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Blood, 15 February 2008, Vol. 111, No. 4, pp. 2269-2279. Prepublished online as a Blood First Edition Paper on December 3, 2007; DOI 10.1182/blood-2007-04-082099. This Article Full Text Full Text (PDF) Supplemental Figures All Versions of this Article: blood-2007-04-082099v1 111/4/2269    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map 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 Dos Santos, C. Articles by Récher, C. Search for Related Content PubMed PubMed Citation Articles by Dos Santos, C. Articles by Récher, C. Related Collections Neoplasia Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA A critical role for Lyn in acute myeloid leukemia Cédric Dos Santos1, Cécile Demur1,2, Valérie Bardet3, Nais Prade-Houdellier1, Bernard Payrastre1, and Christian Récher1,4 1 Inserm U563, Centre de Physiopathologie de Toulouse Purpan, Département d'Oncogenèse, Signalisation et Innovation Thérapeutique, Université Toulouse III Paul Sabatier, IFR30, Toulouse; 2 Centre Hospitalier Universitaire (CHU) Toulouse, Hôpital Purpan, Laboratoire d'Hématologie, Toulouse; 3 Inserm U567, Centre National de la Recherche Scientifique (CNRS)–UMR 8104, Institut Cochin, Service d'Hématologie Biologique, Assistance Publique des Hâpitaux de Paris (AP-HP), Hôpital Cochin, Paris; and 4 CHU Toulouse, Hôpital Purpan, Service d'Hématologie, Toulouse, France Receptor or nonreceptor tyrosine kinases (TKs) are known to play an important role in leukemogenesis. Here we studied the level of protein tyrosine phosphorylations in a series of fresh AML samples and evaluated the effect of TK inhibitors. Compared with normal hematopoietic progenitors, a high level of tyrosine phosphorylation was detected in most acute myeloid leukemia (AML) samples. The Src family kinases (SFKs) appeared constitutively activated in most cases, including in the CD34+CD38–CD123+ compartment as revealed by the level of phosphorylated tyrosine 416. Lyn was the major SFK family member expressed in an active form in AML cells where it was abnormally distributed throughout the plasma membrane and the cytosol as opposed to normal hematopoietic progenitors. The SFK inhibitor, PP2, strongly reduced the global level of tyrosine phosphorylations, inhibited cell proliferation, and induced apoptosis in patient samples without affecting normal granulomonocytic colony forming units. Moreover, silencing Lyn expression by small interfering RNA in primary AML cells strongly inhibited proliferation. Interestingly, a link between Lyn and the mTOR pathway was observed as PP2 and a Lyn knockdown both affected the phosphorylation of mTOR targets without inhibiting Akt phosphorylation. Lyn should be considered as a novel pharmacologic target for AML therapy. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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