Role of the p38 mitogen-activated protein kinase pathway in the generation of the effects of imatinib mesylate (STI571) in BCR-ABL-expressing cells.
Imatinib mesylate (STI571), a specific inhibitor of the BCR-ABL tyrosine kinase, exhibits potent antileukemic effects in vitro and in vivo. Despite the well established role of STI571 in the treatment of chronic myelogenous leukemia, the precise mechanisms by which inhibition of BCR-ABL tyrosine kinase activity results in generation of antileukemic responses remain unknown. In the present study we provide evidence that treatment of CML-derived BCR-ABL-expressing leukemia cells with STI571 results in activation of the p38 mitogen-activated protein (MAP) kinase signaling pathway. Our data indicate that STI571 induces phosphorylation of the p38 and activation of its kinase domain, in KT-1 cells and other BCR-ABL-expressing cell lines. We also identify the kinases MAP kinase-activated protein kinase-2 and Msk1 as two downstream effectors of p38, activated during inhibition of BCR-ABL activity by STI571. Importantly, pharmacological inhibition of p38 reverses the growth inhibitory effects of STI571 on primary leukemic colony-forming unit granulocyte/macrophage progenitors from patients with CML. Altogether, our data establish that activation of the p38 MAP kinase signaling cascade plays an important role in the generation of the effects of STI571 on BCR-ABL-expressing cells. They also suggest that, in addition to activation of mitogenic pathways, BCR-ABL promotes leukemogenesis by suppressing the function of growth inhibitory signaling cascades.
Parmar
Simrit
S
Robert H. Lurie Comprehensive Cancer Center and Division of Hematology Oncology, Northwestern University Medical School, Chicago, Illinois 60611, USA.
Katsoulidis
Efstratios
E
Verma
Amit
A
Li
Yongzhong
Y
Sassano
Antonella
A
Lal
Lakhvir
L
Majchrzak
Beata
B
Ravandi
Farhad
F
Tallman
Martin S
MS
Fish
Eleanor N
EN
Platanias
Leonidas C
LC
D000970:Antineoplastic Agents / Q000494:pharmacology*; D001549:Benzamides; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors*; D006801:Humans; D000068877:Imatinib Mesylate; D016898:Interferon-alpha / Q000494:pharmacology; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology*; D010766:Phosphorylation; D010879:Piperazines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases
D000970:Antineoplastic Agents; D001549:Benzamides; D016898:Interferon-alpha; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases