ESPE Abstracts (2018) 89 FC6.5

The Role of Adipocytes in Childhood Precursor Bcell Lymphoblastic Leukemia

Elena Dorothea Brennera, Julia Zinngrebeb, Meike Dahlhausa, Lueder-Hinrich Meyerb, Martin Wabitscha, Klaus-Michael Debatinb & Pamela Fischer-Posovszkya

aDivision of Pediatric Endocrinology and Diabetes, Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, Ulm, Germany; bDepartment of Pediatrics and Adolescent Medicine, Ulm University Medical Center, Ulm, Germany

Acute lymphoblastic leukemia (ALL) is the most prevalent cancer in childhood. Over the past decades, survival rates increased, but relapse is still associated with a poor prognosis, especially if the bone marrow (BM) is affected. Marrow adipose tissue (MAT) constitutes a major part of the BM niche, but its impact on normal hematopoiesis versus leukemia initiation, progression and relapse has only recently gained attention. MAT is very sensitive to changes in the patient’s metabolic status, e.g. aging, obesity, caloric restriction, anorexia, therapy with steroids or irradiation, hampering a clear definition of its exact role during hematopoiesis and leukemia. To further address the role of adipocytes in B cell-precursor (BCP)-ALL, we established a coculture system of human adipocytes and BCP-ALL cells. For this purpose, we made use of thehuman Simpson-Golabi-Behmel syndrome (SGBS) preadipocyte cell strain, a unique and useful tool for studies of human adipocyte biology.We found that adipocyte-conditioned media from SGBS adipocytes is able to support the survival and proliferation of four different BCP-ALL cell lines (Nalm6, Reh, UoCB6 and RS4;11) under serum-free culture conditions. By using the coculture system of leukemic cells and SGBS adipocytes in comparison to transwell assays we could show that survival and proliferation of leukemic cell lines is independent of direct cell-cell contact, but mediated by adipocyte-secreted factor/s. Interestingly, conditioned media of BCP-ALL cell lines induced the upregulation of inflammatory mediators on mRNA level in adipocytes, among them monocyte chemoattractant protein 1 (MCP-1) orinterleukin-8 (IL-8). Next, we screened a cohort of 28 patient-derived BCP-ALL xenograft samples for their survival capacity in monoculture versus coculture with SGBS adipocytes. Interestingly, survival of patient-derived xenograft cells was heterogeneous anddefined by a characteristic gene expression pattern of leukemic cells identified by Affymetrix Human Genome U133 Plus 2.0 Array. In summary, we show that adipocytes promote survival and proliferation of leukemic cells via secretion of a yet to be identified factor. Leukemic cells in turn induce upregulation of inflammatory mediators in adipocytes, possibly to maintain their own survival. Importantly, survival of primograft cells on adipocytes is not a general phenomenon, but seems to be restricted to a certain cohort of patients defined by a characteristic gene expression profile. Further molecular characterization of this cohort will hopefully lead to the identification of novel targets for the treatment of BCP-ALL.

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