Aberrant LPL Expression, Driven by STAT3, Mediates Free Fatty Acid Metabolism in CLL Cells.
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.


CONCLUSIONS
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.
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Uri
U
Rozovski
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Srdana
S
Grgurevic
Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Carlos
C
Bueso-Ramos
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.
David M
DM
Harris
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Ping
P
Li
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Zhiming
Z
Liu
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Ji Yuan
JY
Wu
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Preetesh
P
Jain
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.
William
W
Wierda
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Jan
J
Burger
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Susan
S
O'Brien
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Nitin
N
Jain
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Alessandra
A
Ferrajoli
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Michael J
MJ
Keating
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas. zestrov@mdanderson.org.
Zeev
Z
Estrov
D005230:Fatty Acids, Nonesterified / Q000378:metabolism*; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000378:metabolism* / Q000473:pathology; D008071:Lipoprotein Lipase / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D014162:Transfection
D005230:Fatty Acids, Nonesterified; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C548261:LPL protein, human; D008071:Lipoprotein Lipase