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Obesity and the risk of chronic myelogenous leukemia: is this another example of the neoplastic effects of increased body fat?

The risk of cancers of varied tissues is increased in persons who are overweight or obese.1, 2, 3, 4 The increased relative risk (RR) of cancer in overweight and obese subjects has also included the hematological malignancies, although the major types of leukemia and lymphoma have not been stratified in several of these large epidemiological studies.1, 2, 5, 6, 7 Myeloma also has been associated with overweight and obesity as has its antecedent, essential monoclonal gammopathy.8, 9 The evidence for an increased risk of leukemia in the aggregate1, 2, 5, 6, 7 and of the four major types of leukemia is noteworthy.10 Given the broad range of tissues for which a risk of neoplasia is increased in overweight and obese persons, there appears to be a global effect of the metabolic, endocrinologic and inflammatory changes resulting from obesity on either the induction of neoplastic clones, or the selection and enhanced growth and survival of preexisting, dormant transformed clones.

BCR-ABL-positive chronic myelogenous leukemia is a very uncommon secondary leukemia. Unlike secondary acute myelogenous leukemia, which can occur as a result of exposure to high-dose ionizing radiation, certain types of chemotherapy (especially, alkylating agents and topoisomerase inhibitors), prolonged inhalation of tobacco smoke or higher-dose prolonged exposure to benzene, only ionizing radiation is an established cause of secondary chronic myelogenous leukemia.11 In addition, there is little evidence that either a familial predisposition gene (non-syndromic) or an inherited predisposing disorder (syndromic predisposition gene) is associated with chronic myelogenous leukemia, as it is with acute myelogenous leukemia.11 Although a proportion of the healthy population carries low copy numbers of the BCR-ABL oncogene in its blood cells, it is not known whether these clones are susceptible to clonal evolution to a clinically overt neoplasm, either spontaneously or under provocation. The apparent effect of increased fat mass on an increased RR of chronic myelogenous leukemia should be of research interest to students of carcinogenesis and leukemogenesis. The relationship of overweight to cancer is a major challenge to the practice of preventive medicine and the soft (cajoling) and hard (pharmacotherapy) science of behavior modification.

In a search of the literature, I have identified eight studies that have examined the relationship of overweight or obesity to the risk of chronic myelogenous leukemia, either as a primary research effort or as a meta-analysis of prior studies. In these studies, the body mass index (BMI) was used as a measure of fat tissue mass. The World Health Organization and the United States Public Health Service considers a BMI of <18 kg/m2 as underweight, 18–24.9 kg/m2 as a normal body fat mass, 25 to 29.9 kg/m2 as overweight and >29.9 kg/m2 as obesity. Obesity may be stratified into Class I (BMI=30–34.9 kg/m2), Class II (BMI=35–39.9 kg/m2), Class III (BMI40 kg/m2).

In 2005, investigators in Melbourne, Victoria, Australia found a five-fold increase in the hazard ratio (HR) for myeloid leukemias (acute and chronic myelogenous leukemia) in overweight, HR=5.3 (95% confidence interval (CI), 1.9–15.2), and obese, HR=5.0 (95% CI, 1.6–15.5), persons as compared with those with a normal BMI (<25.0 kg/m2). The HR was higher for chronic than acute myelogenous leukemia, but the number of cases of chronic myelogenous leukemia was not sufficient to apply statistical tests of homogeneity between the two leukemias.12

In a study of 2 000 611 Norwegian men and women, reported in 2006, the trend of RR of chronic myelogenous leukemia using a normal range of BMI of 18.5–24.9 kg/m2 as the referent value (1.0), and studying degrees of BMI from underweight, to normal, to overweight, to obese, to massively obese, found a significant trend for increased risk of chronic myelogenous leukemia from RR=0.78 in underweight (BMI<18.5 kg/m2) to RR=1.65 in obese men (BMI30.0 kg/m2).13 In women, the same significant trend was observed ranging from RR=0.85 in underweight women to a RR=1.89 in women with Class III obesity (BMI40 kg/m2). The results were ambiguous in that the trends by BMI were highly significant and the RR of chronic myelogenous leukemia increased generally with increased BMI; however, the increased RR at each level of increased BMI was not statistically significant in several cases.

Three reports between 2004 and 2007 found an increased RR of chronic myelogenous leukemia in overweight or obese men of European or African descent,14 and in men and women,13, 15 but the RR (1.15 to 1.65) was either not significant or just missed statistical significance. However, a meta-analysis, published in 2008, of the three studies,13, 14, 15 which included five populations, found a significantly increased meta-relative risk (MRR) of chronic myelogenous leukemia (MRR=1.26 (95% CI, 1.09–1.46)) in the obese study subjects as compared with those with a normal BMI.10

In a population-based case–control study conducted in eight Canadian provinces, published in 2005, an association was found with increased BMI and an increased RR of chronic myelogenous leukemia with a significant dose-response relationship; the increment in risk for chronic myelogenous leukemia from normal to overweight (odds ratio (OR)=1.4; 95% CI, 1.0–2.0) and from normal to obese (OR=2.3; 95% CI, 1.5–3.4) subjects was highly significant.16

Overweight and obesity and the risk of hematological malignancies were studied in a cohort of Swedish and Finnish twins (70 067 persons), who were followed prospectively. An increased RR of chronic myelogenous leukemia was observed in those who were overweight or obese (RR=2.5 95% CI, 1.0–6.2).17

Clinical investigators at the MD Anderson Cancer Center studied 253 cases of chronic myelogenous leukemia and 273 matched controls. They concluded that patients with chronic myelogenous leukemia were more likely to be obese during adulthood at ages 25 years (OR=4.29; 95% CI, 1.63–11.3), 40 years (OR=5.12; 95% CI, 1.92–13.6) and at diagnosis (OR=3.09; 95% CI, 1.56–6.13) than a matched comparison group without the disease. Obesity at all ages was an independent risk factor for the disease and there was a significant dose-response effect based on the increase of BMI. Patients with chronic myelogenous leukemia 45 year of age gained more weight each year between ages 25 and 40 years than matched controls (0.78 versus 0.44 kg/year). A gain of weight of >1.0 kg/year between ages 25 and 40 years had a particular strong association with the risk of developing chronic myelogenous leukemia (OR=3.63; 95% CI, 1.46–9.04). They concluded that obesity and adult weight gain increase the risk of developing chronic myelogenous leukemia.18

Although there are methodological limitations of various types in epidemiologic studies of uncommon diseases, or of large populations, or of case–control comparisons, the overall message from the aggregate of these studies is that weight gain and obesity impose an increased risk of developing chronic myelogenous leukemia.

The possible biological mechanisms that may intervene between obesity and leukemogenesis or carcinogenesis have been considered but are not established, and they vary for cancers of different tissues.19, 20 Candidates relevant to myelogenous leukemia include increased levels of leptin21, 22, 23 and insulin growth factor-124 as a result of an increased fat mass. Leptin and insulin growth factor-1 interact with their receptors on normal and leukemic hematopoietic cells and provide a link between the hormonal changes of obesity and normal and leukemic hematopoiesis. However, interactions specific to the cells relevant to the origin of chronic myelogenous leukemia have not been studied to my knowledge. Fundamental questions of how obesity induces an injury to the genome or the epigenome or acts to select preexisting neoplastic clones remain unanswered.

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Correspondence to M A Lichtman.

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The author has served as a medical expert for the defense in toxic tort cases and, in that context, has relied on research studies of obesity as a risk factor for the development of a hematological malignancy.

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Lichtman, M. Obesity and the risk of chronic myelogenous leukemia: is this another example of the neoplastic effects of increased body fat?. Leukemia 26, 183–184 (2012). https://doi.org/10.1038/leu.2011.190

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