Page 101 - Haematologica - Vol. 105 n. 6 - June 2020

Acute Myeloid Leukemia
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
Luca Mazzarella,1,2 Edoardo Botteri,3 Anthony Matthews,4 Elena Gatti,1 Davide Di Salvatore,5 Vincenzo Bagnardi,6 Massimo Breccia,7 Pau Montesinos,8 Teresa Bernal,9 Cristina Gil,10 Timothy J Ley,11 Miguel Sanz,8 Krishnan Bhaskaran,4 Francesco Lo Coco12✝ and Pier Giuseppe Pelicci1,13
1Department of Experimental Oncology, European Institute of Oncology IRCCS, Milan, Italy; 2Division of Early Drug Development for Innovative Therapies, European Institute of Oncology IRCCS, Milan, Italy; 3Cancer Registry of Norway, Oslo, Norway; 4London School of Hygiene and Tropical Medicine, London, UK; 5IFOM-FIRC Institute of Molecular Oncology, Milan, Italy; 6University of Milan-Bicocca, Milan, Italy; 7Division of Hematology, Department of Cellular Biotechnologies and Hematology, Sapienza University, Rome, Italy; 8Hematology Department, Hospital Universitario y Politécnico La Fe, Valencia, Spain; 9Hospital Central de Asturias, Oviedo, Spain; 10Hospital General, Alicante, Spain; 11Department of Medicine, Division of Oncology, Washington University in St. Louis, Saint Louis, MO, USA; 12Department of Hematology, University Tor Vergata, Roma, Italy and 13Department of Oncology and Hemato-Oncology, University of Milan
ABSTRACT
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/m2 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), lym- phoid 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 con- firmed in the pooled promyelocytic leukemia cohorts (OR=1.22, 1.05-1.43 per 5 kg/m2). 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.
Introduction
The etiology of acute myeloid leukemia (AML) remains poorly understood. Genetic predisposition or clear exposure to environmental mutagenic agents (smoking, benzene, radiation, prior chemotherapy) can be demonstrated only in a minority of cases.1 Age is an independent risk factor, probably linked to the pro-
Ferrata Storti Foundation
Haematologica 2020 Volume 105(6):1559-1566
This paper is dedicated to the memory of our wonderful colleague, Prof. Francesco Lo Coco, who recently passed away
Correspondence:
LUCA MAZZARELLA
luca.mazzarella@ieo.it
PIER GIUSEPPE PELICCI
piergiuseppe.pelicci@ieo.it
Received: Apri 5, 2019.
Accepted: September 11, 2019. Pre-published: September 12, 2019.
doi:10.3324/haematol.2019.223925
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/106/6/1559
©2020 Ferrata Storti Foundation
Material published in Haematologica is covered by copyright. All rights are reserved to the Ferrata Storti Foundation. Use of published material is allowed under the following terms and conditions: https://creativecommons.org/licenses/by-nc/4.0/legalcode. Copies of published material are allowed for personal or inter- nal use. Sharing published material for non-commercial pur- poses is subject to the following conditions: https://creativecommons.org/licenses/by-nc/4.0/legalcode, sect. 3. Reproducing and sharing published material for com- mercial purposes is not allowed without permission in writing from the publisher.
haematologica | 2020; 105(6)
1559
ARTICLE