Clonal evolution and devolution after chemotherapy in adult acute myelogenous leukemia

Abstract

The frequent occurrence of persistent or relapsed disease after induction chemotherapy in AML necessitates a better understanding of the clonal relationship of AML in various disease phases. In this study, we used SNP 6.0 array-based genomic profiling of acquired copy number aberrations (aCNA) and copy neutral LOH (cnLOH) together with sequence analysis of recurrently mutated genes to characterize paired AML genomes. We analyzed 28 AML sample pairs from patients who achieved complete remission with chemotherapy and subsequently relapsed and 11 sample pairs from patients with persistent disease after induction chemotherapy. Through review of aCNA/cnLOH and gene mutation profiles in informative cases, we demonstrate that relapsed AML invariably represents re-emergence or evolution of a founder clone. Furthermore, all individual aCNA or cnLOH detected at presentation persisted at relapse indicating that this lesion type is proximally involved in AML evolution. Analysis of informative paired persistent AML disease samples uncovered cases with 2 coexisting dominant clones of which at least one was chemotherapy sensitive and one resistant, respectively. These data support the conclusion that incomplete eradication of AML founder clones rather than stochastic emergence of fully unrelated novel clones underlies AML relapse and persistence with direct implications for clinical AML research.

Figure 1

Display of dChip-based heatmap images of representative aCNA in AML. Displayed are heatmaps for lesions organized in triplets [buccal DNA (N), AML blast DNA from enrollment samples (T_E) and AML blast DNA from paired relapse (A) or persistent (B) AML samples; T_R or T_P, respectively]. Genomic losses are indicated by the color blue, genomic gains by the color red.

Figure 2

Schema of clonal relatedness in AML cases (paired enrollment and relapse samples) inferred from genomic profiling data. The quantitatively dominant clone as detected at the time of analysis is circled in green. AC: inferred antecedent clone. T_E: enrollment sample, T_R: paired relapse sample. Arrows indicate possible routes of clonal evolution. Circles indicate gene mutations, rectangles indicate aCNA or cnLOH.

Figure 3

Schema of clonal relatedness in AML cases (paired enrollment and persistent disease samples) inferred from genomic profiling data. The quantitatively dominant clone as detected at the time of analysis is circled in green. AC: inferred antecedent clone. T_E: enrollment sample, T_P: paired persistent disease sample. Arrows indicate possible routes of clonal evolution. Circles indicate gene mutations, rectangles indicate aCNA or cnLOH.