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Requirement for antiapoptotic MCL-1 in the survival of BCR-ABL B-lineage acute lymphoblastic leukemia.

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.
AuthorsBrian Koss, Jeffrey Morrison, Rhonda M Perciavalle, Harpreet Singh, Jerold E Rehg, Richard T Williams, Joseph T Opferman
JournalBlood (Blood) Vol. 122 Issue 9 Pg. 1587-98 (Aug 29 2013) ISSN: 1528-0020 [Electronic] United States
PMID23881917 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Fusion Proteins, bcr-abl
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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