Clonal evolution of acute leukemia genomes

Abstract

In large part, cancer results from the accumulation of multiple mutations in a single cell lineage that are sequentially acquired and subject to an evolutionary process where selection drives the expansion of more fit subclones. Owing to the technical challenge of distinguishing and isolating distinct cancer subclones, many aspects of this clonal evolution are poorly understood, including the diversity of different subclones in an individual cancer, the nature of the subclones contributing to relapse, and the identity of pre-cancerous mutations. These issues are not just important to our understanding of cancer biology, but are also clinically important given the need to understand the nature of subclones responsible for the refractory and relapsed disease that cause significant morbidity and mortality in patients. Recently, advanced genomic techniques have been used to investigate clonal diversity and evolution in acute leukemia. Studies of pediatric acute lymphoblastic leukemia (ALL) demonstrated that in individual patients there are multiple genetic subclones of leukemia-initiating cells, with a complex clonal architecture. Separate studies also investigating pediatric ALL determined that the clonal basis of relapse was variable and complex, with relapse often evolving from a clone ancestral to the predominant de novo leukemia clone. Additional studies in both ALL and acute myeloid leukemia have identified pre-leukemic mutations in some individual cases. This review will highlight these recent reports investigating the clonal evolution of acute leukemia genomes and discuss the implications for clinical therapy.

Figure 1. Model for the Clonal Progression of HSC into a Frankly Leukemic Clone

Genomic and functional studies have demonstrated that multiple mutations are necessary to transform normal cells into a leukemic clone (here depicted as 5 mutations). In the case of acute leukemia, these mutations occur in hematopoietic cells in the bone marrow, most of which are short-lived. As hematopoietic stem cells (HSC) are the only self-renewing cells among bone marrow progenitors, a model has been proposed that mutations must sequentially accumulate within distinct clones of HSC over time (x-axis), eventually resulting in the generation of a frankly leukemic clone (y-axis). According to this model, the HSC compartment at the time of diagnosis is heterogeneous with both genetically normal HSC and numerous intermediate pre-leukemic HSC clones, possessing some, but not all of the mutations found in the leukemic clone.

Figure 2. Model for Clonal Heterogeneity in Acute Leukemia

Recent evidence has demonstrated that in some cases of acute leukemia, multiple genetic subclones of leukemia-initiating cells exist within a complex clonal architecture. This clonal heterogeneity usually consists of distinct subpopulations with a dominant leukemic clone (red). There are several possibilities for the generation of the additional leukemic clones. (a) The dominant clone can undergo additional mutational events to generate distinct daughter subclones (brown, tan, and orange). (b) Alternatively, a common pre-leukemic clone can undergo divergent evolution to generate a distinct, but related, leukemic clone (yellow). Ultimately, the total population of leukemic cells consists of these multiple subclones with a complex genetic relationship, and both common and divergent mutations.

Figure 3. Model for the Clonal Basis of Relapse in Acute Leukemia

The clonal heterogeneity of pre-leukemic HSC clones and frankly leukemic clones leads to multiple models for the clonal bases of relapse in acute leukemia. (a) A simple option is that the predominant leukemic clone, and its leukemia stem cells, persist following therapy, eventually expanding to give rise to the refractory, relapsed clone (red). (b) An alternative is that a rare treatment-resistant subclone is selected through the course of therapy that is responsible for relapse (yellow). (c) A third possibility is that treatment with DNA-damaging therapeutic agents contributes to genetic evolution of the leukemia, resulting in a genetically novel relapsed clone (dark brown). (d) A final possibility is that DNA-damaging therapeutic agents act on pre-leukemic cells to induce additional mutations resulting in a novel relapsed clone (pink). It is likely that the clonal basis of relapse will differ between individual patients, as suggested by the studies of pediatric ALL described above. It is also possible, that more than one mechanism can be responsible for relapse in the same patient, giving rise to clonal heterogeneity within relapsed leukemia.