| First Author | Abraham SA | Year | 2016 |
| Journal | Nature | Volume | 534 |
| Issue | 7607 | Pages | 341-6 |
| PubMed ID | 27281222 | Mgi Jnum | J:235742 |
| Mgi Id | MGI:5800614 | Doi | 10.1038/nature18288 |
| Citation | Abraham SA, et al. (2016) Dual targeting of p53 and c-MYC selectively eliminates leukaemic stem cells. Nature 534(7607):341-6 |
| abstractText | 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. |
