Induction of p53 suppresses chronic myeloid leukemia

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.

p53 Gene (NY-CO-13) Levels in Patients with Chronic Myeloid Leukemia: The Role of Imatinib and Nilotinib

“…Finally, tyrosine kinase inhibitors mainly nilotinib produced potential therapeutic effects on the reactivation of the p53 gene in patients with CML as supported by Peterson et al’s study that illustrated activation of the p53 gene in vitro and in vivo by a specific agent that prevented the binding of the p53 gene with negative regulators regarded as potential pathways for the cure of CML [ 31 ].…”

Targeting Abnormal Hematopoietic Stem Cells in Chronic Myeloid Leukemia and Philadelphia Chromosome-Negative Classical Myeloproliferative Neoplasms

“…HDM2, another p53 negative regulator, inhibits TP53 transcription via binding to its transactivation domain [ 18 , 227 , 228 ]. Hyperactivity of CML LSCs leads to p53 proteasomal degradation and evasion of apoptosis.…”

Nuclear-cytoplasmic Shuttling in Chronic Myeloid Leukemia: Implications in Leukemia Maintenance and Therapy

“…As a consequence, shuttling of p53 from the nucleus to the cytoplasm affects its role in tumorigenesis [7,40,41]. The tumor suppressor p53 is essential in CML pathogenesis, even if TP53 mutations were discovered only during the progression of the disease [42,43]. In a recent observation, p53 protein was clearly described as a master regulator of CML stem cells, in a tight correlation with c-Myc [44].…”