Dual targeting of p53 and c-MYC selectively eliminates leukaemic stem cells

• Published in: Nature (London) Vol. 534; no. 7607; pp. 341 - 346
• Main Authors: Abraham, Sheela A, Hopcroft, Lisa E M, Carrick, Emma, Drotar, Mark E, Dunn, Karen, Williamson, Andrew J K, Korfi, Koorosh, Baquero, Pablo, Park, Laura E, Scott, Mary T, Pellicano, Francesca, Pierce, Andrew, Copland, Mhairi, Nourse, Craig, Grimmond, Sean M, Vetrie, David, Whetton, Anthony D, Holyoake, Tessa L
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 16.06.2016
• Subjects: Acetamides - pharmacology; Acetamides - therapeutic use; Animals; Antigens, CD34 - metabolism; Apoptosis; Azepines - pharmacology; Azepines - therapeutic use; Cancer cells; Cancer therapies; Cell cycle; Cell Death - drug effects; Cell Differentiation - drug effects; Chronic myeloid leukemia; Development and progression; DNA-Binding Proteins - metabolism; Female; Fusion Proteins, bcr-abl - metabolism; Genetic aspects; Health aspects; Hematopoietic Stem Cells - cytology; Hematopoietic Stem Cells - drug effects; Hematopoietic Stem Cells - metabolism; Humans; Imatinib Mesylate - pharmacology; Imatinib Mesylate - therapeutic use; Imidazolines - pharmacology; Imidazolines - therapeutic use; Kinases; Leukemia; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - drug therapy; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - genetics; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - metabolism; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - pathology; Male; Methods; Mice; Molecular targeted therapy; Neoplasm Proteins - metabolism; Neoplastic Stem Cells - drug effects; Neoplastic Stem Cells - metabolism; Neoplastic Stem Cells - pathology; Neoplastic Stem Cells - transplantation; Properties; Proteins; Proteomics; Proto-Oncogene Proteins c-myc - antagonists & inhibitors; Proto-Oncogene Proteins c-myc - deficiency; Proto-Oncogene Proteins c-myc - genetics; Proto-Oncogene Proteins c-myc - metabolism; Reproducibility of Results; Signal Transduction - drug effects; Stem cells; Transcription factors; Transcriptome; Tumor proteins; Tumor Suppressor Protein p53 - antagonists & inhibitors; Tumor Suppressor Protein p53 - deficiency; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature18288

Chronic myeloid leukaemia (CML) arises after transformation of a haemopoietic stem cell (HSC) by the protein-tyrosine kinase BCR-ABL. Direct inhibition of BCR-ABL kinase has revolutionized disease management, but fails to eradicate leukaemic stem cells (LSCs), which maintain CML. LSCs are independent of BCR-ABL for survival, providing a rationale for identifying and targeting kinase-independent pathways. Here we show--using proteomics, transcriptomics and network analyses--that in human LSCs, aberrantly expressed proteins, in both imatinib-responder and non-responder patients, are modulated in concert with p53 (also known as TP53) and c-MYC regulation. Perturbation of both p53 and c-MYC, and not BCR-ABL itself, leads to synergistic cell kill, differentiation, and near elimination of transplantable human LSCs in mice, while sparing normal HSCs. This unbiased systems approach targeting connected nodes exemplifies a novel precision medicine strategy providing evidence that LSCs can be eradicated.