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Blood, 15 July 2004, Vol. 104, No. 2, pp. 307-313. Prepublished online as a Blood First Edition Paper on February 24, 2004; DOI 10.1182/blood-2003-11-3876. This Article Full Text (PDF) Supplemental Tables and Figures All Versions of this Article: 2003-11-3876v1 104/2/307    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 HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Tartaglia, M. Articles by Biondi, A. Search for Related Content PubMed PubMed Citation Articles by Tartaglia, M. Articles by Biondi, A. Related Collections Related Article in Blood Online Social Bookmarking                   What's this? Submitted November 12, 2003 Accepted February 5, 2004 Genetic evidence for lineage- and differentiation stage-related contribution of somatic PTPN11 mutations to leukemogenesis in childhood acute leukemia Marco Tartaglia*, Simone Martinelli, Giovanni Cazzaniga, Viviana Cordeddu, Ivano Iavarone, Monica Spinelli, Chiara Palmi, Claudio Carta, Andrea Pession, Maurizio Arico, Giuseppe Masera, Giuseppe Basso, Mariella Sorcini, Bruce D Gelb, and Andrea Biondi Biologia cellulare e Neuroscienze, Istituto Superiore di Sanita, Rome, Italy Clinica Pediatrica, Centro Ricerca M. Tettamanti, Universita di Milano Bicocca, Monza, Italy Ambiente e connessa prevenzione primaria, Istituto Superiore di Sanita, Rome, Italy Pediatria, Universita di Padova, Padova, Italy Pediatria, Universita di Bologna, Bologna, Italy Onco-Ematologia Pediatrica, Ospedale dei Bambini, Palermo, Italy Pediatrics, Mount Sinai School of Medicine, New York, NY, USA; Human Genetics, Mount Sinai School of Medicine, New York, NY, USA * Corresponding author; email: mtartaglia{at}iss.it. SHP-2 is a protein tyrosine phosphatase functioning as signal transducer downstream to growth factor and cytokine receptors. SHP-2 is required during development, and germ-line mutations in PTPN11, the gene encoding SHP-2, cause Noonan syndrome. SHP-2 plays a crucial role in hematopoietic cell development. We recently demonstrated that somatic PTPN11 mutations are the most frequent lesion in juvenile myelomonocytic leukemia, and are observed in a smaller percentage of children with other myeloid malignancies. Here, we report that PTPN11 lesions occur in childhood acute lymphoblastic leukemia (ALL). Mutations were observed in 23 of 317 B-cell precursor ALL cases, but not among 44 children with T-lineage ALL. In the former, lesions prevalently occurred in TEL-AML1-negative cases with CD19+/CD10+/cyIgM- immunophenotype. PTPN11, NRAS and KRAS2 mutations were largely mutually exclusive, and accounted for one-third of common ALL cases. We also show that, among 69 children with acute myeloid leukemia, PTPN11 mutations occurred in 4 of 12 cases with acute monocytic leukemia (FAB-M5). Leukemia-associated PTPN11 mutations were missense, and were predicted to result in SHP-2 gain-of-function. Our findings provide evidence for a wider role of PTPN11 lesions in leukemogenesis, but also suggest a lineage- and differentiation stage-related contribution of these lesions to clonal expansion. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? 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