia",

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.",

author = "Lipka, {Daniel B.} and Tania Witte and Reka Toth and Jing Yang and Manuel Wiesenfarth and Peter N{\"o}llke and Alexandra Fischer and David Brocks and Zuguang Gu and Jeongbin Park and Brigitte Strahm and Marcin Wlodarski and Ayami Yoshimi and Rainer Claus and Michael L{\"u}bbert and Hauke Busch and Melanie Boerries and Mark Hartmann and Maximilian Sch{\"o}nung and Umut Kilik and Jens Langstein and Wierzbinska, {Justyna A.} and Caroline Pabst and Swati Garg and Albert Catal{\'a} and {De Moerloose}, Barbara and Michael Dworzak and Henrik Hasle and Franco Locatelli and Riccardo Masetti and Markus Schmugge and Owen Smith and Jan Stary and Marek Ussowicz and {Van Den Heuvel-Eibrink}, {Marry M.} and Yassen Assenov and Matthias Schlesner and Charlotte Niemeyer and Christian Flotho and Christoph Plass",

note = "Funding Information: We thank all members of the Division of Epigenomics and Cancer Risk Factors (DKFZ) for thoughtful discussions related to this study and we thank Monika Helf and Oliver M{\"u}cke for excellent technical support. We also thank the Microarray unit and the High Throughput Sequencing unit of the Genomics and Proteomics Core Facility, German Cancer Research Center (DKFZ), for providing the Illumina HumanMethylation450 arrays, the Illumina HumanHT-12 v4 Expression BeadChip arrays and related services, as well as for excellent support with exome sequencing services. This work was supported by project funding from the German Jos{\'e} Carreras Leukemia Foundation (DJCLS) to C. P., D.B.L., and C.F. (project: DJCLS R 15/01), and from the German Research Foundation (DFG) to C.F. (projects: CRC992-C05 and FL345/4-2), and to H.B. (EXC 306) and M.B. (CRC 850). M.B. is funded by the German Federal Ministry of Education and Research within the framework of the e:Med research and funding concept, DeCaRe (FKZ 01ZX1409B). U.K. was supported by a joint German Academic Exchange Service (DAAD) and Turkish Education Foundation (TEV) master scholarship. This work was further supported by the German Cancer Consortium (DKTK). Publisher Copyright: {\textcopyright} 2017 The Author(s).",

year = "2017",

month = dec,

day = "1",

doi = "10.1038/s41467-017-02177-w",

language = "English",

volume = "8",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

number = "1",

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Lipka, DB, Witte, T, Toth, R, Yang, J, Wiesenfarth, M, Nöllke, P, Fischer, A, Brocks, D, Gu, Z, Park, J, Strahm, B, Wlodarski, M, Yoshimi, A, Claus, R, Lübbert, M, Busch, H, Boerries, M, Hartmann, M, Schönung, M, Kilik, U, Langstein, J, Wierzbinska, JA, Pabst, C, Garg, S, Catalá, A, De Moerloose, B, Dworzak, M, Hasle, H, Locatelli, F, Masetti, R, Schmugge, M, Smith, O, Stary, J, Ussowicz, M, Van Den Heuvel-Eibrink, MM, Assenov, Y, Schlesner, M, Niemeyer, C, Flotho, C & Plass, C 2017, 'RAS-pathway mutation patterns define epigenetic subclasses in juvenile myelomonocytic leukemia', Nature Communications, vol. 8, no. 1, 2126. https://doi.org/10.1038/s41467-017-02177-w

TY - JOUR

T1 - RAS-pathway mutation patterns define epigenetic subclasses in juvenile myelomonocytic leukemia

AU - Lipka, Daniel B.

AU - Witte, Tania

AU - Toth, Reka

AU - Yang, Jing

AU - Wiesenfarth, Manuel

AU - Nöllke, Peter

AU - Fischer, Alexandra

AU - Brocks, David

AU - Gu, Zuguang

AU - Park, Jeongbin

AU - Strahm, Brigitte

AU - Wlodarski, Marcin

AU - Yoshimi, Ayami

AU - Claus, Rainer

AU - Lübbert, Michael

AU - Busch, Hauke

AU - Boerries, Melanie

AU - Hartmann, Mark

AU - Schönung, Maximilian

AU - Kilik, Umut

AU - Langstein, Jens

AU - Wierzbinska, Justyna A.

AU - Pabst, Caroline

AU - Garg, Swati

AU - Catalá, Albert

AU - De Moerloose, Barbara

AU - Dworzak, Michael

AU - Hasle, Henrik

AU - Locatelli, Franco

AU - Masetti, Riccardo

AU - Schmugge, Markus

AU - Smith, Owen

AU - Stary, Jan

AU - Ussowicz, Marek

AU - Van Den Heuvel-Eibrink, Marry M.

AU - Assenov, Yassen

AU - Schlesner, Matthias

AU - Niemeyer, Charlotte

AU - Flotho, Christian

AU - Plass, Christoph

N1 - Funding Information: We thank all members of the Division of Epigenomics and Cancer Risk Factors (DKFZ) for thoughtful discussions related to this study and we thank Monika Helf and Oliver Mücke for excellent technical support. We also thank the Microarray unit and the High Throughput Sequencing unit of the Genomics and Proteomics Core Facility, German Cancer Research Center (DKFZ), for providing the Illumina HumanMethylation450 arrays, the Illumina HumanHT-12 v4 Expression BeadChip arrays and related services, as well as for excellent support with exome sequencing services. This work was supported by project funding from the German José Carreras Leukemia Foundation (DJCLS) to C. P., D.B.L., and C.F. (project: DJCLS R 15/01), and from the German Research Foundation (DFG) to C.F. (projects: CRC992-C05 and FL345/4-2), and to H.B. (EXC 306) and M.B. (CRC 850). M.B. is funded by the German Federal Ministry of Education and Research within the framework of the e:Med research and funding concept, DeCaRe (FKZ 01ZX1409B). U.K. was supported by a joint German Academic Exchange Service (DAAD) and Turkish Education Foundation (TEV) master scholarship. This work was further supported by the German Cancer Consortium (DKTK). Publisher Copyright: © 2017 The Author(s).

PY - 2017/12/1

Y1 - 2017/12/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85038610246&partnerID=8YFLogxK

U2 - 10.1038/s41467-017-02177-w

DO - 10.1038/s41467-017-02177-w

M3 - Article

C2 - 29259247

AN - SCOPUS:85038610246

SN - 2041-1723

VL - 8

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 2126

ER -

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

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