Exosome-driven lipolysis and bone marrow niche remodeling support leukemia expansion

Kumar, Bijender; Orellana, Marvin; Brooks, Jamison; Madabushi, Srideshikan Sargur; Vishwasrao, Paresh; Parra, Liliana Echavarria; Sanchez, James F.; Salhotra, Amandeep; Stein, Anthony S.; Chen, Ching-Cheng; Marcucci, Guido; Song, Hui

doi:10.3324/haematol.2019.246058

Cited by 15 publications

(8 citation statements)

References 15 publications

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“…In knockin syngeneic AML/acute lymphoblastic leukemia (ALL) mouse models, tumor-derived EVs increased the expression of adipose triglyceride lipase (ATGL) and hormone-sensitive lipase (HSL) enzymes in adipocytes, resulting in increased lipolysis, which supported leukemia cell expansion ( 53 ). Similarly, miR-92a-3p–containing EVs derived from a CML cell line (K562) attenuated adipogenesis of an adipose-derived MSC cell line (ADSCs) by inhibiting CCAAT/enhancer binding protein-α (C/EBPα).…”

Section: Functions Of Evs In Hematologic Malignanciesmentioning

confidence: 99%

Emerging roles of extracellular vesicles in normal and malignant hematopoiesis

Sun¹,

Gu²,

Zheng³

et al. 2022

Journal of Clinical Investigation

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Hematopoietic stem cells, regulated by their microenvironment (or “niche”), sustain the production of mature blood and immune cells. Leukemia cells remodel the microenvironment to enhance their survival, which is accompanied by the loss of support for normal hematopoiesis in hematologic malignancies. Extracellular vesicles (EVs) mediate intercellular communication in physiological and pathological conditions, and deciphering their functions in cell-cell interactions in the ecosystem can highlight potential therapeutic targets. In this Review, we illustrate the utility of EVs derived from various cell types, focusing on the biological molecules they contain and the behavioral alterations they can induce in recipient cells. We also discuss the potential for clinical application in hematologic malignancies, including EV-based therapeutic regimens, drug delivery via EVs, and the use of EVs (or their cargoes) as biomarkers.

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Section: Functions Of Evs In Hematologic Malignanciesmentioning

confidence: 99%

Emerging roles of extracellular vesicles in normal and malignant hematopoiesis

Sun¹,

Gu²,

Zheng³

et al. 2022

Journal of Clinical Investigation

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“…Leukemic cells and leukemic stem cells reside in the bone marrow and lymphatic niches that resemble a glucose-deprived and hypoxic TME, which is comparable to the conditions seen in solid tumors. Two recent studies demonstrated that acute myeloid leukemia (AML) cells remodel their direct environment by secretion of exosomes that, in turn, promote MSC differentiation towards adipocytes and lipolysis in already differentiated adipocytes [ 56 , 57 ]. Moreover, adipose tissue is beneficial for AML blasts and leukemic stem cells (LSCs) by increasing FAO and CD36/FABP4 expression, resulting in the prevention of serum starvation-induced apoptosis and protection from chemotherapy [ 58 , 59 ].…”

Section: Sources Of Lipids Within the Tumor Microenvironmentmentioning

confidence: 99%

Lipotoxicity as a Barrier for T Cell-Based Therapies

et al. 2022

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Nowadays, T-cell-based approaches play an increasing role in cancer treatment. In particular, the use of (genetically engineered) T-cells has heralded a novel era for various diseases with previously poor outcomes. Concurrently, the relationship between the functional behavior of immune cells and their metabolic state, known as immunometabolism, has been found to be an important determinant for the success of immunotherapy. In this context, immune cell metabolism is not only controlled by the expression of transcription factors, enzymes and transport proteins but also by nutrient availability and the presence of intermediate metabolites. The lack of as well as an oversupply of nutrients can be detrimental and lead to cellular dysfunction and damage, potentially resulting in reduced metabolic fitness and/or cell death. This review focusses on the detrimental effects of excessive exposure of T cells to fatty acids, known as lipotoxicity, in the context of an altered lipid tumor microenvironment. Furthermore, implications of T cell-related lipotoxicity for immunotherapy will be discussed, as well as potential therapeutic approaches.

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“…In the context of active leukemia, the bone marrow niche undergoes a number of physical and functional changes. Compared to healthy marrow, leukemic marrow commonly exhibits hypercellularity, enhanced extracellular matrix deposition, vascular adhesion protein expression, and vascular permeability [13][14][15][16][17] . However, little is known regarding the circulation properties of leukemia cells or the factors that regulate circulation.…”

Section: Introductionmentioning

confidence: 99%

Leukemia circulation kinetics revealed through blood exchange method

Miller,

Langenbucher,

Rodriguez

et al. 2023

Preprint

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Leukemias and their bone marrow microenvironment are known to undergo dynamic changes over the course of disease. However, relatively little is known about the circulation kinetics of leukemia cells, nor the impact of specific factors on the clearance of circulating leukemia cells (CLCs) from the blood. To gain a basic understanding of leukemia cell dynamics over the course of disease progression and therapeutic response, we apply a blood exchange method to mouse models of acute leukemia. We find that CLCs circulate in the blood for 1-2 orders of magnitude longer than solid tumor circulating tumor cells. We further observe that: i) leukemia presence in the marrow can limit the clearance of CLCs in a model of acute lymphocytic leukemia (ALL), and ii) CLCs in a model of relapsed acute myeloid leukemia (AML) can clear faster than their untreated counterparts. Our approach can also directly quantify the impact of microenvironmental factors on CLC clearance properties. For example, data from two leukemia models suggest that E-selectin, a vascular adhesion molecule, alters CLC clearance. Our research highlights that clearance rates of CLCs can vary in response to tumor and treatment status and provides a strategy for identifying basic processes and factors that govern the kinetics of circulating cells.

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Exosome-driven lipolysis and bone marrow niche remodeling support leukemia expansion

Cited by 15 publications

References 15 publications

Emerging roles of extracellular vesicles in normal and malignant hematopoiesis

Emerging roles of extracellular vesicles in normal and malignant hematopoiesis

Lipotoxicity as a Barrier for T Cell-Based Therapies

Leukemia circulation kinetics revealed through blood exchange method

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