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

Abstract

BackgroundThe 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 reviewRecently, 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.ConclusionsTogether, 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s13045-017-0416-0) contains supplementary material, which is available to authorized users.

Uncovering the Genomic Landscape in Newly Diagnosed and Relapsed Pediatric Cytogenetically Normal FLT3‐ITD AML

“…It has been suggested that there are three major clonal patterns to relapse: (i) the regrowth of leukemic stem cells (LSCs) without additional mutations making the mutation profile (not accounting for VAF) at relapse indistinguishable from diagnosis, (ii) the outgrowth of diagnostic LSC clones with newly acquired mutations, or (iii) the outgrowth of preleukemic hematopoietic stem cells containing early acquired mutations and newly acquired mutations not present at diagnosis . When analyzing diagnosis to relapse samples, although the mutation burden is low, a characteristic of AML, we observed all three clonal patterns ( Figure c, Figure ).…”

Prognostic significance of recurring chromosomal abnormalities in transplanted patients with acute myeloid leukemia

“…Notwithstanding the incorporation of novel innovative molecular risk stratification models into modern prognostication schemas of AML patients [8,19,20], baseline cytogenetic studies still serve as an invaluable prognostic tool for prediction of outcome at key clinical time points during the therapeutic sequence of AML patients [7]. Indeed, cytogenetic abnormalities have been previously established as robust predictors of the risk of primary induction resistance [21], risk of relapse [22,23], and outcome following transplant for primary refractory disease [24]. Yet, to what extent these chromosomal abnormalities impact on patients undergoing allo-HSCT has not been fully addressed hitherto.…”

Biology of DNMT3 and LSD1 inhibition in acute myeloid leukaemia (AML)

“…Critical ongoing efforts include further accurate pre-clinical models to elucidate how mutations in epigenetic modifiers interact with other AML disease alleles, and clinical studies to assess the efficacy of epigenetic therapies alone or in combination with other antileukemic agents. It is unlikely that any single approach employing the agents described above, including the most targeted, will be successful in eradicating AML cells due to the related problems of intrinsic or acquired forms of resistance [63]. Indeed, dual inhibition of DNMTs and LSD1 in acute myeloid leukaemia by synergistic re-activation of epigenetically silenced genes has been reported [64].…”