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Adipocytes Cause Leukemia Cell Resistance to L-Asparaginase via Release of Glutamine

Adipocytes Cause Leukemia Cell Resistance to L-Asparaginase via Release of Glutamine Obesity is a significant risk factor for cancer. A link between obesity and a childhood cancer has been identified: obese children diagnosed with high-risk acute lymphoblastic leukemia (ALL) had a 50% greater risk of relapse than their lean counterparts. l -asparaginase (ASNase) is a first-line therapy for ALL that breaks down asparagine and glutamine, exploiting the fact that ALL cells are more dependent on these amino acids than other cells. In the present study, we investigated whether adipocytes, which produce significant quantities of glutamine, may counteract the effects of ASNase. In children being treated for high-risk ALL, obesity was not associated with altered plasma levels of asparagine or glutamine. However, glutamine synthetase was markedly increased in bone marrow adipocytes after induction chemotherapy. Obesity substantially impaired ASNase efficacy in mice transplanted with syngeneic ALL cells and, like in humans, without affecting plasma asparagine or glutamine levels. In coculture, adipocytes inhibited leukemic cell cytotoxicity induced by ASNase, and this protection was dependent on glutamine secretion. These findings suggest that adipocytes work in conjunction with other cells of the leukemia microenvironment to protect leukemia cells during ASNase treatment. Cancer Res; 73(10); 2998–3006. ©2013 AACR . http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Cancer Research American Association of Cancer Research

Adipocytes Cause Leukemia Cell Resistance to L-Asparaginase via Release of Glutamine

Adipocytes Cause Leukemia Cell Resistance to L-Asparaginase via Release of Glutamine

Cancer Research , Volume 73 (10): 2998 – May 15, 2013

Abstract

Obesity is a significant risk factor for cancer. A link between obesity and a childhood cancer has been identified: obese children diagnosed with high-risk acute lymphoblastic leukemia (ALL) had a 50% greater risk of relapse than their lean counterparts. l -asparaginase (ASNase) is a first-line therapy for ALL that breaks down asparagine and glutamine, exploiting the fact that ALL cells are more dependent on these amino acids than other cells. In the present study, we investigated whether adipocytes, which produce significant quantities of glutamine, may counteract the effects of ASNase. In children being treated for high-risk ALL, obesity was not associated with altered plasma levels of asparagine or glutamine. However, glutamine synthetase was markedly increased in bone marrow adipocytes after induction chemotherapy. Obesity substantially impaired ASNase efficacy in mice transplanted with syngeneic ALL cells and, like in humans, without affecting plasma asparagine or glutamine levels. In coculture, adipocytes inhibited leukemic cell cytotoxicity induced by ASNase, and this protection was dependent on glutamine secretion. These findings suggest that adipocytes work in conjunction with other cells of the leukemia microenvironment to protect leukemia cells during ASNase treatment. Cancer Res; 73(10); 2998–3006. ©2013 AACR .

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References (55)

Publisher
American Association of Cancer Research
Copyright
Copyright © 2014 American Association for Cancer Research
ISSN
0008-5472
eISSN
1538-7445
DOI
10.1158/0008-5472.CAN-12-4402
pmid
23585457
Publisher site
See Article on Publisher Site

Abstract

Obesity is a significant risk factor for cancer. A link between obesity and a childhood cancer has been identified: obese children diagnosed with high-risk acute lymphoblastic leukemia (ALL) had a 50% greater risk of relapse than their lean counterparts. l -asparaginase (ASNase) is a first-line therapy for ALL that breaks down asparagine and glutamine, exploiting the fact that ALL cells are more dependent on these amino acids than other cells. In the present study, we investigated whether adipocytes, which produce significant quantities of glutamine, may counteract the effects of ASNase. In children being treated for high-risk ALL, obesity was not associated with altered plasma levels of asparagine or glutamine. However, glutamine synthetase was markedly increased in bone marrow adipocytes after induction chemotherapy. Obesity substantially impaired ASNase efficacy in mice transplanted with syngeneic ALL cells and, like in humans, without affecting plasma asparagine or glutamine levels. In coculture, adipocytes inhibited leukemic cell cytotoxicity induced by ASNase, and this protection was dependent on glutamine secretion. These findings suggest that adipocytes work in conjunction with other cells of the leukemia microenvironment to protect leukemia cells during ASNase treatment. Cancer Res; 73(10); 2998–3006. ©2013 AACR .

Journal

Cancer ResearchAmerican Association of Cancer Research

Published: May 15, 2013

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