Genetic evidence for lineage-related 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 Aricò, Giuseppe Masera, Giuseppe Basso, Mariella Sorcini, Bruce D. Gelb, Andrea Biondi

Research output: Contribution to journalArticlepeer-review

232 Scopus citations

Abstract

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 germline 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- 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-related and differentiation stage-related contribution of these lesions to clonal expansion.

Original languageEnglish
Pages (from-to)307-313
Number of pages7
JournalBlood
Volume104
Issue number2
DOIs
StatePublished - 15 Jul 2004

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