A critical role for Lyn in acute myeloid leukemia.
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.
Dos Santos
Cédric
C
Inserm U563, Centre de Physiopathologie de Toulouse Purpan, Département d'Oncogenèse, Signalisation et Innovation Thérapeutique, Université Toulouse III Paul Sabatier, IFR30, Toulouse, France.
Demur
Cécile
C
Bardet
Valérie
V
Prade-Houdellier
Nais
N
Payrastre
Bernard
B
Récher
Christian
C
D017209:Apoptosis / Q000187:drug effects; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects / Q000473:pathology; D045744:Cell Line, Tumor; D002867:Chromones / Q000494:pharmacology; D004791:Enzyme Inhibitors; D005434:Flow Cytometry; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000473:pathology*; D009025:Morpholines / Q000494:pharmacology; D009856:Oncogene Proteins, Viral / Q000502:physiology*; D019000:Phosphotyrosine / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D012016:Reference Values; D020123:Sirolimus / Q000494:pharmacology; D020298:U937 Cells; D019061:src-Family Kinases / Q000502:physiology*
D002867:Chromones; D004791:Enzyme Inhibitors; D009025:Morpholines; D009856:Oncogene Proteins, Viral; D034741:RNA, Small Interfering; D019000:Phosphotyrosine; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases; D020123:Sirolimus