Evolutionary trajectory of leukemic clones and its clinical implications

Abstract

The ontogeny of acute myeloid leukemia is a multistep process. It is driven both by features of the malignant clone itself as well as by environmental pressures, making it a unique process in each individual. The technological advancements of recent years has increased our understanding about the different steps that take place at the genomic level. It is now clear that malignant clones evolve, expand and change even during what seem to be clinically healthy or "cured" periods. This opens a wide window for new therapeutic and monitoring opportunities. Moreover, prediction and even early prevention have become possible goals to be pursued. The aim of this review is to shed light upon recent observations in leukemia evolution and their clinical implications. We present a critical view of these concepts in order to assist clinicians when interpreting results of the ever growing myriad of genomic diagnostic tests. We wish to help clinicians incorporate genetic tests into their clinical assessment and enable them to provide genetic counseling to their patients.

Figure 1.

High-risk and low-risk pre-leukemic somatic mutations. X: an acquired somatic mutation. Clone size [as manifested by variant allele frequency (VAF) value] is represented by the size of the oval shape. Clonal expansion is represented by the rising curve. (A) Low-risk age-related clonal hematopoiesis (ARCH) mutations, such as DNMT3A or TET2 mutations, are acquired at a relatively young age (marked in white). Most of these clones will not progress to acute myeloid leukemia (AML). (B) Pre-leukemic clones, characterized by similar low-risk mutations have an increased fitness (as manifested by an increased VAF). They acquire additional pre-leukemic mutations (marked in yellow and red), not necessarily in the same clone. These cells are hematopoietic stem and progenitor cells (HSPCs), still capable of differentiation and sustain hematopoiesis. Once a clone acquires a leukemic, transforming, mutation (NPM1, for instance, marked in green) it will progress rapidly to an overt AML with loss of differentiation capacity and uncontrolled proliferation. Retrospectively, its preceding clones are referred to as pre-leukemic. Leukemic mutations are shared by all the leukemic blasts, hence they have a high VAF (50%) in the leukemic clone. Late events (e.g. FLT3-ITD, marked in purple) appear later along the AML evolutionary trajectory, are shared by subclones, and represent the clonal heterogeneity of the leukemia; they have VAFs ≤50%. The exact timing of AML diagnosis can vary. Therefore, late events are usually already present when the actual diagnosis is made. Single cells or sub-populations have to be sequenced in order to accurately determine the order of acquisition of the mutations. (C) Spliceosomal machinery, and other high-risk mutations (such as SRSF2, U2AF1, IDH1, IDH2 and TP53 that are marked in pink) are usually acquired at a more advanced age. These clones expand more rapidly (as manifested by the rate of increase of their VAF value) and most will lead to AML.

Figure 2.

Pre-leukemic clones have inherent chemoresistance. Pre-leukemic clones (blue) undergo positive selection by chemotherapy administered for a non-related cancer [other than acute myeloid leukemia (AML)]. They expand and evolve into t-AML (green). Pre-leukemic hematopoietic stem and progenitor cells (HSPCs) have inherent chemoresistance, thus they also survive following AML induction chemotherapy and reconstitute clonal hematopoiesis. Most relapses occur within the first 2 years and originate from residual leukemic clones that can be identified at diagnosis and that were not eradicated by AML therapy. Rare events of second AML (red) stem from (mostly, the same) pre-leukemic clones that evolved again into AML following a more prolonged latency.