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. 2015 Dec 10;127(1):29–41. doi: 10.1182/blood-2015-07-604496

Figure 3.

Figure 3

Clonal architecture, patterns of relapse, and the existence of preleukemic stem cells. (A) Clonal evolution and clonal heterogeneity of AML. Evolution of AML in a hypothetical patient whose tumor carries cooperating DNMT3A, NPM1c, and FLT3-ITD mutations. Mutation of DNMT3A is the earliest event, and although facilitating clonal expansion, occurs prior to overt disease development. Subsequently, NPM1c occurs as the disease-defining mutation in the founding clone, with further acquisition of a FLT3-ITD mutation in a hyperproliferative clone during leukemia expansion, which becomes dominant at diagnosis. Quantification of the variant allele frequency (VAF) of each mutation (by VAF, right) allows a demonstration of the temporal acquisition of mutations and the clonal hierarchy of the bulk tumor. For simplicity, a linear evolutionary pattern is shown, although commonly branching evolution can be demonstrated. (B) Heterogeneous clonal pattern of relapse in AML. Potential patterns of relapse from the hypothetical tumor in panel A are shown in the Fish plots: 1, relapse of the dominant clone at diagnosis; 2, relapse of a subclone present at diagnosis; 3, relapse from an ancestrally related clone; 4, “apparent relapse,” where the new tumor is not clonally related to the initial leukemia, such as might happen in therapy-related AML. (C) Existence of preleukemic clones that precede overt AML and may persist through treatment. Recently, the existence of preleukemic stem cells has been demonstrated.50-52 These harbor AML-associated mutations such as DNMT3A, TET2, and IDH2 that permit multipotent differentiation, but also facilitate clonal expansion within the stem and progenitor compartment (panel, second right). Upon the acquisition of further mutations (again NPM1c and FLT3-ITD are shown in the third panel), overt disease develops. However, treatment, although successful in eradicating the AML blasts, does not eradicate the preleukemic stem cells. Evidence suggests that these cells form the reservoir for relapse and resistance (left panel), although further study is required to characterize their biology and prognostic significance.