Obesity is a risk factor for acute promyelocytic leukemia: evidence from population and cross-sectional studies studies and correlation with flt3 mutations and polyunsaturated fatty acid metabolism.

Autores de IIS La Fe

• Pau Montesinos Fernández

  Autor

• Miguel Ángel Sanz Alonso

  Autor

Participantes ajenos a IIS La Fe

• Mazzarella L
• Botteri E
• Matthews A
• Gatti E
• Di Salvatore D
• Bagnardi V
• Breccia M
• Bernal T
• Gil C
• Ley TJ
• Bhaskaran K
• Lo Coco F
• Pelicci PG

Grupos

• Hematología y Hemoterapia

Abstract

Obesity correlates with hematological malignances 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 and molecular features. In a population-based study (n=5.2 million), we correlated Body Mass Index with promyelocytic, other acute myeloid, lymphoid or other leukemias. In cross-sectional studies, we tested body mass index deviation in promyelocytic leukemia trial cohorts from what expected based on national surveys. We interrogated The Cancer Genome Atlas for transcriptional signatures and mutations enriched in promyelocytic leukemia and/or obesity and confirmed 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 (1.10-1.26); lymphoid leukemias 1.04 (1.0-1.09); other 1.10 (1.04-1.15). In cross-sectional studies, body mass deviated significantly from expected (Italy p0.001, Spain p=0.011, USA p0.001). Promyelocytic leukemia showed upregulation of polyunsaturated fatty acid metabolism genes. Oddds 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 underappreciated role in obesity-associated leukemogenesis.

Keywords

• Acute Myeloid Leukemia, Acute Promyelocytic Leukemia, Clinical and Molecular Epidemiology, Cytogenetics and Molecular Genetics