cpi203 and Leukemia--Myelogenous--Chronic--BCR-ABL-Positive

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.

Topics: Acetamides; Animals; Antigens, CD34; Azepines; Cell Death; Cell Differentiation; DNA-Binding Proteins; Female; Fusion Proteins, bcr-abl; Hematopoietic Stem Cells; Humans; Imatinib Mesylate; Imidazolines; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Male; Mice; Neoplasm Proteins; Neoplastic Stem Cells; Proteomics; Proto-Oncogene Proteins c-myc; Reproducibility of Results; Signal Transduction; Transcriptome; Tumor Suppressor Protein p53