Molecular-defined clonal evolution in patients with chronic myeloid leukemia who were exposed to ionizing radiation following the Chernobyl nuclear disaster

Abstract

In 1986, the worst accident in the history of the nuclear industry occurred, when a series of explosions destroyed Unit 4 of the Chernobyl nuclear power plant, after a misguided safety test, which simulated a power failure, went disastrously wrong. An estimated 10–20 million people were exposed to significant levels of radioactive fallout. In subsequent recovery work, about 600,000 people, known as liquidators, were employed to decontaminate the immediate area and build the sarcophagus over the destroyed reactor [1]. A number of epidemiological studies have predominantly shown a dose-related increased incidence of thyroid cancer due to radioiodine exposure from Chernobyl fallout, with a higher risk for those exposed at a younger age. In addition, an increase in incidence and mortality from non-thyroid cancers has been reported [2]. Two casecontrolled studies have provided evidence of increased leukemia risks for liquidators from Belarus, the Russian Federation, and Baltic countries [3], as well as Ukrainian recovery workers [4]. Despite the well-established link between radiation exposure and cancer risk [5, 6], analyses regarding the molecular background of radiation-related leukemic disease are incomplete. In general, radiation damage results in cell death or viable molecularly altered cells. Damage caused by cell death is known as deterministic radiation damage, with tissue damage increasing with radiation dose. An important example of deterministic damage is bone marrow depletion. Stochastic damages are those whose risk of occurrence is increased with increasing radiation dose, i.e., tumor development and hereditary damage. They are the result of living, but molecularly altered somatic and germ cells [7]. As cancer cells are abnormal clones from a single aberrant cell, radiation can be understood as an initiating event in the multistep pathogenesis of cancer. In this context, we sought to analyze a cohort of patients who developed BCR-ABL1-positive chronic myelogenous leukemia (CML) after the Chernobyl nuclear disaster. In general, CML represents an ideal disease model for hematologic malignancies. The identification of the underlying cytogenetic aberration, the Philadelphia chromosome with the BCR-ABL1 gene fusion, enabled the development of selective BCR-ABL1 tyrosine kinase inhibitors, such as imatinib, which have shown remarkable success in the treatment of CML [8]. Recent studies have shown that about one-third of patients with spontaneously occurring CML carry leukemia-associated mutations other than the characteristic BCR-ABL1 fusion gene [9]. In some cases, these additional molecular aberrations have been shown to occur prior to the acquisition of BCR-ABL1 [10, 11]. To investigate the prevalence and mutational patterns of such mutations in Ukrainian CML patients affected by radiation, targeted next-generation sequencing (NGS) of leukemia-associated genes was carried out using blood slides of 25 patients (12 male), who were diagnosed between June 2005 and April 2017. Ten of the patients worked as cleanup workers (liquidators) at the Chernobyl power plant between 1986 and 1988 after the accident, two patients were evacuated in 1986, and 13 patients were inhabitants of the radiation-contaminated area. The patients * Thomas Ernst [email protected]