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, Edoardo Botteri, Anthony Matthews, Elena Gatti, Davide Di Salvatore, Vincenzo Bagnardi, Massimo Breccia, Pau Montesinos, Teresa Bernal, Cristina Gil, Timothy J. Ley, Miguel Sanz, Krishnan Bhaskaran, Francesco Lo Coco, Pier Giuseppe Pelicci

Research output: Contribution to journalArticle

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), 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/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.

Original languageEnglish
Pages (from-to)1559-1566
Number of pages8
JournalHaematologica
Volume105
Issue number6
DOIs
StatePublished - Jun 1 2020

Fingerprint Dive into the research topics of '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'. Together they form a unique fingerprint.

  • Cite this

    Mazzarella, L., Botteri, E., Matthews, A., Gatti, E., Di Salvatore, D., Bagnardi, V., Breccia, M., Montesinos, P., Bernal, T., Gil, C., Ley, T. J., Sanz, M., Bhaskaran, K., Coco, F. L., & Pelicci, P. G. (2020). 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. Haematologica, 105(6), 1559-1566. https://doi.org/10.3324/haematol.2019.223925