Back to Search
Start Over
Juvenile myelomonocytic leukemia displays mutations in components of the RAS pathway and the PRC2 network
- Source :
- Nature Genetics, Nature Genetics, Nature Publishing Group, 2015, 47 (11), pp.1334-1340. ⟨10.1038/ng.3420⟩
- Publication Year :
- 2015
- Publisher :
- HAL CCSD, 2015.
-
Abstract
- International audience; Juvenile myelomonocytic leukemia (JMML) is a rare and severe myelodysplastic and myeloproliferative neoplasm of early childhood initiated by germline or somatic RAS-activating mutations. Genetic profiling and whole-exome sequencing of a large JMML cohort (118 and 30 cases, respectively) uncovered additional genetic abnormalities in 56 cases (47%). Somatic events were rare (0.38 events/Mb/case) and restricted to sporadic (49/78; 63%) or neurofibromatosis type 1 (NF1)-associated (8/8; 100%) JMML cases. Multiple concomitant genetic hits targeting the RAS pathway were identified in 13 of 78 cases (17%), disproving the concept of mutually exclusive RAS pathway mutations and defining new pathways activated in JMML involving phosphoinositide 3-kinase (PI3K) and the mTORC2 complex through RAC2 mutation. Furthermore, this study highlights PRC2 loss (26/78; 33% of sporadic JMML cases) that switches the methylation/acetylation status of lysine 27 of histone H3 in JMML cases with altered RAS and PRC2 pathways. Finally, the association between JMML outcome and mutational profile suggests a dose-dependent effect for RAS pathway activation, distinguishing very aggressive JMML rapidly progressing to acute myeloid leukemia.
- Subjects :
- Male
DNA Copy Number Variations
Somatic cell
Biology
medicine.disease_cause
Methylation
Germline
Histones
Phosphatidylinositol 3-Kinases
Genetics
medicine
Humans
Gene Regulatory Networks
Child
PI3K/AKT/mTOR pathway
Myeloproliferative neoplasm
Mutation
[SDV.GEN]Life Sciences [q-bio]/Genetics
Microscopy, Confocal
Juvenile myelomonocytic leukemia
Polycomb Repressive Complex 2
Infant
Myeloid leukemia
Acetylation
Sequence Analysis, DNA
medicine.disease
Survival Analysis
3. Good health
Protein Subunits
Leukemia
Leukemia, Myelomonocytic, Juvenile
Leukemia, Myeloid
Child, Preschool
Acute Disease
Disease Progression
ras Proteins
Cancer research
Female
Transcriptome
Signal Transduction
Subjects
Details
- Language :
- English
- ISSN :
- 10614036 and 15461718
- Database :
- OpenAIRE
- Journal :
- Nature Genetics, Nature Genetics, Nature Publishing Group, 2015, 47 (11), pp.1334-1340. ⟨10.1038/ng.3420⟩
- Accession number :
- edsair.doi.dedup.....2f00f01cc3d98c8561ac6971cae84245