Page 53 - Haematologica-April 2018

Myelodysplastic Syndrome
Leptin-deficient obesity prolongs survival in a murine model of myelodysplastic syndrome
Michael J. Kraakman,1,2* Helene L. Kammoun,1,3* Dragana Dragoljevic,1,3 Annas Al-Sharea,1,3 Man K.S. Lee,1,3 Michelle C. Flynn,1,3 Christian J. Stolz,1,3 Andrew A. Guirguis,4 Graeme I. Lancaster,1,3 Jaye Chin-Dusting,3
David J. Curtis4 and Andrew J. Murphy1,3
1Baker Heart and Diabetes Institute, Melbourne, VIC, Australia; 2Naomi Berrie Diabetes Center and Department of Medicine, Columbia University, NY, USA; 3Monash University, Melbourne, VIC, Australia and 4Australian Centre for Blood Diseases, Monash University, Melbourne, VIC, Australia
Ferrata Storti Foundation
*MJK AND HLK contributed equally to this work.
Haematologica 2018 Volume 103(4):597-606
ABSTRACT
Obesity enhances the risk of developing myelodysplastic syn- dromes. However, the effect of obesity on survival is unclear. Obese people present with monocytosis due to inflammatory signals emanating from obese adipose tissue. We hypothesized that obe- sity-induced myelopoiesis would promote the transition of myelodys- plastic syndrome to acute myeloid leukemia and accelerate mortality in obesity. Obese Ob/Ob mice or their lean littermate controls received a bone marrow transplant from NUP98-HOXD13 transgenic mice, a model of myelodysplastic syndrome. The metabolic parameters of the mice were examined throughout the course of the study, as were blood leukocytes. Myeloid cells were analyzed in the bone, spleen, liver and adipose tissue by flow cytometry halfway through the disease progres- sion and at the endpoint. Survival curves were also calculated. Contrary to our hypothesis, transplantation of NUP98-HOXD13 bone marrow into obese recipient mice significantly increased survival time compared with lean recipient controls. While monocyte skewing was exacerbated in obese mice receiving NUP98-HOXD13 bone marrow, transformation to acute myeloid leukemia was not enhanced. Increased survival of obese mice was associated with a preservation of fat mass as well as increased myeloid cell deposition within the adipose tissue, and a con- comitant reduction in detrimental myeloid cell accumulation within other organs. The study herein revealed that obesity increases survival in animals with myelodysplastic syndrome. This may be due to the greater fat mass of Ob/Ob mice, which acts as a sink for myeloid cells, prevent- ing their accumulation in other key organs, such as the liver.
Introduction
Obesity represents a major health risk and is independently associated with the development of a cluster of disorders commonly referred to as metabolic diseases, including type 2 diabetes mellitus (T2DM), cardiovascular disease, stroke, neuro- degeneration, and liver diseases. Furthermore, causal associations between body mass index (BMI) and many cancers are becoming increasingly apparent.1-4
In the last decade, obesity has been associated not only with most forms of tumor-based cancer, but also with hematological malignancies.5 Obese patients have an increased risk of leukemia,6 and, in children, excess fat mass is linked both to enhanced incidence and lower overall survival for leukemia.7 In addition, obe- sity has been increasingly associated with an enhanced risk for the incidence of myelodysplastic syndromes (MDS).8,9
MDS encompass a group of bone marrow disorders characterized by defective hematopoiesis.10 The risk of progressing to leukemia is high in individuals with MDS, with approximately 30% proceeding to develop acute myeloid leukemia (AML), an aggressive hematopoietic malignancy with a low 5-year survival prog- nosis. While the environmental factors for developing MDS and its progression to AML remain poorly understood, recent epidemiological studies have revealed
Correspondence:
andrew.murphy@baker.edu.au
Received: October 3, 2017. Accepted: January 19, 2018. Pre-published: January 25, 2018.
doi:10.3324/haematol.2017.181958
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/103/4/597
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haematologica | 2018; 103(4)
597
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