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

Brian Koss, Jeffrey Morrison, Rhonda M. Perciavalle, Harpreet Singh, Jerold E. Rehg, Richard T. Williams and Joseph T. Opferman

Key points

  • Using a mouse genetic mouse model of Philadelphia-chromosome B-ALL, endogenous anti-apoptotic MCL-1 is required for leukemia survival.

  • In BCR-ABL+ B-ALL human and mouse cells, combining TKIs with small molecule inhibitors of BCL-2 can potentiate sensitivity to cell death.

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 (B-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 pro-survival 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 anti-apoptotic 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 anti-apoptotic molecules. We further demonstrate that strategies to inhibit MCL-1 expression potentiate the pro-apoptotic 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.

  • Submitted June 28, 2012.
  • Accepted July 7, 2013.