Elsevier

Leukemia Research

Volume 38, Issue 10, October 2014, Pages 1162-1164
Leukemia Research

Commentary
Why is there so much therapy-related AML and MDS and so little therapy-related CML?

https://doi.org/10.1016/j.leukres.2014.08.002Get rights and content

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.

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Department of Quantitative Health Sciences, Cleveland Clinic, Cleveland, OH, United States.

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