|
|
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.
 Previous Article | Next Article 
Submitted April 6, 2007
Accepted November 18, 2007
A critical role for Lyn in Acute Myeloid Leukemia
Cedric Dos Santos, Cecile Demur, Valerie Bardet, Nais Prade-Houdellier, Bernard Payrastre, and Christian Recher*
Inserm, U563, Centre de Physiopathologie de Toulouse Purpan et Universite Paul Sabatier, Dep d'Oncogenese, Signalisation et Innovation therapeutique, & Universite Toulouse III Paul Sabatier, Toulouse, France
Laboratoire d'Hematologie, CHU Toulouse, Hopital Purpan, Toulouse, France
Universite Paris Descartes, Institut Cochin (Inserm U567, CNRS-UMR 8104), Service d'Hematologie Biologique, AP-HP, Hopital Cochin, Paris, France
Service d'Hematologie, CHU Toulouse, Hopital Purpan, Toulouse, France
* Corresponding author; email: recher.c{at}chu-toulouse.fr.
Receptor or non-receptor 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 to normal haematopoietic progenitors, a high level of tyrosine phosphorylation was detected in most 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 haematopoietic 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 granulo-monocytic 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 pharmacological target for AML therapy.
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
This article has been cited by other articles:
|
|
|
|
 
J. Tamburini, A. S. Green, V. Bardet, N. Chapuis, S. Park, L. Willems, M. Uzunov, N. Ifrah, F. Dreyfus, C. Lacombe, et al.
Protein synthesis is resistant to rapamycin and constitutes a promising therapeutic target in acute myeloid leukemia
Blood,
August 20, 2009;
114(8):
1618 - 1627.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. G. Renner, C. Dos Santos, C. Recher, C. Bailly, L. Creancier, A. Kruczynski, B. Payrastre, and S. Manenti
Polo-like kinase 1 is overexpressed in acute myeloid leukemia and its inhibition preferentially targets the proliferation of leukemic cells
Blood,
July 16, 2009;
114(3):
659 - 662.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
N. K. Williams, I. S. Lucet, S. P. Klinken, E. Ingley, and J. Rossjohn
Crystal Structures of the Lyn Protein Tyrosine Kinase Domain in Its Apo- and Inhibitor-bound State
J. Biol. Chem.,
January 2, 2009;
284(1):
284 - 291.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
W. Yu, X. Sun, N. Clough, E. Cobos, Y. Tao, and Z. Dai
Abi1 gene silencing by short hairpin RNA impairs Bcr-Abl-induced cell adhesion and migration in vitro and leukemogenesis in vivo
Carcinogenesis,
September 1, 2008;
29(9):
1717 - 1724.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
