Page 16 - Haematologica-April 2018

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Editorials
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 pro- tein 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, sug- gesting 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 nat- ural 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 coun- terparts, including decreased mature blood cell counts and bone marrow progenitors; Ob/Ob mice also demon- strate an increase in circulating monocytes and splenic hematopoiesis, which may reflect the signals induced by the obese inflammatory state as suggested by the accu- mulation of Ly6Chigh 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 evolu- tion 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 over- weight and obese patients.16 Howbeit, the opposite obser- vation 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 ani- mals is related to the absence of leptin would foster the
therapeutic development of leptin antagonists, including leptin analogs and antibodies targeting leptin or its trans- membrane 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 vali- date this premise, explore the cellular and molecular mechanisms involved, and determine if this protective effect also applies to the therapeutic response.
References
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