Tracing the origins of relapse in acute myeloid leukaemia to stem cells

Abstract

In acute myeloid leukaemia, long-term survival is poor as most patients relapse despite achieving remission. Historically, the failure of therapy has been thought to be due to mutations that produce drug resistance, possibly arising as a consequence of the mutagenic properties of chemotherapy drugs. However, other lines of evidence have pointed to the pre-existence of drug-resistant cells. For example, deep sequencing of paired diagnosis and relapse acute myeloid leukaemia samples has provided direct evidence that relapse in some cases is generated from minor genetic subclones present at diagnosis that survive chemotherapy, suggesting that resistant cells are generated by evolutionary processes before treatment and are selected by therapy. Nevertheless, the mechanisms of therapy failure and capacity for leukaemic regeneration remain obscure, as sequence analysis alone does not provide insight into the cell types that are fated to drive relapse. Although leukaemia stem cells have been linked to relapse owing to their dormancy and self-renewal properties, and leukaemia stem cell gene expression signatures are highly predictive of therapy failure, experimental studies have been primarily correlative and a role for leukaemia stem cells in acute myeloid leukaemia relapse has not been directly proved. Here, through combined genetic and functional analysis of purified subpopulations and xenografts from paired diagnosis/relapse samples, we identify therapy-resistant cells already present at diagnosis and two major patterns of relapse. In some cases, relapse originated from rare leukaemia stem cells with a haematopoietic stem/progenitor cell phenotype, while in other instances relapse developed from larger subclones of immunophenotypically committed leukaemia cells that retained strong stemness transcriptional signatures. The identification of distinct patterns of relapse should lead to improved methods for disease management and monitoring in acute myeloid leukaemia. Moreover, the shared functional and transcriptional stemness properties that underlie both cellular origins of relapse emphasize the importance of developing new therapeutic approaches that target stemness to prevent relapse.

The contributions of cancer cell metabolism to metastasis

“…One important conclusion of several of these studies is that CSCs display molecular and functional heterogeneity. Interestingly, this heterogeneity seems to be established early during tumorigenesis because genetically distinct CSC sub-clones are already present in primary tumours, some of which fade or become dominant during tumour progression and response to chemotherapy (Ben-David et al, 2017; Shlush et al, 2017; Zehir et al, 2017). However, it is still a matter of debate whether all cells capable of initiating and promoting primary tumour growth are equally competent to initiate metastasis.…”

“…In addition, epidermal stem cells that lack Dnmt3A and 3B upregulate a unique lipid transcriptional network that is associated with CD36 + MICs, and are consequently much more predisposed to generating metastatic epidermal tumours (Pascual et al, 2017; Rinaldi et al, 2017). Considering that the genes encoding Dnmt3a and TET proteins are among the most frequently mutated in human cancers (Shlush et al, 2017; Zehir et al, 2017), it will be interesting to study how their mutations influence tumour metabolism, and vice versa , during metastatic progression.…”

Clonal evolution mechanisms in NT5C2 mutant-relapsed acute lymphoblastic leukaemia

“…Resistance-driving mutations have been linked to enhanced leukemia growth and proliferation, clonal expansion at early stages of tumor development and increased leukemia stem cell activity 20–22 . However, studies of resistance to bacterial antibiotics have uncovered frequent examples of evolutionary trade-offs in which the acquisition of drug resistance is coupled with a reduced fitness phenotype 23 .…”

Metabolism as master of hematopoietic stem cell fate

“…Leukemia stem cells (LSCs, also known as leukemia-initiating cells) are believed to not only drive disease initiation, progression, and drug resistance, but also contribute to relapse [101–105]. Elimination of every single LSC is, therefore, essential to a long-term cure.…”