Autophagy induction by Bcr-Abl-expressing cells facilitates their recovery from a targeted or nontargeted treatment.
AffiliationLeslie C. Quick Laboratory, Cork Cancer Research Centre, BioSciences Institute,, University College Cork and Mercy University Hospital, Grenville Place, Cork,, Ireland.
Cell Line, Tumor
Fusion Proteins, bcr-abl/*biosynthesis/genetics
Gene Knockdown Techniques
Leukemia, Myelogenous, Chronic, BCR-ABL Positive/*drug
Molecular Targeted Therapy/methods
RNA, Small Interfering/administration & dosage/genetics
MetadataShow full item record
CitationAm J Hematol. 2011 Jan;86(1):38-47.
JournalAmerican journal of hematology
AbstractAlthough Imatinib has transformed the treatment of chronic myeloid leukemia (CML), it is not curative due to the persistence of resistant cells that can regenerate the disease. We have examined how Bcr-Abl-expressing cells respond to two mechanistically different therapeutic agents, etoposide and Imatinib. We also examined Bcr-Abl expression at low and high levels as elevated expression has been associated with treatment failure. Cells expressing low levels of Bcr-Abl undergo apoptosis in response to the DNA-targeting agent (etoposide), whereas high-Bcr-Abl-expressing cells primarily induce autophagy. Autophagic populations engage a delayed nonapoptotic death; however, sufficient cells evade this and repopulate following the withdrawal of the drug. Non-Bcr-Abl-expressing 32D or Ba/F3 cells induce both apoptosis and autophagy in response to etoposide and can recover. Imatinib treatment induces both apoptosis and autophagy in all Bcr-Abl-expressing cells and populations rapidly recover. Inhibition of autophagy with ATG7 and Beclin1 siRNA significantly reduced the recovery of Imatinib-treated K562 cells, indicating the importance of autophagy for the recovery of treated cells. Combination regimes incorporating agents that disrupt Imatinib-induced autophagy would remain primarily targeted and may improve response to the treatment in CML.
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