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Ferrata Storti Foundation
Haematologica 2019 Volume 104(5):872-880
Evolutionary trajectory of leukemic clones and its clinical implications
Amos Tuval1,2 and Liran I Shlush1,3
1Department of Immunology, Weizmann Institute of Science, Rehovot; 2Hematology Department, Meir Medical Center, Kfar Saba and 3Hematology Department, Rambam Healthcare Campus, Haifa, Israel
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 indi- vidual. 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 clini- cal assessment and enable them to provide genetic counseling to their patients.
Introduction
Acute myeloid leukemia (AML) is a clonal disorder that originates in leukemic stem and progenitor cells, termed blasts.1 AML clinically manifests with the accu- mulation of these immature cells that exhibit uncontrolled growth and decreased apoptosis, and that lack normal differentiation. AML is clinically defined when blasts make up 20% or more of the cellular component of the bone marrow (BM). These cells inhibit normal hematopoiesis resulting in BM failure.2 Although most of the leukemic cells can be eradicated during the first course of therapy, most patients succumb to disease relapse within the first two years.3
Acute myeloid leukemia is characterized by a relatively small (compared to solid tumors), recurrent set of somatic mutations, designated leukemia driver mutations.4 The various mutations can be used to classify AML subtypes. Genomic analysis of 1540 AML patients identified distinct AML subgroups according to their mutational background. Some mutations (such as in the DNMT3A gene) are shared by few sub- groups, some of the mutations co-occur (e.g. DNMT3A, NPM1 and FLT3-ITD), while others are not usually found in the same clone (TP53 and NPM1).5
Most somatic mutations in AML occur stochastically across the genome without any foci of localized hypermutation.6 Theoretically, if the effective size of the stem cell population had been large enough, and it had been given enough replication cycles, it would have been reasonable to assume that almost every possible muta- tion can be found at the single cell level. Yet, not all mutations are shared by all AML subtypes. Moreover, a specific mutational signature with an elevated rate of C>T transitions was found in AML. This mutational signature was related to spon- taneous deamination of 5-methyl-cytosine and was correlated with age.6 This implies that the aging BM niche exerts a selective pressure on the leukemic stem cells and shapes their mutational profile.
Clones become fitter as they accumulate mutations and evolve. However, stud- ies in other malignancies suggest that most mutations that are being accumulated during cancer evolution are deleterious to tumor fitness,7 and are called “passenger
Correspondence:
AMOS TUVAL
amos.tuval@weizmann.ac.il
LIRAN I SHLUSH
liran.shlush@weizmann.ac.il
Received: January 21, 2019. Accepted: April 4, 2019. Pre-published: April 18 2019.
doi:10.3324/haematol.2018.195289
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/104/5/872
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