Early genetic changes may be key to identifying seemingly healthy individuals who face an increased risk of developing acute myeloid leukemia (AML), according to new findings.
These findings illuminate the "black box of leukemia" and answer the question of where, when, and how the disease begins, said study coauthor John Dick, PhD, senior scientist at Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
"We have been able to identify people in the general population who have traces of mutations in their blood that represent the first steps in how normal blood cells begin on a pathway of becoming increasingly abnormal and puts them at risk of progressing to AML," he said in a press release.
"We can find these traces up to 10 years before AML actually develops, and this long time window gives us the first opportunity to think about how to prevent AML," he added.
The study was published June 9 in Nature.
The incidence of AML increases with age, and mortality exceeds 90% when it is diagnosed after age 65 years, note the authors. However, most patients remain initially asymptomatic and generally present with acute complications of bone marrow failure.
The current study builds on research from 2014, when Dick and colleagues identified a preleukemic stem cell in blood samples obtained at the initial diagnosis of AML. The preleukemic stem cell, they noted, continues to maintain normal function but has begun the process of generating a pathway of cells that become increasingly abnormal and culminate in AML.
"Our 2014 study predicted that people with early mutations in their blood stem cells, long before the disease appears and makes them sick, should be able to be detected within the general population by testing a blood sample for the presence of the mutation," Dick explained in the press statement.
Identifying AML vs ARCH
For their study, Dick and colleagues collaborated with the European Prospective Investigation Into Cancer and Nutrition (EPIC) study, which tracked 521,000 participants recruited across 10 European countries and followed them for almost 15 years. Stored blood samples from this trial were used to determine the genetic changes were already present years before AML actually developed.
The onset of AML is generally preceded by the accumulation of somatic mutations in preleukemic hematopoietic stem and progenitor cells (HSPCs) that undergo clonal expansion, but recurrent AML mutations also accumulate in HSPCs of healthy individuals who do not develop AML. This benign process is known as age-related clonal hematopoiesis (ARCH). The authors first conducted deep sequencing to differentiate between individuals who have a high risk of developing AML and those with benign ARCH.
The team identified 95 individuals who had participated in the EPIC trial and then went on to develop AML, and they found blood samples that were obtained an average of 6.3 years before diagnosis.
They also identified 414 unselected age- and sex-matched controls.
When they compared peripheral blood cells between the cases and controls, they found distinct genetic differences, with cases showing more mutations per sample, higher variant allele frequencies, and enrichment of mutations in specific genes.
Genetic parameters were used to develop a model that accurately predicted AML-free survival, which was validated in an independent cohort of 29 pre-AML cases and 262 controls.
In the combined initial and validation cohorts, the authors observed that ARCH, defined on the basis of putative driver mutations (ARCH-PD), appeared in 73.4% of the pre-AML cases at a median of 7.6 years before diagnosis but was detected in only 36.7% of controls (P < 2.2 × 10−16, two-sided Fisher exact test). In addition, 39% of pre-AML cases who were older than age 50 years had a driver mutation with a variant allele frequency of more than 10% vs 4% of controls.
DNMT3A and TET2 were the most commonly mutated genes in both groups, and canonical NPM2 mutations or FLT3-internal tandem duplication mutations were not observed, which is consistent with previous findings that these mutations occur late in leukemogenesis.
Another observation was that recurrent CEBPA mutations, which have been implicated in about 10% of de novo AML cases, were also not observed, suggesting that driver events in this gene may also occur late in the disease process.
"Overall, these findings demonstrate notable differences in the mutational landscape of ARCH and pre-AML," they note. "Moreover, this work, in conjunction with recent insights into the origins of AML relapse, suggests that AML progression typically occurs over many years through clonal evolution of pre-leukaemic HSPCs before acquisition of late mutations leads to overt malignant transformation."
Coauthor George Vassiliou, FRCPath, MRCP(UK), PhD, from the Wellcome Sanger Institute and the Wellcome-MRC Cambridge Stem Cell Institute, and consultant hematologist at Cambridge University Hospitals NHS Trust, outlined plans for future research in a press statement.
"We hope to build on these findings to develop robust screening tests for identifying those at risk and drive research into how to prevent or stall progression towards AML," he said. "Our aspiration is that one day AML prevention would provide a compelling alternative to treatment."
The UHN research team was funded by the Leukemia and Lymphoma Society, Ontario Institute for Cancer Research, Canadian Cancer Society, Canadian Institutes for Health Research, International Development Research Centre, Terry Fox Research Institute, Medicine by Design– Canada First Research Excellence Fund, the Benjamin Pearl Fellowship from the McEwen Centre for Regenerative Medicine, the Ontario Ministry of Health and Long-term Care, and The Princess Margaret Cancer Foundation; also funded by the Wellcome Trust, UK Medical Research Council, Cancer Research UK. The authors have disclosed no relevant financial relationships.
Nature. Published online June 9, 2018. Abstract
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Cite this: New Findings Illuminate 'Black Box of Leukemia' - Medscape - Jul 12, 2018.
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