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Forced expression of cyclin-dependent kinase 6 confers resistance of pro-B acute lymphocytic leukemia to Gleevec treatment.
- Source :
-
Molecular and cellular biology [Mol Cell Biol] 2011 Jul; Vol. 31 (13), pp. 2566-76. Date of Electronic Publication: 2011 May 02. - Publication Year :
- 2011
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Abstract
- The gene encoding c-ABL, a nonreceptor protein tyrosine kinase, is involved in a chromosomal translocation resulting in expression of a BCR-Abl fusion protein that causes most chronic myelogenous and some acute lymphocytic leukemias (CML and ALL) in humans. The Abelson murine leukemia virus (A-MuLV) expresses an alternative form of c-Abl, v-Abl, that transforms murine pro-B cells, resulting in acute leukemia and providing an experimental model for human disease. Gleevec (STI571) inhibits the Abl kinase and has shown great utility against CML and ALL in humans, although its usefulness is limited by acquired resistance. Since STI571 is active against A-MuLV-transformed cells in vitro, we performed a retroviral cDNA library screen for genes that confer resistance to apoptosis induced by STI571. We found that forced expression of Cdk6 promotes continued cell division and decreased apoptosis of leukemic cells. We then determined that the transcription factor E2A negatively regulates Cdk6 transcription in leukemic pro-B cells and that the v-Abl kinase stimulates Cdk6 expression via an extracellular signal-regulated kinase 1-dependent pathway. Finally, we show that the cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor PD0332991 can act synergistically with STI571 to enhance leukemic cell death, suggesting a potential role for CDK6 inhibitors in the treatment of STI571-resistant CML or ALL.
- Subjects :
- Benzamides
Cell Cycle
Cell Line, Tumor
Cyclin-Dependent Kinase 6 antagonists & inhibitors
Gene Library
Humans
Imatinib Mesylate
Piperazines pharmacology
Precursor B-Cell Lymphoblastic Leukemia-Lymphoma enzymology
Pyridines pharmacology
Transcription, Genetic
Antineoplastic Agents therapeutic use
Cyclin-Dependent Kinase 6 genetics
Drug Resistance, Neoplasm genetics
Piperazines therapeutic use
Precursor B-Cell Lymphoblastic Leukemia-Lymphoma drug therapy
Protein Kinase Inhibitors therapeutic use
Pyrimidines therapeutic use
Subjects
Details
- Language :
- English
- ISSN :
- 1098-5549
- Volume :
- 31
- Issue :
- 13
- Database :
- MEDLINE
- Journal :
- Molecular and cellular biology
- Publication Type :
- Academic Journal
- Accession number :
- 21536647
- Full Text :
- https://doi.org/10.1128/MCB.01349-10