Page 15 - Haematologica-April 2018

E-mail: eric.solary@gustaveroussy.fr doi:10.3324/haematol.2018.188854
Being overweight or obese, defined as having an abnor- mal or excessive accumulation of body fat, have been associated with an increased risk of cancer development in the bone marrow and other tissues.1 Through its metabolic, endocrine and inflammatory consequences, obesity could have either an inductive or a selective effect on a malignant clone.2 While the effect of a patient being overweight or obese on cancer prevalence appears to be clear, the impact of excess body fat on patient survival at the time of cancer diagnosis is less well-defined. In this issue of Haematologica, Kraakman et al. demonstrate that in a mouse model of myelodysplastic syndrome (MDS) obesity improves survival in the absence of treatment, and propose some biological explanations to this survival advantage.3
Based on their previous results,4 Kraakman and colleagues began their study by applying the hypothesis that, through generating an inflammatory setting that includes overpro- duction of interleukin-1 (IL)-1β, obesity may promote the progression of MDS to acute myeloid leukemia (AML) and decrease survival. They tested this hypothesis in Ob/Ob mice in which the Lep gene was mutated.5 Leptin is an adipocyte-released cytokine/adipokine that regulates food intake, and its mutation leads to rapid weight gain that, importantly, persists following bone marrow transplantation procedures.3 Ob/Ob animals were engrafted with marrow from NHD13 transgenic mice expressing the NUX98- HOXD3 fusion protein, which induces an MDS phenotype that can subsequently evolve into acute leukemia.6
Seven months post-transplantation of NHD13 bone mar- row cells, Ob/Ob mice and their lean counterparts all remained alive and demonstrated a defective bone marrow hematopoiesis. These animals subsequently showed macro- cytic anemia, severe lymphocytopenia, decreased platelet count, and splenomegaly. In addition to these background abnormalities, obesity was associated with a stronger increase in the fraction of circulating monocytes and a spe- cific shift of hematopoiesis from the bone marrow to the spleen.
Unexpectedly, follow up of these animals showed that Ob/Ob mice lived, on average, 100 days longer with MDS than lean animals with the same disease, despite the fact that a complete bone marrow failure had been observed in both genetic settings. The prevalence of secondary AML was similar in Ob/Ob and lean animals, however, the exacerbat- ed monocytosis which developed in the obese animals mim- icked chronic myelomonocytic leukemia, whereas the lean MDS animals developed more T-cell acute lymphoblastic leukemias.
A striking difference between Ob/Ob and lean animals was the lower loss of body fat in Ob/Ob mice developing MDS. In addition, morphological analysis of visceral adipose tissue detected a massive infiltration of activated CD11b+ myeloid cells and CD11c+ pro-inflammatory macrophages
surrounding remodeled adipocytes in obese MDS mice (Figure 1). Conversely, infiltration of the spleen and the liver by myeloid cells was significantly higher in lean MDS ani- mals. The proposed hypothesis is that the expanded adipose tissue acts as a sink for myeloid cells, which spares other organs, such as the liver, from myeloid cell infiltration and functional degradation.
This model stresses the complexity of the relationship between obesity and cancer. In 2014, an estimated 640 mil- lion adults worldwide were obese, and the obesity-related cancer burden was estimated as being between 3% and 4% of the entire cancer burden.1 The risk is generally higher in women compared with men, reaching 9% among women in countries, including North America, Europe, and the Middle East, where the body mass index (BMI) is the highest.7 Regarding hematological malignancies, the report from the International Agency for Research on Cancer (IARC) Working Group1 emphasized a positive association between increased BMI and the risk of multiple myeloma, with rela- tive risks ranging from 1.2 for overweight to 1.5 for severe obesity. This report did not comment on other hematopoiet- ic malignancies, including that of MDS, but a significant association between increased BMI and the risk of MDS had been suggested by previous independent studies.8-10
Obesity is a chronic and complex pathological state that affects bone marrow homeostasis. Increased fat mass changes the composition of the bone marrow niche, either
Figure 1. Ob/Ob animals and their lean littermates engrafted with marrow from transgenic mice expressing the NUX98-HOXD3 fusion protein develop an MDS phe- notype that can secondarily evolve into acute leukemia. Increased survival of Ob/Ob animals correlates with the retention of CD11b+ myeloid cells in the adipose tissue. According to the hypothesis proposed Kraakman et al., this retention could protect other organs, such as the liver, from myeloid cell infiltration and functional degradation.
EDITORIALS
Does being overweight contribute to longer survival rates in myelodysplastic syndrome?
Eric Solary1,2 and Michaela Fontenay3,4
1Université Paris-Sud, Faculté de Médecine, Le Kremlin-Bicêtre; 2INSERM U1170, Gustave Roussy, Villejuif; 3Université Paris-Descartes, Faculté de Médecine, Paris and 4Institut Cochin, INSERM U1016, CNRS UMR 8104, Paris, France
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