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Abstract
It is suspected that bone marrow (BM) microenvironmental factors may influence the evolution of chronic myeloid leukaemia (CML). In this study, we postulated that adipocytes and lipids could be involved in the progression of CML. To test this hypothesis, adipocytes were co-cultured with two BCR-ABL positive cell lines (PCMDS and K562). T cell (Jurkat) and stroma cell (HS-5) lines were used as controls. In the second set of experiments, leukemic cell lines were treated with stearic, oleic, linoleic or α-linolenic acids in presence or absence of leptin. Survival, proliferation, leptin production, OB-R isoforms (OB-Ra and OB-Rb), phosphoinositide 3-kinase (PI3k) and BCL-2 expression have been tested after 24h, 48h and 72h of treatment. Our results showed that adipocytes induced a decrease of CML proliferation and an increase in lipid accumulation in leukemic cells. In addition, CML cell lines induced adipocytes cell death. Chromatography analysis showed that BM microenvironment cells were full of saturated (SFA) and monounsaturated (MUFA) fatty acids, fatty acids that protect tumor cells against external agents. Stearic acid increased Bcl-2 expression in PCMDS, whereas oleic and linoleic acids had no effects. In contrast, α-linolenic acid decreased the proliferation and the survival of CML cell lines as well as BCL-2 and OB-R expression. The effect of α-linolenic acids seemed to be due to PI3K pathway and Bcl-2 inhibition. Leptin production was detected in the co-culture medium. In the presence of leptin, the effect of α-linolenic acid on proliferation, survival, OB-R and BCl-2 expression was reduced.
Highlights
Chronic myelogenous leukemia (CML) is a malignant disorder of the hematopoietic stem cell (HSC) characterized by a reciprocal translocation between chromosomes 9 and 22 (t(9;22)(q34;q11)) [1]
It was previously shown that fibroblast-like fat cell (FLFC) obtained from bone marrow (BM) adipocytes exerted a negative control on granulocyte differentiation [10]
FLFCs were cultured with a BCR-ABL positive myelomonocytic leukemic cell line, PCMDS and HS-5 stromal cell line was used as control
Summary
Chronic myelogenous leukemia (CML) is a malignant disorder of the hematopoietic stem cell (HSC) characterized by a reciprocal translocation between chromosomes 9 and 22 (t(9;22)(q34;q11)) [1]. The translocation results in formation of the BCR-ABL fusion oncogene encoding a protein with constitutive tyrosine kinase activation, which plays a central role in the pathogenesis of the disease. Many mechanisms are involved in the malignant transformation orchestrated by the BCR-ABL oncoprotein [2]. It constitutively activates mitogenic signaling pathways such as the phosphoinositide-3 (PI3) kinase pathway [3]. Alterations in the bone marrow microenvironment were widely described These alterations include deregulated patterns of cytokine production that promoted a proinflammatory environment. These alterations induce a deficient of hematopoietic supportive capacity and decreased the number of cells in certain stromal cell populations [5]
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