Page 107 - Haematologica - Vol. 105 n. 6 - June 2020

Obesity and risk of AML/APL, FLT3 muts and fat metabolism
population (5.2 million). The largest prospective study to date (EPIC), which revealed a statistically significant high- er risk only in female AML, but not in other gender and biological subgroups,4 was based on a relatively small number of incident cases: only 671 out of 375,021 partici- pants over 11.5 years of median follow up. The use of orthogonal epidemiological approaches is a strength of the study, as it attempts to mitigate some weaknesses of each design. Registry-based studies have little patient selection bias, providing results that are more comparable to real- life scenarios. However, the quality of case identification is likely to be sub-optimal; erroneous assignment of APL to the general AML ICD code might "deplete" incident cases and further reduce statistical power. Case-control studies in the context of clinical trials, on the other hand, offer the advantage of gold standard diagnosis but might be affected by significant patient selection biases. This may have counter-selected obese patients in the present study, since the correlated comorbidities may be associat- ed with limited access to clinical trials.
Another limitation of the study is that we could not pro- vide the same degree of geographical homogeneity for control subjects in the case-control studies. This may be particularly relevant for the USA, known to have wide state-specific differences in BMI distribution. However, this variation is mainly due to demographic parameters,22 such as age, gender and race, and is, therefore, at least partly accounted for in our multivariate analysis. We also note that our US APL cohort includes a single patient of hispanic ethnicity. Hispanics are considered at higher inci- dence of APL, although some large studies based on Surveillance, Epidemiology, and End Results (SEER) data dispute this commonly held conclusion.23
Understanding the molecular mechanism causing increased cancer risk in obese subjects is crucial for ade- quate nutritional management in disease prevention, given the sustained rise of obesity worldwide, particularly in emerging economies. The possibility of matching tran- scriptional and mutational profiles from TCGA to patient clinical and BMI data provided an opportunity to generate hypotheses grounded on actual data. However, extracting biological significance from large molecular datasets remains challenging. Shifting the analytical focus from sin- gle genes to gene sets or pathways may allow signals to be captured even when the changes affecting individual genes are minimal, provided they are coherent. The gene set- based method we used here for transcriptional analysis does not assume equal variances, resulting in improved sensitivity and specificity over similar competing methods.15 Our main finding is the upregulation of several genes involved in the metabolism of pro-inflammatory ω- 6 polyunsaturated fatty acids (PUFA, linoleic and arachi- donic) in APL. These molecules are increased in the plasma of metabolically impaired subjects, including the obese,24
and may lead to elevated production of derivative mole- cules with multiple effects in signaling and inflammation, enhancing leukemogenesis through several independent mechanisms: direct growth promotion, generation of genotoxic oxidative stress, immune modulation,18,25 and generation of endogenous agonists for Peroxisome prolifer- ator-activated receptors (PPAR).26 PPAR are known insulin sensitizers27 and their transcriptional targets are up-regulat- ed in APL (Online Supplementary Table S2); APL expressed higher levels of insulin and IGF1 receptors, and its growth may thus be favored by the increased insulin/IGF1 levels in obese subjects.3,28 Elevated generation of PUFA-derived eicosanoids by APL cells may also explain the association between obesity and ATRA differentiation syndrome (DS),10 as eicosanoids strongly promote leukocyte adhesion and chemokine release in the lungs.29
Finally, the association between FLT3 mutations and a higher BMI, although unconfirmed in the larger Spanish cohort, is an intriguing finding that we think deserves addi- tional research. FLT3 mutations are associated with specif- ic metabolic dependencies which may be differentially affected according to the systemic nutritional status.30 It cannot be entirely ruled out that geographical differences in dietary composition may account for the discrepancies in the association between BMI and APL risk (weakest in Spain) and FLT3 mutations (null in Spain). Consistent with this highly speculative view, a recent EPIC substudy revealed marked differences in nutritional patterns between European nations. Despite sharing a theoretical propensity for “Mediterranean” diets, Italy and Spain were highly polarized, especially in terms of average polyunsat- urated fatty acid consumption (3% vs. 38% of the partici- pants in the highest quintile, respectively).31 More mecha- nistic studies are needed to clarify whether FLT3 mutations are favored by specific nutritional components.
In conclusion, based on evidence provided here, we pro- pose including obesity among environmental factors increasing risk for myeloid neoplasms and in particular APL. Additional studies with experimental models will clarify the molecular determinants of this relationship, and test whether and how specific nutritional components like PUFA can determine specific mutational and transcription- al alterations able to influence the natural history of the disease.
Acknowledgments
AIRC-Cariplo Foundation, Italian Ministry of Health, European Hematology Association, Wellcome Trust and Royal Society
Role of the funding source
Funding sources had no role in study design, collection, analy- sis, and interpretation of data; report writing nor decision to sub- mit the paper for publication.
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