Molecular and genetic alterations associated with therapy resistance and relapse of acute myeloid leukemia

Abstract

Background: The majority of individuals with acute myeloid leukemia (AML) respond to initial chemotherapy and achieve a complete remission, yet only a minority experience long-term survival because a large proportion of patients eventually relapse with therapy-resistant disease. Relapse therefore represents a central problem in the treatment of AML. Despite this, and in contrast to the extensive knowledge about the molecular events underlying the process of leukemogenesis, information about the mechanisms leading to therapy resistance and relapse is still limited.

Purpose and content of review: Recently, a number of studies have aimed to fill this gap and provided valuable information about the clonal composition and evolution of leukemic cell populations during the course of disease, and about genetic, epigenetic, and gene expression changes associated with relapse. In this review, these studies are summarized and discussed, and the data reported in them are compiled in order to provide a resource for the identification of molecular aberrations recurrently acquired at, and thus potentially contributing to, disease recurrence and the associated therapy resistance. This survey indeed uncovered genetic aberrations with known associations with therapy resistance that were newly gained at relapse in a subset of patients. Furthermore, the expression of a number of protein coding and microRNA genes was reported to change between diagnosis and relapse in a statistically significant manner.

Conclusions: Together, these findings foster the expectation that future studies on larger and more homogeneous patient cohorts will uncover pathways that are robustly associated with relapse, thus representing potential targets for rationally designed therapies that may improve the treatment of patients with relapsed AML, or even facilitate the prevention of relapse in the first place.

Keywords: Acute myeloid leukemia; Clonal evolution; Copy number variation; Cytogenetics; DNA methylation; Gene expression profiling; Relapse; Single nucleotide variants; Therapy resistance.

Fig. 1

Genetic and molecular events investigated for possible changes between diagnosis and relapse of AML. A diagram representing clonal evolution in a hypothetical patient with AML is shown in the top panel. The other panels represent genetic and molecular alterations between diagnosis and relapse of AML that are discussed in this article; methods used to investigate these aberrations are indicated to the left of the respective panels. HSCs hematopoietic stem cells, CR complete remission, transloc translocation, SNP single nucleotide polymorphism

Fig. 2

Circos plot summarizing genetic aberrations recurrently acquired at relapse in adult patients with non-APL AML. Inner circle, unbalanced cytogenetic aberrations newly acquired at relapse in at least 2 patients [–56, 63, 68, 122]; middle circle, CNAs and UPDs newly acquired at relapse in at least 2 patients [–69]. Within each type of aberration, overlapping lesions were considered recurrent events unless an aberration was reported only in 1 patient and became recurrent due to the same type of aberration affecting the corresponding entire chromosome in another single patient. For high patient numbers, different scales were used and patient numbers color-coded as indicated in the graphical legend. Outer circle, genes affected by SNVs or indels in a relapse-specific manner in at least 2 patients according to next generation sequencing-based studies [34, 36, 38, 39, 68, 95, 96]. The plot was constructed using the R package “circlize” [123]. Genomic positions of genes and chromosome bands were retrieved from the UCSC genome browser, human genome version hg19. Detailed data are provided in Additional file 1: Table S1A, Additional file 2: Table S2A, and Additional file 3: Table S3A. These also include studies containing exclusively pediatric patients or patients with APL, which were not considered for this figure. Recurrently gained aberrations are shown in this graph irrespective of whether or not they were recurrently lost in other patients; information about recurrent loss at relapse is provided in Additional file 1: Table S1B, Additional file 2: Table S2B, and Additional file 3: Table S3B

Fig. 3

Different pathways leading to relapse of AML. Gray dots, age-related, pathogenetically irrelevant passenger mutations; orange dots, early (pre-) leukemic driver mutations; red dots, late leukemic driver mutations; bright yellow dots, non-synonymous mutations newly acquired at relapse. All HSCs are assumed to accumulate mostly innocuous mutations during aging; only mutations that would be found as passenger mutations in AML are depicted in the figure. The figure does not intend to illustrate the duration of CR, or the presence or absence of minimal residual disease detectable by routine methods. Dx diagnosis, CR complete remission, LSC leukemic stem cell, HSC hematopoietic stem cell