Dual targeting of p53 and c-MYC selectively eliminates leukaemic stem cells

Abstract

SummaryChronic 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.

Regulation of normal and leukemic stem cells through cytokine signaling and the microenvironment

“…HH hedgehog, IL interleukin, NICD Notch intracellular domain, PTCH patched, SMO smoothened, TFs transcription factors, THPO thrombopoetin, TNF tumor necrosis factor been observed in leukemic cells [72]. Additional studies that support these findings show that dual targeting of p53 and c-MYC simultaneously improves the selectivity for targeting LSCs in CML as compared to tyrosine kinase inhibitors alone that are unable to eradicate the LSCs responsible for relapse [73]. Moreover, resistance to BET inhibitors (Bromodomain and extra terminal protein that bind acetylated chromatin marks) as seen in leukemic cells, is partially due to activation of Wnt/β-catenin signaling, and targeting this pathway restored the sensitivity of cells towards these inhibitors [74].…”

Single-cell molecular analysis defines therapy response and immunophenotype of stem cell subpopulations in CML

“…33,34 However, the LSC population is heterogeneous, consisting of a mixture of leukemic cells with differences in TKI sensitivity as well as residual healthy stem cells and progenitors. 10,31,35 Single-cell gene expression analysis offers the possibility to identify distinct subpopulations within the stem cell population in CML while directly discriminating between leukemic and normal cells based on BCR-ABL expression.…”

CML cells actively evade host immune surveillance through cytokine-mediated downregulation of MHC-II expression

“…16 All microarray data sets are summarized with respect to sample size, sorting strategy, and the relevant figure in supplemental Table 1; by combining these data sets, transcriptional profiles of 19 independent CML samples and 10 independent normal samples were analyzed. Where genes were represented by multiple probes, expression was summarized using the median value.…”