Dual targeting of p53 and c-MYC selectively eliminates leukaemic stem cells.
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.
Paul O'Gorman Leukaemia Research Centre, Institute of Cancer Sciences, University of Glasgow, Gartnavel General Hospital, 1053 Great Western Road, Glasgow G12 0YN, UK.
Sheela A
SA
Abraham
Paul O'Gorman Leukaemia Research Centre, Institute of Cancer Sciences, University of Glasgow, Gartnavel General Hospital, 1053 Great Western Road, Glasgow G12 0YN, UK.
Lisa E M
LE
Hopcroft
Stem Cell and Leukaemia Proteomics laboratory, University of Manchester, Manchester M20 3LJ, UK.|Manchester Precision Medicine Institute, University of Manchester, Manchester M20 3LJ, UK.
Emma
E
Carrick
Paul O'Gorman Leukaemia Research Centre, Institute of Cancer Sciences, University of Glasgow, Gartnavel General Hospital, 1053 Great Western Road, Glasgow G12 0YN, UK.
Mark E
ME
Drotar
Paul O'Gorman Leukaemia Research Centre, Institute of Cancer Sciences, University of Glasgow, Gartnavel General Hospital, 1053 Great Western Road, Glasgow G12 0YN, UK.
Karen
K
Dunn
Stem Cell and Leukaemia Proteomics laboratory, University of Manchester, Manchester M20 3LJ, UK.|Manchester Precision Medicine Institute, University of Manchester, Manchester M20 3LJ, UK.
Andrew J K
AJ
Williamson
Paul O'Gorman Leukaemia Research Centre, Institute of Cancer Sciences, University of Glasgow, Gartnavel General Hospital, 1053 Great Western Road, Glasgow G12 0YN, UK.|Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Glasgow G61 1QH, UK.
Koorosh
K
Korfi
Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Glasgow G61 1QH, UK.
Pablo
P
Baquero
Paul O'Gorman Leukaemia Research Centre, Institute of Cancer Sciences, University of Glasgow, Gartnavel General Hospital, 1053 Great Western Road, Glasgow G12 0YN, UK.
Laura E
LE
Park
Paul O'Gorman Leukaemia Research Centre, Institute of Cancer Sciences, University of Glasgow, Gartnavel General Hospital, 1053 Great Western Road, Glasgow G12 0YN, UK.
Mary T
MT
Scott
Paul O'Gorman Leukaemia Research Centre, Institute of Cancer Sciences, University of Glasgow, Gartnavel General Hospital, 1053 Great Western Road, Glasgow G12 0YN, UK.
Francesca
F
Pellicano
Stem Cell and Leukaemia Proteomics laboratory, University of Manchester, Manchester M20 3LJ, UK.|Manchester Precision Medicine Institute, University of Manchester, Manchester M20 3LJ, UK.
Andrew
A
Pierce
Paul O'Gorman Leukaemia Research Centre, Institute of Cancer Sciences, University of Glasgow, Gartnavel General Hospital, 1053 Great Western Road, Glasgow G12 0YN, UK.
Mhairi
M
Copland
Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Glasgow G61 1QH, UK.
Craig
C
Nourse
University of Melbourne Centre for Cancer Research, University of Melbourne, Victoria 3010, Australia.
Sean M
SM
Grimmond
Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Glasgow G61 1QH, UK.
David
D
Vetrie
Stem Cell and Leukaemia Proteomics laboratory, University of Manchester, Manchester M20 3LJ, UK.|Manchester Precision Medicine Institute, University of Manchester, Manchester M20 3LJ, UK.|Stoller Biomarker Discovery Centre, University of Manchester, Manchester M20 3LJ, UK.
Anthony D
AD
Whetton
Paul O'Gorman Leukaemia Research Centre, Institute of Cancer Sciences, University of Glasgow, Gartnavel General Hospital, 1053 Great Western Road, Glasgow G12 0YN, UK.
Tessa L
TL
Holyoake
D000081:Acetamides / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism; D001381:Azepines / Q000494:pharmacology / Q000627:therapeutic use; D016923:Cell Death / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000378:metabolism; D005260:Female; D016044:Fusion Proteins, bcr-abl / Q000378:metabolism; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D000068877:Imatinib Mesylate / Q000494:pharmacology / Q000627:therapeutic use; D048288:Imidazolines / Q000494:pharmacology / Q000627:therapeutic use; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D051379:Mice; D009363:Neoplasm Proteins / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology* / Q000637:transplantation; D040901:Proteomics; D016271:Proto-Oncogene Proteins c-myc / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D015203:Reproducibility of Results; D015398:Signal Transduction / Q000187:drug effects; D059467:Transcriptome; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000235:genetics / Q000378:metabolism
D000081:Acetamides; D018952:Antigens, CD34; D001381:Azepines; C000599185:CPI203; D004268:DNA-Binding Proteins; D048288:Imidazolines; C489427:MYC protein, human; D009363:Neoplasm Proteins; D016271:Proto-Oncogene Proteins c-myc; C579783:RG7112; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C403666:ZNF331 protein, human; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl