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RAS-pathway mutation patterns define epigenetic subclasses in juvenile myelomonocytic leukemia.
- Source :
-
Nature communications [Nat Commun] 2017 Dec 19; Vol. 8 (1), pp. 2126. Date of Electronic Publication: 2017 Dec 19. - Publication Year :
- 2017
-
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.
- Subjects :
- Antineoplastic Agents therapeutic use
Biopsy
Child
Child, Preschool
Chromatin genetics
Chromatin metabolism
DNA (Cytosine-5-)-Methyltransferase 1 metabolism
DNA (Cytosine-5-)-Methyltransferases metabolism
DNA Mutational Analysis
Epigenomics
Female
Gene Expression Regulation, Leukemic
Hematopoietic Stem Cell Transplantation
Humans
Infant
Leukemia, Myelomonocytic, Juvenile mortality
Leukemia, Myelomonocytic, Juvenile pathology
Leukemia, Myelomonocytic, Juvenile therapy
Male
Mutation
Noonan Syndrome pathology
Prognosis
Prospective Studies
Protein Tyrosine Phosphatase, Non-Receptor Type 11 metabolism
Proto-Oncogene Proteins c-cbl
Proto-Oncogene Proteins p21(ras) metabolism
Up-Regulation
DNA Methyltransferase 3B
DNA Methylation
Leukemia, Myelomonocytic, Juvenile genetics
Noonan Syndrome genetics
Protein Tyrosine Phosphatase, Non-Receptor Type 11 genetics
Proto-Oncogene Proteins p21(ras) genetics
Signal Transduction genetics
Subjects
Details
- Language :
- English
- ISSN :
- 2041-1723
- Volume :
- 8
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Nature communications
- Publication Type :
- Academic Journal
- Accession number :
- 29259247
- Full Text :
- https://doi.org/10.1038/s41467-017-02177-w