Abstract |
The response of Philadelphia chromosome (Ph(+)) acute lymphoblastic leukemia (ALL) to treatment by BCR-ABL tyrosine kinase inhibitors (TKIs) has been disappointing, often resulting in short remissions typified by rapid outgrowth of drug-resistant clones. Therefore, new treatments are needed to improve outcomes for Ph(+) ALL patients. In a mouse model of Ph(+) B-lineage ALL, MCL-1 expression is dysregulated by the BCR-ABL oncofusion protein, and TKI treatment results in loss of MCL-1 expression prior to the induction of apoptosis, suggesting that MCL-1 may be an essential prosurvival molecule. To test this hypothesis, we developed a mouse model in which conditional allele(s) of Mcl-1 can be deleted either during leukemia transformation or later after the establishment of leukemia. We report that endogenous MCL-1's antiapoptotic activity promotes survival during BCR-ABL transformation and in established BCR-ABL(+) leukemia. This requirement for MCL-1 can be overcome by overexpression of other antiapoptotic molecules. We further demonstrate that strategies to inhibit MCL-1 expression potentiate the proapoptotic action of BCL-2 inhibitors in both mouse and human BCR-ABL(+) leukemia cell lines. Thus, strategies focused on antagonizing MCL-1 function and expression would be predicted to be effective therapeutic strategies.
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Authors | Brian Koss, Jeffrey Morrison, Rhonda M Perciavalle, Harpreet Singh, Jerold E Rehg, Richard T Williams, Joseph T Opferman |
Journal | Blood
(Blood)
Vol. 122
Issue 9
Pg. 1587-98
(Aug 29 2013)
ISSN: 1528-0020 [Electronic] United States |
PMID | 23881917
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Chemical References |
- Myeloid Cell Leukemia Sequence 1 Protein
- Fusion Proteins, bcr-abl
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Topics |
- Animals
- Apoptosis
(genetics, physiology)
- B-Lymphocytes
(metabolism, physiology)
- Cell Lineage
(genetics)
- Cell Survival
(genetics)
- Cells, Cultured
- Disease Models, Animal
- Fusion Proteins, bcr-abl
(genetics)
- Gene Expression Regulation, Leukemic
- Humans
- Mice
- Mice, Inbred C57BL
- Mice, Transgenic
- Myeloid Cell Leukemia Sequence 1 Protein
(genetics, physiology)
- Precursor Cell Lymphoblastic Leukemia-Lymphoma
(drug therapy, genetics, pathology)
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