CommentaryWhy is there so much therapy-related AML and MDS and so little therapy-related CML?
Introduction
Therapeutic exposure to DNA-damaging drugs accounts for 10–20% of cases of AML and MDS but few if any cases of CML [1], [2], [3]. In contrast, exposure to sparsely ionizing radiation increases risks of AML, MDS and CML comparably [4], [5]. Both exposures cause mutations in DNA, so why is CML so rare after DNA-damaging drugs compared with after sparsely ionizing radiation? We suggest it is because sparsely ionizing radiation is particularly effective at producing DNA double-strand breaks (DSBs) under conditions that favor a balanced reciprocal translocation between BCR and ABL1, necessary and sufficient to cause all cases of CML. Ionizing radiation produces many DSBs during the G0/G1 phase of the cell cycle, and there is a bias for the DSBs to be proximal in space and time [6]. These features favor production of the BCR/ABL1 oncogene. Balanced reciprocal translocations between other potentially oncogenic genes occur less frequently and are not necessary and/or not sufficient to cause most cases of AML or MDS.
Section snippets
Hypothesis
Our hypothesis has 3 parts:
- (1)
Exposure to sparsely ionizing radiation increases frequencies of AML, MDS and CML comparably.
- (2)
Exposure to DNA-damaging drugs, especially alkylators, increases frequencies of AML and MDS far more than it increases the frequency of CML. The difference in increased frequencies is 100- to 1000-fold.
- (3)
The reason for (1) and (2) is sparsely ionizing radiation is a relatively powerful inducer of balanced reciprocal translocations which are stably transmissible to daughter cells
Sparsely ionizing radiation
Hsu and co-workers reported data on leukemia incidence amongst the A-bomb survivors [4], [5]. The estimated AML relative risk (RR) after exposure to 1 Gy is RR = 2.11 (95% confidence interval, 1.53–3). The estimated CML RR was city-dependent: Hiroshima, RR = 6.24 (2.92–12.8), Nagasaki RR = 2.17 (0.9–5.71). The reason(s) for the difference between cities is unknown. Importantly, the dose-response curves of AML and CML differ: AML has a quadratic radiation dose-response whereas CML has a linear
Biological mechanisms
Leukemogenic DNA mutations include small-scale alterations (such as point mutations, small inversions and indels) and large-scale alterations such as aneuploidy (missing or extra chromosomes) and structural chromosome aberrations. Although large-scale DNA mutations are rare compared with small-scale mutations, they are important [17] because they involve many genes and unstable karyotype alterations can evolve into comparatively stable ones in a somatic-cell analog of speciation [18].
The
Discussion
We discussed several dichotomies: therapy-related AML and MDS versus therapy-related CML, sparsely ionizing radiation versus DNA-damaging drugs, large- versus small-scale DNA alterations and stably versus unstably transmissible mutations. These observations led us to hypothesize that exposure to sparsely ionizing radiation favors development of CML and some forms of AML and MDS which are associated with synchronous proximal DSB lesions (balanced reciprocal translocations and interstitial
Conflict of interest statement
RPG is a part time employee of Celgene Corp.
Acknowledgement
LH and RKS were supported by Award Number U54CA149233 from the National Cancer Institute (to LH) and by the National Aeronautics and Space Administration under grant nos. NNJ06HA28G/NNX11AK26G and NNX13AJ01G issued through the Human Research Program (to LH). NIH RO1CA138858 (TR). RPG thanks the NIHR Biomedical Research Centre funding scheme. Dr. Ricardo Aguiar kindly reviewed the typescript.
References (20)
- et al.
Evolving risk of therapy-related acute myeloid leukemia following cancer chemotherapy among adults in the United States, 1975–2008
Blood
(2013) - et al.
Biological consequences of formation and repair of complex DNA damage
Cancer Lett
(2012) - et al.
Chronic myelogenous leukemia stem and progenitor cells demonstrate chromosomal instability related to repeated breakage-fusion-bridge cycles mediated by increased nonhomologous end joining
Blood
(2012) Risk of acute myelogenous leukaemia and myelodysplasia following cancer treatment
Baillieres Clin Haematol
(1996)- et al.
Therapy-related myeloid leukemia
Semin Oncol
(2008) - et al.
A prognostic model of therapy-related myelodysplastic syndrome for predicting survival and transformation to acute myeloid leukemia
Clin Lymphoma Myeloma Leuk
(2014) Therapy-related chronic myeloid leukemia: an epidemiological, clinical and pathogenetic appraisal
Leuk Lymphoma
(1998)- et al.
The incidence of leukemia, lymphoma and multiple myeloma among atomic bomb survivors: 1950–2001
Radiat Res
(2013) - et al.
Risk of myelodysplastic syndromes in people exposed to ionizing radiation: a retrospective cohort study of Nagasaki atomic bomb survivors
J Clin Oncol
(2011) Second primary cancers and cardiovascular disease after radiation therapy
Recommendations of the national council on radiation protection and measurements: Bethesda
(2013)
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Department of Quantitative Health Sciences, Cleveland Clinic, Cleveland, OH, United States.