Page 61 - Haematologica-April 2018

Obesity and myelodysplasia
text of obesity. Exploring the liver, initially at a macro- scopic level, it appeared that MDS resulted in the prefer- ential accumulation of immune cells in lean mice, and to a lesser extent in the obese MDS mice (Figure 5E). Quantitative flow cytometry data confirmed this observa- tion, where MDS resulted in similar F4/80+ macrophages in lean and obese hepatic tissue, but significantly more hepatic CD11b+ myeloid cells in the lean animals (Figure 5F). These findings were correlated with the observed liver fibrosis, which appeared to be more prevalent in the livers of lean MDS mice (Figure 5G). Interestingly, the fatty liver phenotype observed in obese mice (Figure 5E) was associated with an increase in circulating liver enzymes aspartate transaminase (AST)/ alanine transami- nase (ALT) (Figure 5H). Although MDS did not influence ALT levels, lean MDS mice presented with increased AST levels when obese MDS mice showed no difference with their obese healthy counterparts (Figure 5H). Interestingly, in support of impaired liver function, lean MDS mice had higher levels of bilirubin, indicative of impaired uptake and degradation by the liver of these mice (Figure 5I), effects that were not apparent in the obese MDS mice. Finally, we assessed the basal levels of circulating creatine kinase as a proxy measure of muscle damage. This tended to be higher in the lean MDS mice, suggesting a possible impact of MDS on muscle integrity which did not appear to occur in their obese counterparts (Online Supplementary Figure S4).
Overall, these data support the idea that the obese VAT preferentially attracts specific myeloid cell populations in MDS mice which results in a concomitant decrease in the accumulation of these cells in other tissues, such as the spleen and liver.
Discussion
Obesity has become increasingly associated with cancer and is now recognized as a risk factor for many malignant pathologies.5,23 In addition to solid tumors, obesity has also been linked with different forms of leukemia.11 Obesity is associated with an increased prevalence of MDS, however the data is less clear regarding survival outcome in obese patients presenting with MDS. We have previously demonstrated that the obese adipose tissue interacts with the BM, and promotes monocytosis through the stimulation of the myeloid pathway via IL-1β. In this context, we hypothesized that this increased basal rate of myelopoiesis would contribute to MDS and the progression to AML, thereby decreasing survival. Surprisingly, while obesity-induced myelopoiesis was observed in the setting of MDS, this was associated with significantly improved survival. We hypothesize that the expanded adipose tissue in obese mice acts as a sink for the increased myeloid cells, sparing other vital organs from myeloid cell burden and subsequent dysfunction. Furthermore, we propose that the preservation of fat mass observed in obese MDS mice likely contributes to their survival advantage relative to their lean counterparts (Figure 6).
Our paradoxical findings highlight that obesity might not always be associated with enhanced mortality risk in people suffering from hematological disorders. One major difference between our pre-clinical data and the clinical course of MDS resides in the fact that patients with this
disease may be treated with transfusions, chemotherapy, including epigenetic modifiers, and occasionally BMT. In general, studies supporting an obesity paradox in cancer tend to describe a ‘U-shape’ correlation between BMI and overall survival.24 This could indicate that increased energy stores in overweight and moderately obese patients could allow for longer survival, but severely obese patients with comorbidities would be at risk of decreased survival rate.
Consistent with this obesity paradox, there are accumu- lating reports demonstrating that adipose tissue can be critical for patient’s health and survival. In particular, sub- cutaneous adipose tissue has been associated with increased survival in several conditions, including the hematological disorder multiple myeloma.25-27 Adipose tis- sue is the main energy store in the human body, hence, conserving enough fat stores could lead to better survival outcomes by allowing slower rates of muscle proteolysis, another important source of energy. In addition, the adi- pose tissue has now been fully recognized as an endocrine organ impacting various bodily functions. Indeed, deple- tion of white adipose tissue has been associated with increased inflammatory signalling and disrupted circadian regulation.28 Low levels of adiponectin, one of the main hormones secreted by the VAT, has been associated with an increased risk of cancer and poor diagnosis.29 Thus, the maintenance of fat stores in the Ob/Ob mice transplanted with NHD13 may play a crucial role in their prolonged survival compared to the lean MDS that lose the majority of their VAT.
In the obese mice with MDS we found cells homed in to the VAT in significant numbers. In the absence of treat- ment, it appeared that the preferential homing of cells to the adipose tissue could partially protect other organs from infiltration, providing an explanation for the pro- longed survival of obese mice when confronted with NHD13-induced MDS. Transformation from MDS to AML takes place in the stem and progenitor cells, not mature myeloid cells. Interestingly, transformation could have occurred in the obese VAT and at the same time pre- vented outgrowth of the leukemia, keeping these cells somewhat dormant. Prescience comes from the discovery that leukemic stem cells can reside within the VAT in a quiescent nature, conferring their protection from chemotherapy.30,31
One striking observation was the different cellular makeup of the BM between WT and obese mice that died of MDS. While the marrow of the WT mice that died of MDS displayed classical signs of dysplasia, with fewer hematopoietic cells, the marrow from the obese MDS mice was full of adipocytes, with few hematopoietic cells evident. Whether marrow adiposity alters the course of the disease requires further investigation. Of note, the bones of lean and obese mice that died from AML looked similar, thus there is a possibility that the leukemic cells, upon transition from MDS to AML, could have used this stored lipid in the early stages of proliferation as a source of energy, which in the lean mice would have come from peripheral organs (i.e., adipose tissue). The role of BM adipocytes is not well described, but was recently shown to play an important role in hematopoietic regeneration following ablation via chemotherapy or irradiation.21 Given the blood profile of the obese MDS mouse, where there was an increase in the Ly6-Chi monocytes, an early transition to CMML could be occurring; however, this hypothesis requires further investigation. Moreover, the
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