학술논문
Dual targeting of p53 and c-MYC selectively eliminates leukaemic stem cells
Document Type
Report
Author
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.
Source
Nature. June 16, 2016, p341, 18 p.
Subject
Language
English
ISSN
0028-0836
Abstract
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.
BCR-ABL1 is a chimaeric oncogene arising from the t(9;22)(q34;q11) chromosomal translocation. The resultant protein tyrosine kinase (PTK) drives signalling events (1) and transforms HSCs. BCR-ABL activity in HSCs causes CML, [...]
BCR-ABL1 is a chimaeric oncogene arising from the t(9;22)(q34;q11) chromosomal translocation. The resultant protein tyrosine kinase (PTK) drives signalling events (1) and transforms HSCs. BCR-ABL activity in HSCs causes CML, [...]