Leukemic Stem Cells Evade Chemotherapy by Metabolic Adaptation to an Adipose Tissue Niche

• Published in: Cell stem cell Vol. 19; no. 1; pp. 23 - 37
• Main Authors: Ye, Haobin, Adane, Biniam, Khan, Nabilah, Sullivan, Timothy, Minhajuddin, Mohammad, Gasparetto, Maura, Stevens, Brett, Pei, Shanshan, Balys, Marlene, Ashton, John M., Klemm, Dwight J., Woolthuis, Carolien M., Stranahan, Alec W., Park, Christopher Y., Jordan, Craig T.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 07.07.2016
• Subjects: Adaptation, Physiological; Adipose Tissue - pathology; Animals; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Blast Crisis - drug therapy; Blast Crisis - pathology; CD36 Antigens - metabolism; Cytoprotection - drug effects; Drug Resistance, Neoplasm - drug effects; Energy Metabolism - drug effects; Fatty Acids - metabolism; Gonads - pathology; Humans; Inflammation - pathology; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - drug therapy; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - pathology; Leukemia, Myeloid, Acute - drug therapy; Leukemia, Myeloid, Acute - pathology; Lipolysis - drug effects; Mice, Inbred C57BL; Mice, Knockout; Neoplastic Stem Cells - drug effects; Neoplastic Stem Cells - metabolism; Neoplastic Stem Cells - pathology; Oxidation-Reduction - drug effects; Tumor Burden - drug effects
• ISSN: 1934-5909; 1875-9777
• DOI: 10.1016/j.stem.2016.06.001

Adipose tissue (AT) has previously been identified as an extra-medullary reservoir for normal hematopoietic stem cells (HSCs) and may promote tumor development. Here, we show that a subpopulation of leukemic stem cells (LSCs) can utilize gonadal adipose tissue (GAT) as a niche to support their metabolism and evade chemotherapy. In a mouse model of blast crisis chronic myeloid leukemia (CML), adipose-resident LSCs exhibit a pro-inflammatory phenotype and induce lipolysis in GAT. GAT lipolysis fuels fatty acid oxidation in LSCs, especially within a subpopulation expressing the fatty acid transporter CD36. CD36+ LSCs have unique metabolic properties, are strikingly enriched in AT, and are protected from chemotherapy by the GAT microenvironment. CD36 also marks a fraction of human blast crisis CML and acute myeloid leukemia (AML) cells with similar biological properties. These findings suggest striking interplay between leukemic cells and AT to create a unique microenvironment that supports the metabolic demands and survival of a distinct LSC subpopulation. [Display omitted] •Gonadal adipose tissue (GAT) serves as a reservoir for LSCs•Interplay between leukemia cells and GAT fuels leukemia cell fatty acid metabolism•CD36 segregates LSCs into two metabolically and functionally distinct subsets•GAT provides a niche that confers chemo-resistance for CD36+ LSCs Ye et al. show that LSCs co-opt the adipose tissue niche to create a microenvironment that supports leukemic growth and resistance to chemotherapy. They also detect metabolically and functionally distinct mouse and human LSC subpopulations delineated by expression of the fatty acid transporter CD36.