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Blood, 1 May 2008, Vol. 111, No. 9, pp. 4716-4722. Prepublished online as a Blood First Edition Paper on February 25, 2008; DOI 10.1182/blood-2007-10-113068. This Article Full Text (PDF) Supplemental Tables and Figure All Versions of this Article: blood-2007-10-113068v1 111/9/4716    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Kim, W. J. Articles by Haber, D. A Search for Related Content PubMed PubMed Citation Articles by Kim, W. J. Articles by Haber, D. A Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted October 3, 2007 Accepted February 3, 2008 Mutations in the neutral sphingomyelinase gene SMPD3 implicate the ceramide pathway in human leukemias Woo Jae Kim, Ross A Okimoto, Louise E Purton, Meagan Goodwin, Sara M Haserlat, Farshid Dayyani, David A Sweetser, Andrea I McClatchey, Olivier A. Bernard, A. Thomas Look, Daphne W Bell, David T Scadden, and Daniel A Haber* Massachusetts General Hospital Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States Center for Regenerative Medicine and Harvard Stem Cell Institute, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States Department of Pediatric Hematology/Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States Universite Rene Descartes, and Institut National de la Sante et de la Recherche Medicale (INSERM), Paris, France Department of Pediatric Oncology, Dana-Farber Cancer Institute, and Division of Hematology, Children's Hospital Boston, Harvard Medical School, Boston, MA, United States * Corresponding author; email: haber{at}helix.mgh.harvard.edu. Ceramide is a lipid second messenger derived from the hydrolysis of sphingomyelin by sphingomyelinases (SMases) and implicated in diverse cellular responses, including growth arrest, differentiation and apoptosis. Defects in the neutral sphingomyelinase (nSMase) gene Smpd3, the primary regulator of ceramide biosynthesis, are responsible for developmental defects of bone and regulation of ceramide levels have been implicated in macrophage differentiation, but this pathway has not been directly implicated in human cancer. In a genomic screen for gene copy losses contributing to tumorigenesis in a mouse osteosarcoma model, we identified a somatic homozygous deletion specifically targeting Smpd3. Reconstitution of SMPD3 expression in mouse tumor cells lacking the endogenous gene enhanced tumor necrosis factor (TNF)-induced reduction of cell viability. Nucleotide sequencing of the highly conserved SMPD3 gene in a large panel of human cancers revealed mutations in 5/92 (5%) of acute myeloid leukemias (AML) and 8/131 (6%) of acute lymphoid leukemias (ALL), but not in other tumor types. In a subset of them, functional analysis indicated defects in protein stability and localization. Taken together, these observations suggest that disruption of the ceramide pathway may contribute to a subset of human leukemias. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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