The genomic landscape of juvenile myelomonocytic leukemia

• Published in: Nature genetics Vol. 47; no. 11; pp. 1326 - 1333
• Main Authors: Stieglitz, Elliot, Taylor-Weiner, Amaro N, Chang, Tiffany Y, Gelston, Laura C, Wang, Yong-Dong, Mazor, Tali, Esquivel, Emilio, Yu, Ariel, Seepo, Sara, Olsen, Scott, Rosenberg, Mara, Archambeault, Sophie L, Abusin, Ghada, Beckman, Kyle, Brown, Patrick A, Briones, Michael, Carcamo, Benjamin, Cooper, Todd, Dahl, Gary V, Emanuel, Peter D, Fluchel, Mark N, Goyal, Rakesh K, Hayashi, Robert J, Hitzler, Johann, Hugge, Christopher, Liu, Y Lucy, Messinger, Yoav H, Mahoney, Jr, Donald H, Monteleone, Philip, Nemecek, Eneida R, Roehrs, Philip A, Schore, Reuven J, Stine, Kimo C, Takemoto, Clifford M, Toretsky, Jeffrey A, Costello, Joseph F, Olshen, Adam B, Stewart, Chip, Li, Yongjin, Ma, Jing, Gerbing, Robert B, Alonzo, Todd A, Getz, Gad, Gruber, Tanja, Golub, Todd, Stegmaier, Kimberly, Loh, Mignon L
• Format: Journal Article
• Language: English
• Published: United States Nature Publishing Group 01.11.2015
• Subjects: Acute Disease; Cancer; Child; Child, Preschool; Development and progression; Disease Progression; Disease-Free Survival; DNA Copy Number Variations; Female; Gene mutations; Genetic aspects; Genetic Predisposition to Disease - genetics; Genetic transcription; Genome-Wide Association Study - methods; Grants; Health aspects; High-Throughput Nucleotide Sequencing - methods; Humans; Infant; Kinases; Leukemia; Leukemia in children; Leukemia, Myeloid - diagnosis; Leukemia, Myeloid - genetics; Leukemia, Myelomonocytic, Juvenile - diagnosis; Leukemia, Myelomonocytic, Juvenile - genetics; Male; Mutation; Myelocytic leukemia; Nonlymphoid leukemia; Patients; Prognosis; Signal transduction; Signal Transduction - genetics
• ISSN: 1061-4036; 1546-1718
• DOI: 10.1038/ng.3400

Juvenile myelomonocytic leukemia (JMML) is a myeloproliferative neoplasm (MPN) of childhood with a poor prognosis. Mutations in NF1, NRAS, KRAS, PTPN11 or CBL occur in 85% of patients, yet there are currently no risk stratification algorithms capable of predicting which patients will be refractory to conventional treatment and could therefore be candidates for experimental therapies. In addition, few molecular pathways aside from the RAS-MAPK pathway have been identified that could serve as the basis for such novel therapeutic strategies. We therefore sought to genomically characterize serial samples from patients at diagnosis through relapse and transformation to acute myeloid leukemia to expand knowledge of the mutational spectrum in JMML. We identified recurrent mutations in genes involved in signal transduction, splicing, Polycomb repressive complex 2 (PRC2) and transcription. Notably, the number of somatic alterations present at diagnosis appears to be the major determinant of outcome.