title: 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.
authors.affiliation: Department of Biochemistry, St. Jude Children’s Research Hospital, Memphis, TN 38105-3678, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Koss
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Morrison
authors.forename: Rhonda M
authors.initials: RM
authors.lastname: Perciavalle
authors.forename: Harpreet
authors.initials: H
authors.lastname: Singh
authors.forename: Jerold E
authors.initials: JE
authors.lastname: Rehg
authors.forename: Richard T
authors.initials: RT
authors.lastname: Williams
authors.forename: Joseph T
authors.initials: JT
authors.lastname: Opferman
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D001402:B-Lymphocytes / Q000378:metabolism / Q000502:physiology; D019070:Cell Lineage / Q000235:genetics*; D002470:Cell Survival / Q000235:genetics; D002478:Cells, Cultured; D004195:Disease Models, Animal; D016044:Fusion Proteins, bcr-abl / Q000235:genetics*; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000235:genetics / Q000502:physiology*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology*
chemical_list: D064549:Myeloid Cell Leukemia Sequence 1 Protein; D016044:Fusion Proteins, bcr-abl