Sebastien Malinge

Publications (5)49.49 Total impact

• Article: Notch: of mice and men?

  Sebastien Malinge, John Crispino
  Blood 12/2010; 116(25):5438-9. · 9.90 Impact Factor
• Article: Genetic characterization of TET1, TET2, and TET3 alterations in myeloid malignancies.

  Omar Abdel-Wahab, Ann Mullally, Cyrus Hedvat, Guillermo Garcia-Manero, Jay Patel, Martha Wadleigh, Sebastien Malinge, JinJuan Yao, Outi Kilpivaara, Rukhmi Bhat, [......], Elisabeth Paietta, Michelle M Le Beau, Miloslav Beran, Martin S Tallman, Benjamin L Ebert, Hagop M Kantarjian, Richard M Stone, D Gary Gilliland, John D Crispino, Ross L Levine
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  ABSTRACT: Disease alleles that activate signal transduction are common in myeloid malignancies; however, there are additional unidentified mutations that contribute to myeloid transformation. Based on the recent identification of TET2 mutations, we evaluated the mutational status of TET1, TET2, and TET3 in myeloproliferative neoplasms (MPNs), chronic myelomonocytic leukemia (CMML), and acute myeloid leukemia (AML). Sequencing of TET2 in 408 paired tumor/normal samples distinguished between 68 somatic mutations and 6 novel single nucleotide polymorphisms and identified TET2 mutations in MPN (27 of 354, 7.6%), CMML (29 of 69, 42%), AML (11 of 91, 12%), and M7 AML (1 of 28, 3.6%) samples. We did not identify somatic TET1 or TET3 mutations or TET2 promoter hypermethylation in MPNs. TET2 mutations did not cluster in genetically defined MPN, CMML, or AML subsets but were associated with decreased overall survival in AML (P = .029). These data indicate that TET2 mutations are observed in different myeloid malignancies and may be important in AML prognosis.
  Blood 06/2009; 114(1):144-7. · 9.90 Impact Factor
• Article: Insights into the manifestations, outcomes, and mechanisms of leukemogenesis in Down syndrome.

  Sébastien Malinge, Shai Izraeli, John D Crispino
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  ABSTRACT: Children with Down syndrome (DS) show a spectrum of clinical anomalies, including cognitive impairment, cardiac malformations, and craniofacial dysmorphy. Moreover, hematologists have also noted that these children commonly show macrocytosis, abnormal platelet counts, and an increased incidence of transient myeloproliferative disease (TMD), acute megakaryocytic leukemia (AMKL), and acute lymphoid leukemia (ALL). In this review, we summarize the clinical manifestations and characteristics of these leukemias, provide an update on therapeutic strategies and patient outcomes, and discuss the most recent advances in DS-leukemia research. With the increased knowledge of the way in which trisomy 21 affects hematopoiesis and the specific genetic mutations that are found in DS-associated leukemias, we are well on our way toward designing improved strategies for treating both myeloid and lymphoid malignancies in this high-risk population.
  Blood 02/2009; 113(12):2619-28. · 9.90 Impact Factor
• Article: Activating mutations in human acute megakaryoblastic leukemia.

  Sébastien Malinge, Christine Ragu, Veronique Della-Valle, Didier Pisani, Stefan N Constantinescu, Christelle Perez, Jean-Luc Villeval, Dirk Reinhardt, Judith Landman-Parker, Lucienne Michaux, Nicole Dastugue, André Baruchel, William Vainchenker, Jean-Pierre Bourquin, Virginie Penard-Lacronique, Olivier A Bernard
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  ABSTRACT: Oncogenic activation of tyrosine kinase signaling pathway is recurrent in human leukemia. To gain insight into the oncogenic process leading to acute megakaryoblastic leukemia (AMKL), we performed sequence analyses of a subset of oncogenes known to be activated in human myeloid and myeloproliferative disorders. In a series of human AMKL samples from both Down syndrome and non-Down syndrome patients, mutations were identified within KIT, FLT3, JAK2, JAK3, and MPL genes, with a higher frequency in DS than in non-DS patients. The novel mutations were analyzed using BaF3 cells, showing that JAK3 mutations were activating mutations. Finally, we report a novel constitutively active MPL mutant, MPLT487A, observed in a non-Down syndrome childhood AMKL that induces a myeloproliferative disease in mouse bone marrow transplantation assay.
  Blood 09/2008; 112(10):4220-6. · 9.90 Impact Factor
• Source

  Available from: hematologylibrary.org

  Article: Novel activating JAK2 mutation in a patient with Down syndrome and B-cell precursor acute lymphoblastic leukemia.

  Sebastien Malinge, Raouf Ben-Abdelali, Catherine Settegrana, Isabelle Radford-Weiss, Marianne Debre, Kheira Beldjord, Elizabeth A Macintyre, Jean-Luc Villeval, William Vainchenker, Roland Berger, Olivier A Bernard, Eric Delabesse, Virginie Penard-Lacronique
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  ABSTRACT: Activation of tyrosine kinase genes is a frequent event in human hematologic malignancies. Because gene activation could be associated with gene dysregulation, we attempted to screen for activating gene mutation based on high-level gene expression. We focused our study on the Janus kinase 2 (JAK2) gene in 90 cases of acute leukemia. This strategy led to the identification of a novel JAK2-acquired mutation in a patient with Down syndrome (DS) with B-cell precursor acute lymphoblastic leukemia (BCP-ALL). This mutation involves a 5-amino acid deletion within the JH2 pseudokinase domain (JAK2DeltaIREED). Expression of JAK2DeltaIREED in Ba/F3 cells induced constitutive activation of the JAK-STAT pathway and growth factor-independent cell proliferation. These results highlight the JAK2 pseudokinase domain as an oncogenic hot spot and indicate that activation of the JAK-STAT pathway may contribute to lymphoid malignancies and hematologic disorders observed in children with DS.
  Blood 04/2007; 109(5):2202-4. · 9.90 Impact Factor