Induction of p53 suppresses chronic myeloid leukemia

Luke F. PetersonComprehensive Cancer Center, University of Michigan, Ann Arbor, MI, USA; ;Department of Internal Medicine, Division of Hematology and Oncology, University of Michigan, Ann Arbor, MI, USA; Correspondence[email protected]

Miao-Chia LoCollege of Pharmacy, University of Michigan, Ann Arbor, MI, USA;

Yihong LiuComprehensive Cancer Center, University of Michigan, Ann Arbor, MI, USA; ;Department of Internal Medicine, Division of Hematology and Oncology, University of Michigan, Ann Arbor, MI, USA;

Diane GiannolaComprehensive Cancer Center, University of Michigan, Ann Arbor, MI, USA;

Emilija MitrikeskaComprehensive Cancer Center, University of Michigan, Ann Arbor, MI, USA; ;Department of Internal Medicine, Division of Hematology and Oncology, University of Michigan, Ann Arbor, MI, USA;

Nicholas J. DonatoComprehensive Cancer Center, University of Michigan, Ann Arbor, MI, USA; ;Department of Internal Medicine, Division of Hematology and Oncology, University of Michigan, Ann Arbor, MI, USA;

Craig N. JohnsonDNA Sequencing and Microarray Core, University of Michigan, Ann Arbor, MI, USA;

Shaomeng WangDepartment of Pharmacology and Medicinal Chemistry, University of Michigan, Ann Arbor, MI, USA

Jessica MercerComprehensive Cancer Center, University of Michigan, Ann Arbor, MI, USA; ;Department of Internal Medicine, Division of Hematology and Oncology, University of Michigan, Ann Arbor, MI, USA;

Moshe TalpazComprehensive Cancer Center, University of Michigan, Ann Arbor, MI, USA; ;Department of Internal Medicine, Division of Hematology and Oncology, University of Michigan, Ann Arbor, MI, USA;

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Abstract

Chronic myeloid leukemia (CML) is characterized by the chromosomal translocation 9;22, known as the Philadelphia chromosome (Ph), which produces the BCR-ABL fusion tyrosine kinase. Although well-managed by BCR-ABL tyrosine kinase inhibitors (TKIs), treatment fails to eliminate Ph + primitive progenitors, and cessation of therapy frequently results in relapse. The p53 protein is an important regulator of cell cycle and apoptosis. The small molecules MI-219 target the interaction between p53 and its negative regulator HDM2, leading to its stabilization and activation. We show that treatment with MI-219 reduced the number of CML cells in both in vitro and in vivo settings but not that of normal primitive progenitors, and activated different gene signatures in CML potentially explaining the differential impact of this agent on each population. Our data suggest that a p53-activating agent may be an effective approach in the management and potential operational cure of CML.

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Disclosure forms provided by the authors are available with the full text of this article online at http://dx.doi.org/10.1080/10428194.2016.1272682.

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Induction of p53 suppresses chronic myeloid leukemia

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Induction of p53 suppresses chronic myeloid leukemia

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