Being overweight or obese, defined as having an abnormal 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 overproduction 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 marrow cells, Ob/Ob mice and their lean counterparts all remained alive and demonstrated a defective bone marrow hematopoiesis. These animals subsequently showed macrocytic 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 specific 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 exacerbated monocytosis which developed in the obese animals mimicked 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 animals. 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.

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Figure 1.

Ob/Ob animals and their lean littermates engrafted with marrow from transgenic mice expressing the NUX98-HOXD3 fusion protein develop an MDS phenotype 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.

This model stresses the complexity of the relationship between obesity and cancer. In 2014, an estimated 640 million 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 relative risks ranging from 1.2 for overweight to 1.5 for severe obesity. This report did not comment on other hematopoietic 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 directly, by modifying the composition of local adipose tissue,^11,12 or indirectly, through diet-induced modification of the gut microbiota.¹³ In turn, these alterations of the niche disrupt the hematopoietic stem cell compartment, e.g., through deregulating the transcription factor Gfi1,¹⁴ promoting myeloid skewing and overproduction of monocytes and neutrophils.⁴ A link has recently been established between saturated fatty acids that accumulate in the serum of obese people - the fatty acid binding protein FABP4 to which they bind, which is highly expressed in leukemic cells - and a cellular pathway that leads to DNA hypermethylation and fuels AML cell growth, suggesting innovative therapeutic strategies in this disease.¹⁵

A pertinent question is whether and how overweight and obesity affect the progression of established disease. The murine model described in this issue of Haematologica³ suggests some effect of obesity on the natural evolution of the disease. Seven months after the engraftment of NHD3 bone marrow cells, Ob/Ob mice share a largely common phenotype with their lean counterparts, including decreased mature blood cell counts and bone marrow progenitors; Ob/Ob mice also demonstrate an increase in circulating monocytes and splenic hematopoiesis, which may reflect the signals induced by the obese inflammatory state as suggested by the accumulation of Ly6C^high monocyte subsets.⁴ This deregulated myelopoiesis, which occurs at an intermediate time point in disease evolution, contrasts with the dramatic increase in the overall survival of obese animals. At the time of animal sacrifice, the adipose tissue of Ob/Ob mice engrafted with NHD3 cells had recruited more myeloid cells, including CD11b⁺ myeloid cells and macrophages, that, by contrast, were less present in the spleen and the liver. However, it remains unclear whether, and how, this distinct repartition of myeloid cells affects disease evolution and promotes monocyte accumulation rather than acute leukemia evolution.

The authors did not evaluate the impact of obesity on disease response to treatment. As surprising as it may sound, the retrospective analysis of 1,974 AML patients enrolled in SWOG studies had identified an increased response rate to a chemotherapeutic regimen in overweight and obese patients.¹⁶ Howbeit, the opposite observation was made in a cohort of childhood AML,¹⁷ which could be related to the demonstrated ability of adipocytes to sequester chemotherapeutic drugs.¹⁸ The influence of BMI on MDS and AML therapeutic response therefore deserves further investigation.

As acknowledged by Kraakman et al.,³ a limitation of their study is the use of Ob/Ob mice in which the Lep gene is disrupted. Leptin levels are elevated in overweight individuals in which this pro-inflammatory adipokine was shown to affect the behavior of tumor cells and their microenvironment. A proliferative and anti-apoptotic effect of leptin has also been depicted on AML blast cells.¹⁹ Therefore, the absence of leptin in the tested model may alter the natural history of the disease in an overweight setting, which demands validation in another model of obesity in which leptin secretion is maintained. The demonstration that improved survival in MDS animals is related to the absence of leptin would foster the therapeutic development of leptin antagonists, including leptin analogs and antibodies targeting leptin or its transmembrane receptor.²⁰

The manuscript by Kraakman et al. points to a counter-intuitive, and thus thrilling hypothesis of a protective effect of obesity on the progression of installed MDS, and suggests a series of future investigations in order to validate this premise, explore the cellular and molecular mechanisms involved, and determine if this protective effect also applies to the therapeutic response.

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