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

Haobin Ye; Biniam Adane; Nabilah Khan; Timothy Sullivan; Mohammad Minhajuddin; Maura Gasparetto; Brett Stevens; Shanshan Pei; Marlene Balys; John M Ashton; Dwight J Klemm; Carolien M Woolthuis; Alec W Stranahan; Christopher Y Park; Craig T Jordan

doi:10.1016/j.stem.2016.06.001

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

Haobin Ye, Biniam Adane, Nabilah Khan, Timothy Sullivan, Mohammad Minhajuddin, Maura Gasparetto, Brett Stevens, Shanshan Pei, Marlene Balys, John M Ashton, Dwight J Klemm, Carolien M Woolthuis, Alec W Stranahan, Christopher Y Park, Craig T Jordan

Research output: Contribution to journal › Article › Academic › peer-review

414 Citations (Scopus)

Abstract

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.

Original language	English
Pages (from-to)	23-37
Number of pages	15
Journal	Cell stem cell
Volume	19
Issue number	1
DOIs	https://doi.org/10.1016/j.stem.2016.06.001
Publication status	Published - 7-Jul-2016
Externally published	Yes

Keywords

Adaptation, Physiological
Adipose Tissue/pathology
Animals
Antineoplastic Agents/pharmacology
Blast Crisis/drug therapy
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, Myeloid, Acute/drug therapy
Lipolysis/drug effects
Mice, Inbred C57BL
Mice, Knockout
Neoplastic Stem Cells/drug effects
Oxidation-Reduction/drug effects
Tumor Burden/drug effects

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Leukemic Stem Cells Evade Chemotherapy by Metabolic Adaptation to an Adipose Tissue Niche
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Ye, H., Adane, B., Khan, N., Sullivan, T., Minhajuddin, M., Gasparetto, M., Stevens, B., Pei, S., Balys, M., Ashton, J. M., Klemm, D. J., Woolthuis, C. M., Stranahan, A. W., Park, C. Y., & Jordan, C. T. (2016). Leukemic Stem Cells Evade Chemotherapy by Metabolic Adaptation to an Adipose Tissue Niche. Cell stem cell, 19(1), 23-37. https://doi.org/10.1016/j.stem.2016.06.001

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abstract = "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.",

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author = "Haobin Ye and Biniam Adane and Nabilah Khan and Timothy Sullivan and Mohammad Minhajuddin and Maura Gasparetto and Brett Stevens and Shanshan Pei and Marlene Balys and Ashton, {John M} and Klemm, {Dwight J} and Woolthuis, {Carolien M} and Stranahan, {Alec W} and Park, {Christopher Y} and Jordan, {Craig T}",

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AU - Ye, Haobin

AU - Adane, Biniam

AU - Khan, Nabilah

AU - Sullivan, Timothy

AU - Minhajuddin, Mohammad

AU - Gasparetto, Maura

AU - Stevens, Brett

AU - Pei, Shanshan

AU - Balys, Marlene

AU - Ashton, John M

AU - Klemm, Dwight J

AU - Woolthuis, Carolien M

AU - Stranahan, Alec W

AU - Park, Christopher Y

AU - Jordan, Craig T

PY - 2016/7/7

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N2 - 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.

AB - 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.

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KW - Antineoplastic Agents/pharmacology

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KW - CD36 Antigens/metabolism

KW - Cytoprotection/drug effects

KW - Drug Resistance, Neoplasm/drug effects

KW - Energy Metabolism/drug effects

KW - Fatty Acids/metabolism

KW - Gonads/pathology

KW - Humans

KW - Inflammation/pathology

KW - Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy

KW - Leukemia, Myeloid, Acute/drug therapy

KW - Lipolysis/drug effects

KW - Mice, Inbred C57BL

KW - Mice, Knockout

KW - Neoplastic Stem Cells/drug effects

KW - Oxidation-Reduction/drug effects

KW - Tumor Burden/drug effects

U2 - 10.1016/j.stem.2016.06.001

DO - 10.1016/j.stem.2016.06.001

M3 - Article

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SN - 1934-5909

VL - 19

SP - 23

EP - 37

JO - Cell stem cell

JF - Cell stem cell

IS - 1

ER -

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

Abstract

Keywords

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