Allelic Imbalances in Radiation—Associated Acute Myeloid Leukemia

Klymenko, Sergiy; Smida, Jan; Atkinson, Michael J.; Bebeshko, Volodymir G.; Nathrath, Michaela; Rosemann, Michael

doi:10.3390/genes2020384

Cited by 5 publications

(3 citation statements)

References 18 publications

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“…26,27 Epidemiologic studies of individuals living in proximity to nuclear sites and exposed to low doses of ionizing radiation have demonstrated higher frequencies of point mutations in RUNX1 and loss of heterozygosity at chromosome 5q and 7. 28,29 A recent analysis of patients diagnosed with AML or MDS after exposure to RT alone reported cytogenetic features and outcomes more similar to patients with de novo AML. 30 This report prompted the question whether AML or MDS after RT monotherapy should be considered therapy related.…”

Section: Introductionmentioning

confidence: 99%

Therapy-Related Myeloid Neoplasms in 109 Patients Following Radiation Monotherapy

et al. 2021

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Therapy-related myeloid neoplasms (t-MNs) are a late complication of cytotoxic therapy and are defined as a distinct entity by the World Health Organization. While the link between chemotherapy exposure and risk of subsequent t-MN is well-described, the association between radiation monotherapy (RT) and t-MN risk is less definitive. We analyzed 109 consecutive patients who developed t-MNs after RT and describe latencies, cytogenetic profile, mutation analyses, and clinical outcomes. The most common cytogenetic abnormality was a clonal abnormality in chromosome 5 and/or 7, which was present in 45% of patients. The median latency from RT to t-MN diagnosis was 6.5 years, with the shortest latency in patients with balanced translocations. 1-year overall survival (OS) was 52% and 5-year OS was 22% for the entire cohort. Patients with chromosome 5 and/or 7 abnormalities experienced worse 1-year OS (37%) and 5-year OS (2%) when compared to other cytogenetic groups (p<0.0001). 16 patients underwent NGS; ASXL1 and TET2 were the most commonly mutated genes (n=4). In addition, 17 patients underwent germline variant testing and 3 carried pathogenic or likely pathogenic germline variants. In conclusion, patients with t-MN after RT monotherapy have increased frequencies of chromosome 5 and/or 7 abnormalities, which are associated with poor overall survival. In addition, pathogenic germline variants may be common in patients with t-MN after RT monotherapy.

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Section: Introductionmentioning

confidence: 99%

Therapy-Related Myeloid Neoplasms in 109 Patients Following Radiation Monotherapy

et al. 2021

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“…A “second-hit” in these cells, in the form of a point mutation in the second Sfpi1 (PU.1) allele in its DNA binding domain (R235), is believed to transform these cells leading to clonal expansion and cancer [30,31]. Sequencing of AML samples from survivors of the Chernobyl accident showed similar mutational pattern with large chromosomal deletions and loss-of-heterozygosity (LOH) in multiple locations in the genome [32]. Experimental irradiation was also shown to accelerate the development of leukaemia in engineered mouse models, for example, such as the acute lymphoblastic leukaemia (ALL) associated with t(12;21)(p13;q22) leading to a TEL-AML1 (aka ETV6-RUNX1 ) fusion, coupled with a loss of the CDKN2A cell cycle regulator gene [33].…”

Section: Aml Mouse Models Induced By Chemicals Viral Infection Ormentioning

confidence: 99%

Murine Models of Acute Myeloid Leukaemia

Almosailleakh

Schwaller

2019

IJMS

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Acute myeloid leukaemia (AML) is a rare but severe form of human cancer that results from a limited number of functionally cooperating genetic abnormalities leading to uncontrolled proliferation and impaired differentiation of hematopoietic stem and progenitor cells. Before the identification of genetic driver lesions, chemically, irradiation or viral infection-induced mouse leukaemia models provided platforms to test novel chemotherapeutics. Later, transgenic mouse models were established to test the in vivo transforming potential of newly cloned fusion genes and genetic aberrations detected in patients’ genomes. Hereby researchers constitutively or conditionally expressed the respective gene in the germline of the mouse or reconstituted the hematopoietic system of lethally irradiated mice with bone marrow virally expressing the mutation of interest. More recently, immune deficient mice have been explored to study patient-derived human AML cells in vivo. Unfortunately, although complementary to each other, none of the currently available strategies faithfully model the initiation and progression of the human disease. Nevertheless, fast advances in the fields of next generation sequencing, molecular technology and bioengineering are continuously contributing to the generation of better mouse models. Here we review the most important AML mouse models of each category, briefly describe their advantages and limitations and show how they have contributed to our understanding of the biology and to the development of novel therapies.

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“…Exposure to IR is associated with the induction of solid cancers and hematological malignancies including myeloproliferative neoplasms (MPNs). 1,2 On April 25–26, 1986, the Chernobyl nuclear power plant accident at reactor 4 occurred in Ukraine, classified as a level 7 event by the International Nuclear Event Scale. Over 500,000 people were involved in clean-up work following the accident during 1986–1991.…”

Section: Introductionmentioning

confidence: 99%

Characteristics of myeloproliferative neoplasms in patients exposed to ionizing radiation following the Chernobyl nuclear accident

et al. 2018

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Myeloproliferative neoplasms (MPNs) driver mutations are usually found in JAK2, MPL and CALR genes, however, 10–15% of cases are triple negative (TN). A previous study showed lower rate of JAK2 V617F in Primary Myelofibrosis (PMF) patients exposed to low doses of ionizing radiation (IR) from Chernobyl accident. To examine distinct driver mutations, we enrolled 281 Ukrainian IR-exposed and unexposed MPN patients. Genomic DNA was obtained from peripheral blood leukocytes. JAK2 V617F, MPL W515, type 1- and 2-like CALR mutations were identified by Sanger Sequencing and RT-PCR. Chromosomal alterations were assessed by oligo-SNP microarray platform. Additional genetic variants were identified by whole exome and targeted sequencing. Statistical significance was evaluated by Fisher’s exact test and Wilcoxon’s rank sum test (R, version 3.4.2). IR-exposed MPN patients exhibited a different genetic profile versus unexposed: lower rate of JAK2 V617F (58.4% vs 75.4%, P = 0.0077), higher rate of type 1-like CALR mutation (12.2% vs 3.1%, P = 0.0056), higher rate of TN cases (27.8% vs 16.2%, P = 0.0366), higher rate of potentially pathogenic sequence variants (mean numbers: 4.8 vs 3.1, P = 0.0242). Furthermore, we identified several potential drivers specific to IR-exposed TN MPN patients: ATM p.S1691R with copy-neutral loss of heterozygosity at 11q; EZH2 p.D659G at 7q and SUZ12 p.V71M at 17q with copy number loss. Thus, IR-exposed MPN patients represent a group with distinct genomic characteristics worthy of further study.

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Allelic Imbalances in Radiation—Associated Acute Myeloid Leukemia

Cited by 5 publications

References 18 publications

Therapy-Related Myeloid Neoplasms in 109 Patients Following Radiation Monotherapy

Therapy-Related Myeloid Neoplasms in 109 Patients Following Radiation Monotherapy

Murine Models of Acute Myeloid Leukaemia

Characteristics of myeloproliferative neoplasms in patients exposed to ionizing radiation following the Chernobyl nuclear accident

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