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Cited by 83Chronic Lymphocytic Leukemia ResearchCancer, Lipids, and MetabolismLipid metabolism and disorders

Aberrant LPL expression, driven by STAT3, mediates free fatty acid metabolism in CLL cells

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Rozovski, Uri, Grgurevic, Srdana, Bueso-Ramos, Carlos, Harris, David M., Li, Ping, Liu, Zhiming, Wu, Ji Yuan, Jain, Preetesh +7 more·2015·Molecular Cancer Research
DOI 10.1158/1541-7786.mcr-14-0412PMC PMC4433415

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Abstract

UNLABELLED: While reviewing chronic lymphocytic leukemia (CLL) bone marrow slides, we identified cytoplasmic lipid vacuoles in CLL cells but not in normal B cells. Because lipoprotein lipase (LPL), which catalyzes hydrolysis of triglycerides into free fatty acids (FFA), is aberrantly expressed in CLL, we investigated whether LPL regulates the oxidative metabolic capacity of CLL cells. We found that unlike normal B cells, CLL cells metabolize FFAs. Because STAT3 is constitutively activated in CLL cells and because we identified putative STAT3 binding sites in the LPL promoter, we sought to determine whether STAT3 drives the aberrant expression of LPL. Transfection of luciferase reporter gene constructs driven by LPL promoter fragments into MM1 cells revealed that STAT3 activates the LPL promoter. In addition, chromatin immunoprecipitation confirmed that STAT3 binds to the LPL promoter. Furthermore, transfection of CLL cells with STAT3-shRNA downregulated LPL transcripts and protein levels, confirming that STAT3 activates the LPL gene. Finally, transfection of CLL cells with LPL-siRNAs decreased the capacity of CLL cells to oxidize FFAs and reduced cell viability. IMPLICATIONS: Our study suggests that CLL cells adopt their metabolism to oxidize FFA. Activated STAT3 induces LPL, which catalyzes the hydrolysis of triglycerides into FFA. Therefore, inhibition of STAT3 is likely to prevent the capacity of CLL cells to utilize FFA.

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Authors
Rozovski, U., Grgurevic, S., Bueso-Ramos, C., Harris, D. M., Li, P., Liu, Z., Wu, J. Y., Jain, P., Wierda, W., Burger, J., O'Brien, S., Jain, N., Ferrajoli, A., Keating, M. J., & Estrov, Z.
Affiliations
  • The University of Texas MD Anderson Cancer Center (US)
  • 1Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Corresponding author
Estrov, Zeev
ORCID
Venue
Molecular Cancer Research
Publisher
American Association for Cancer Research (AACR)
Published
2015-05-01
Volume
13
Issue
5
Pages
944-953
ISSN
  • 1541-7786 (ISSN-L)
  • 1557-3125
DOI
10.1158/1541-7786.mcr-14-0412
PMC
PMC4433415
OpenAlex
W2023653659
Cited by
83
References
1
Citations by year
2025: 6 · 2024: 5 · 2023: 12 · 2022: 6 · 2021: 14 · 2020: 8 · 2019: 9 · 2018: 10 · 2017: 4 · 2016: 7 · 2015: 2
FWCI
4.29
Type
journal article
Language
en
Open access
Locations
  • Molecular Cancer Research (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
National Cancer Institute (P30CA16672, P30CA016672)
Topics
  • Health Sciences › Medicine › Genetics › Chronic Lymphocytic Leukemia Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
Keywords
chronic lymphocytic leukemia, lipoprotein lipase, STAT3, free fatty acid metabolism, fatty acid oxidation, lipolysis, STAT3 binding sites, B cell metabolism, STAT3 inhibition
MeSH terms
Fatty Acids, Nonesterified, Humans, Lipoprotein Lipase, Transfection, Leukemia, Lymphocytic, Chronic, B-Cell, STAT3 Transcription Factor

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