Obesity is a risk factor for acute promyelocytic leukemia: evidence from population and cross-sectional studies and correlation with FLT3 mutations and polyunsaturated fatty acid metabolism.

Autor:	Mazzarella L; Department of Experimental Oncology, European Institute of Oncology IRCCS, Milan, Italy luca.mazzarella@ieo.it.; Division of Early Drug Development for Innovative Therapies, European Institute of Oncology IRCCS, Milan, Italy., Botteri E; Cancer Registry of Norway, Oslo, Norway., Matthews A; London School of Hygiene and Tropical Medicine, London, UK., Gatti E; Department of Experimental Oncology, European Institute of Oncology IRCCS, Milan, Italy., Di Salvatore D; IFOM-FIRC Institute of Molecular Oncology, Milan, Italy., Bagnardi V; University of Milan-Bicocca, Milan, Italy., Breccia M; Division of Hematology, Department of Cellular Biotechnologies and Hematology, Sapienza University, Rome, Italy., Montesinos P; Hematology Department, Hospital Universitario y Politécnico La Fe, Valencia, Spain., Bernal T; Hospital Central de Asturias, Oviedo, Spain., Gil C; Hospital General, Alicante, Spain., Ley TJ; Department of Medicine, Division of Oncology, Washington University in St. Louis, Saint Louis, MO, USA., Sanz M; Hematology Department, Hospital Universitario y Politécnico La Fe, Valencia, Spain., Bhaskaran K; London School of Hygiene and Tropical Medicine, London, UK., Coco FL; Department of Hematology, University Tor Vergata, Roma, Italy., Pelicci PG; Department of Experimental Oncology, European Institute of Oncology IRCCS, Milan, Italy piergiuseppe.pelicci@ieo.it.; Department of Oncology and Hemato-Oncology, University of Milan.
Jazyk:	angličtina
Zdroj:	Haematologica [Haematologica] 2020 Jun; Vol. 105 (6), pp. 1559-1566. Date of Electronic Publication: 2019 Sep 12.
DOI:	10.3324/haematol.2019.223925
Abstrakt:	Obesity correlates with hematologic malignancies including leukemias, but risk of specific leukemia subtypes like acute promyelocytic leukemia and underlying molecular mechanisms are poorly understood. We explored multiple datasets for correlation between leukemia, body mass index (BMI) and molecular features. In a population-based study (n=5.2 million), we correlated BMI with promyelocytic leukemia, and other acute myeloid, lymphoid or other leukemias. In cross-sectional studies, we tested BMI deviation in promyelocytic leukemia trial cohorts from that expected based on national surveys. We explored The Cancer Genome Atlas for transcriptional signatures and mutations enriched in promyelocytic leukemia and/or obesity, and confirmed a correlation between body mass and FLT3 mutations in promyelocytic leukemia cohorts by logistic regression. In the population-based study, hazard ratio per 5 kg/m 2 increase was: promyelocytic leukemia 1.44 (95%CI: 1.0-2.08), non-promyelocytic acute myeloid leukemias 1.17 (95%CI: 1.10-1.26), lymphoid leukemias 1.04 (95%CI: 1.0-1.09), other 1.10 (95%CI: 1.04-1.15). In cross-sectional studies, body mass deviated significantly from that expected (Italy: P <0.001; Spain: P =0.011; USA: P <0.001). Promyelocytic leukemia showed upregulation of polyunsaturated fatty acid metabolism genes. Odds of FLT3 mutations were higher in obese acute myeloid leukemias (odds ratio=2.4, P =0.007), whether promyelocytic or not, a correlation confirmed in the pooled promyelocytic leukemia cohorts (OR=1.22, 1.05-1.43 per 5 kg/m 2 ). These results strengthen the evidence for obesity as a bona fide risk factor for myeloid leukemias, and in particular APL. FLT3 mutations and polyunsaturated fatty acid metabolism may play a previously under-appreciated role in obesity-associated leukemogenesis. (Copyright© 2020 Ferrata Storti Foundation.)
Databáze:	MEDLINE
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