Dual targeting of p53 and c Myc selectively eliminates leukaemic stem cells
Summary Chronic myeloid leukaemia (CML) arises following transformation of a haemopoietic stem cell (HSC) by protein tyrosine kinase BCR ABL1. Direct inhibition of BCR ABL1 kinase has revolutionized disease management, but fails to eradicate leukaemic stem cells (LSC) which maintain CML. LSC are independent of BCR ABL1 for survival, providing a rationale to identify and target kinase independent pathways. Here we show using proteomics, transcriptomics and network analyses, that in human LSC aberrantly expressed proteins, in both imatinib responder and non responder patients are modulated in concert with p53 and c Myc regulation. Perturbation of both p53 and c Myc, not BCR ABL1 itself, leads to synergistic kill, differentiation and near elimination of transplantable human LSC in mice, whilst sparing normal HSC. This unbiased systems approach targeting connected nodes exemplifies a novel precision medicine strategy providing evidence that LSC can be eradicated.
Nature