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Metabolism Pathways In Chronic Lymphocytic Leukemia
U. Rozovski, Inbal Hazan-Halevy, M. Barzilai, M. Keating, Z. Estrov
Published 2016 · Medicine, Biology
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Abstract Alterations in chronic lymphocytic leukemia (CLL) cell metabolism have been studied by several investigators. Unlike normal B lymphocytes or other leukemia cells, CLL cells, like adipocytes, store lipids and utilize free fatty acids (FFA) to produce chemical energy. None of the recently identified mutations in CLL directly affects metabolic pathways, suggesting that genetic alterations do not directly contribute to CLL cells’ metabolic reprogramming. Conversely, recent data suggest that activation of STAT3 or downregulation of microRNA-125 levels plays a crucial role in the utilization of FFA to meet the CLL cells’ metabolic needs. STAT3, known to be constitutively activated in CLL, increases the levels of lipoprotein lipase (LPL) that mediates lipoprotein uptake and shifts the CLL cells’ metabolism towards utilization of FFA. Herein, we review the evidence for altered lipid metabolism, increased mitochondrial activity and formation of reactive oxygen species (ROS) in CLL cells, and discuss the possible therapeutic strategies to inhibit lipid metabolism pathways in patient with CLL.
This paper references
Metformin and reduced risk of cancer in diabetic patients
J. Evans (2005)
Hallmarks of Cancer: The Next Generation
D. Hanahan (2011)
450K-array analysis of chronic lymphocytic leukemia cells reveals global DNA methylation to be relatively stable over time and similar in resting and proliferative compartments
N. Cahill (2013)
B lymphocytes from patients with chronic lymphocytic leukemia contain signal transducer and activator of transcription (STAT) 1 and STAT3 constitutively phosphorylated on serine residues.
D. Frank (1997)
Targeting the interleukin-6/Jak/stat pathway in human malignancies.
P. Sansone (2012)
Antigen receptor-mediated changes in glucose metabolism in B lymphocytes: role of phosphatidylinositol 3-kinase signaling in the glycolytic control of growth.
Cheryl A Doughty (2006)
STAT3-Activated GM-CSFRα Translocates to the Nucleus and Protects CLL Cells from Apoptosis
P. Li (2014)
Simvastatin induces apoptosis of B-CLL cells by activation of mitochondrial caspase 9.
D. Chapman-Shimshoni (2003)
Mitochondrial DNA mutations in primary leukemia cells after chemotherapy: clinical significance and therapeutic implications
J. Carew (2003)
Mitochondrial diseases in man and mouse.
D. Wallace (1999)
ABNORMAL CARBOHYDRATE METABOLISM IN PATIENTS WITH MALIGNANT BLOOD DYSCRASIAS
B. S. A. LISKER (1966)
The activity of atorvastatin and rosiglitazone on CD38, ZAP70 and apoptosis in lymphocytes of B-cell chronic lymphocytic leukemia in vitro
I. Yavaşoğlu (2013)
The Jak-STAT pathway.
K. Imada (2000)
The CD16- CD56(bright) NK cell subset is resistant to reactive oxygen species produced by activated granulocytes and has higher antioxidative capacity than the CD16+ CD56(dim) subset.
H. Harlin (2007)
Mitochondrial DNA copy number and future risk of B-cell lymphoma in a nested case-control study in the prospective EPIC cohort.
F. Hosnijeh (2014)
Dysregulation of fatty acid synthesis and glycolysis in non-Hodgkin lymphoma
A. Bhatt (2012)
C6ceramide nanoliposomes target the Warburg effect in chronic lymphocytic leukemia
LK Ryland (2013)
Coupling of Phosphorylation to Electron and Hydrogen Transfer by a Chemi-Osmotic type of Mechanism
P. Mitchell (1961)
Metabolic reprogramming: a cancer hallmark even warburg did not anticipate.
Patrick S Ward (2012)
Expression of Functional Sphingosine-1 Phosphate Receptor-1 Is Reduced by B Cell Receptor Signaling and Increased by Inhibition of PI3 Kinase δ but Not SYK or BTK in Chronic Lymphocytic Leukemia Cells
K. J. Till (2015)
Statins and protein prenylation in cancer cell biology and therapy.
C. Garcia-Ruiz (2012)
C6-Ceramide Nanoliposomes Target the Warburg Effect in Chronic Lymphocytic Leukemia
Lindsay K Ryland (2013)
Targeting cancer cells by ROS-mediated mechanisms: a radical therapeutic approach?
D. Trachootham (2009)
PPAR-alpha is a therapeutic target for chronic lymphocytic leukemia
D. Spaner (2013)
ROS as signalling molecules: mechanisms that generate specificity in ROS homeostasis
B. D'autréaux (2007)
Chronic lymphocytic leukemia--an accumulative disease of immunolgically incompetent lymphocytes.
W. Dameshek (1967)
Statin and aspirin use is associated with improved outcome of FCR therapy in relapsed/refractory chronic lymphocytic leukemia.
Y. Chae (2014)
Total lesion glycolysis in positron emission tomography is a better predictor of outcome than the International Prognostic Index for patients with diffuse large B cell lymphoma
T. Kim (2013)
Oxidative burst of neutrophils against melanoma B16-F10.
Morana Živković (2007)
Relation of Gene Expression Phenotype to Immunoglobulin Mutation Genotype in B Cell Chronic Lymphocytic Leukemia
A. Rosenwald (2001)
Reactive oxygen species: role in the development of cancer and various chronic conditions
G. Waris (2006)
Free radical stress in chronic lymphocytic leukemia cells and its role in cellular sensitivity to ROS-generating anticancer agents.
Y. Zhou (2003)
Dysregulation of apoptosis genes in hematopoietic malignancies
S. Kitada (2002)
The ATP-phosphate cycle.
F. Lipmann (1981)
The mitochondrial genome: structure, transcription, translation and replication.
J. Taanman (1999)
Camouflage and sabotage: tumor escape from the immune system
I. Poschke (2011)
Impaired pentose phosphate shunt and decreased glycolytic activity in lymphocytes of chronic lymphocytic leukemia. Metabolic pathway.
J. Brody (1969)
Preferential Cell Death of CD8+ Effector Memory (CCR7−CD45RA−) T Cells by Hydrogen Peroxide-Induced Oxidative Stress 1
Akihiro Takahashi (2005)
Cholesterol Levels In Patients With Newly Diagnosed Chronic Lymphocytic Leukemia: A retrospective Multicenter Study
Gokhan Pektas (2013)
Lipoprotein lipase: structure, function, regulation, and role in disease
J. R. Mead (2002)
Stat3 Activates the Receptor Tyrosine Kinase Like Orphan Receptor-1 Gene in Chronic Lymphocytic Leukemia Cells
P. Li (2010)
The down-regulation of miR-125b in chronic lymphocytic leukemias leads to metabolic adaptation of cells to a transformed state.
E. Tili (2012)
Tumor cell lysis by activated human neutrophils: Analysis of neutrophil-delivered oxidative attack and role of leukocyte function-associated antigen 1
F. Dallegri (2004)
Lipoprotein lipase and lipolysis: central roles in lipoprotein metabolism and atherogenesis.
I. Goldberg (1996)
Identification of patterns in biological sequences at the ALGGEN server: PROMO and MALGEN
D. Farré (2003)
Early ROS-mediated DNA damage and oxidative stress biomarkers in Monoclonal B Lymphocytosis.
R. Collado (2012)
The CD16−CD56bright NK Cell Subset Is Resistant to Reactive Oxygen Species Produced by Activated Granulocytes and Has Higher Antioxidative Capacity Than the CD16+CD56dim Subset1
H. Harlin (2007)
Nuclear factor-kappaB and STAT3 are constitutively active in CD138+ cells derived from multiple myeloma patients, and suppression of these transcription factors leads to apoptosis.
A. Bharti (2004)
Cell proliferation and death: forgotten features of chronic lymphocytic leukemia B cells.
N. Chiorazzi (2007)
Correlation between FDG/PET, histology, characteristics, and survival in 332 patients with chronic lymphoid leukemia.
L. Falchi (2014)
Exome sequencing identifies recurrent mutations of the splicing factor SF3B1 gene in chronic lymphocytic leukemia
V. Quesada (2012)
Cellular and molecular mechanisms of metformin: an overview.
B. Viollet (2012)
The LPL/ADAM29 expression ratio is a novel prognosis indicator in chronic lymphocytic leukemia.
P. Oppezzo (2005)
über den Stoffwechsel der Carcinomzelle
O. Warburg (2005)
Resistance to Dasatinib in primary chronic lymphocytic leukemia lymphocytes involves AMPK-mediated energetic re-programming
Veronica L. Martinez Marignac (2013)
Cellular Metabolism and Disease: What Do Metabolic Outliers Teach Us?
R. DeBerardinis (2012)
Stromal control of cystine metabolism promotes cancer cell survival in chronic lymphocytic leukemia
W. Zhang (2012)
Modulation of oxidative stress as an anticancer strategy
C. Gorrini (2013)
SF3B1 and other novel cancer genes in chronic lymphocytic leukemia.
L. Wang (2011)
Monocytic AML cells inactivate antileukemic lymphocytes: role of NADPH oxidase/gp91(phox) expression and the PARP-1/PAR pathway of apoptosis.
J. Aurelius (2012)
Positron emission tomography (PET) with 18F-fluorodeoxyglucose (18F-FDG) for the staging of low-grade non-Hodgkin's lymphoma (NHL).
G. Jerusalem (2001)
Aberrant morphology, proliferation, and apoptosis of B-cell chronic lymphocytic leukemia cells.
C. Bueso-Ramos (2004)
Über den Stoffwechsel der Carzinomzelle
O. Warburg (1925)
2-[18F]fluoro-2-deoxy-d-glucose positron emission tomography/computed tomography examination in patients with chronic lymphocytic leukemia may reveal Richter transformation
T. Papajík (2014)
A User's Guide to the Encyclopedia of DNA Elements (ENCODE)
R. Myers (2011)
Prolonged Production of Reactive Oxygen Species in Response to B Cell Receptor Stimulation Promotes B Cell Activation and Proliferation
Matthew L. Wheeler (2012)
PROMO: detection of known transcription regulatory elements using species-tailored searches
Xavier Messeguer (2002)
Acute myeloid leukemia with IDH1 or IDH2 mutation: frequency and clinicopathologic features.
K. Patel (2011)
Statin use and reduced cancer-related mortality.
S. F. Nielsen (2012)
Role of fluorine‐18 fluoro‐deoxyglucose positron emission tomography scan in the evaluation and follow‐up of patients with low‐grade lymphomas
M. Karam (2006)
Circular Dimer and Catenate Forms of Mitochondrial DNA in Human Leukaemic Leucocytes
DAVID A. Clayton (1967)
Investigating and targeting chronic lymphocytic leukemia metabolism with the human immunodeficiency virus protease inhibitor ritonavir and metformin
Kehinde U. A. Adekola (2015)
The apoptotic pathway: a target for therapy in chronic lymphocytic leukemia
D. Bentley (2000)
Measurement in vivo of proliferation rates of slow turnover cells by 2H2O labeling of the deoxyribose moiety of DNA
R. Neese (2002)
STAT3 is constitutively phosphorylated on serine 727 residues, binds DNA, and activates transcription in CLL cells.
I. Hazan-Halevy (2010)
Uncovering the DNA methylome in chronic lymphocytic leukemia
N. Cahill (2013)
Platelet transfusion can mimic somatic mtDNA mutations
D. Meierhofer (2006)
High Mitochondrial DNA Stability in B-Cell Chronic Lymphocytic Leukemia
María Cerezo (2009)
Metabolic alterations in cancer cells and therapeutic implications
N. Hammoudi (2011)
Gene Expression Profiling of B Cell Chronic Lymphocytic Leukemia Reveals a Homogeneous Phenotype Related to Memory B Cells 〉
U. Klein (2001)
Integrated physiology and systems biology of PPARα
S. Kersten (2014)
Oxidative phosphorylation in cancer cells.
G. Solaini (2011)
Organometallic nucleosides induce non-classical leukemic cell death that is mitochondrial-ROS dependent and facilitated by TCL1-oncogene burden
C. Prinz (2015)
Otto Warburg's contributions to current concepts of cancer metabolism
W. Koppenol (2011)
VLDL hydrolysis by LPL activates PPAR-α through generation of unbound fatty acids
Maxwell A. Ruby (2010)
Adaphostin-induced apoptosis in CLL B cells is associated with induction of oxidative stress and exhibits synergy with fludarabine.
T. Shanafelt (2005)
Aberrant LPL Expression, Driven by STAT3, Mediates Free Fatty Acid Metabolism in CLL Cells
U. Rozovski (2015)
Statin and non-steroidal anti-inflammatory drug use in relation to clinical outcome among patients with Rai stage 0 chronic lymphocytic leukemia
T. Shanafelt (2010)
Mitochondrial metabolism contributes to oxidative stress and reveals therapeutic targets in chronic lymphocytic leukemia.
R. Jitschin (2014)
Deregulated expression of fat and muscle genes in B-cell chronic lymphocytic leukemia with high lipoprotein lipase expression
M. Bilban (2006)
Wratschebnaje obosrnije 1921
A B. (1921)
Statin and nonsteroidal anti-inflammatory drug use in relation to clinical outcome among patients with Rai stage 0 chronic lymphocytic leukemia
TD Shanafelt (2010)
Metabolic and Biosynthetic Features of Lymphocytes from Patients with Diabetes Mellitus: Similarities to Lymphocytes in Chronic Lymphocytic Leukaemia
J. Brody (1970)
Special Article: Chronic Lymphocytic Leukemia—an Accumulative Disease of Immunologically Incompetent Lymphocytes
W. Dameshek (1967)
Is there a role for carbohydrate restriction in the treatment and prevention of cancer?
R. Klement (2011)
T cell apoptosis and reactive oxygen species.
David A Hildeman (2003)
Next-generation sequencing of the TET2 gene in 355 MDS and CMML patients reveals low-abundance mutant clones with early origins, but indicates no definite prognostic value.
A. E. Smith (2010)
HVCN1 modulates BCR signal strength via regulation of BCR-dependent generation of reactive oxygen species
M. Capasso (2010)
A prospective study of mitochondrial DNA copy number and risk of non-Hodgkin lymphoma.
Q. Lan (2008)
High expression of lipoprotein lipase in poor risk B-cell chronic lymphocytic leukemia
D. Heintel (2005)
Stimulation of the B-cell receptor activates the JAK2/STAT3 signaling pathway in chronic lymphocytic leukemia cells.
U. Rozovski (2014)
Transcriptional deficits in oxidative phosphorylation with statin myopathy
Monica Jeanne Hubal (2011)
This paper is referenced by
Prognostic relevance of oxidative stress measurement in chronic lymphocytic leukaemia
G. D'Arena (2017)
The Metabolomic Profile of Lymphoma Subtypes: A Pilot Study
Luigi Barberini (2019)
Tumor Metabolism as a Regulator of Tumor–Host Interactions in the B-Cell Lymphoma Microenvironment—Fueling Progression and Novel Brakes for Therapy
Anna C Beielstein (2019)
STAT3-activated CD36 facilitates fatty acid uptake in chronic lymphocytic leukemia cells
U. Rozovski (2018)
B1a B cells require autophagy for metabolic homeostasis and self-renewal
Alexander J Clarke (2017)
The Role for Myc in Coordinating Glycolysis, Oxidative Phosphorylation, Glutaminolysis, and Fatty Acid Metabolism in Normal and Neoplastic Tissues
E. Goetzman (2018)
Bruton’s tyrosine kinase is at the crossroads of metabolic adaptation in primary malignant human lymphocytes
Bahram Sharif-Askari (2019)
CYP2B6 polymorphism and lipoprotein lipase expression in chronic lymphocytic leukemia: impact on the outcome of fludarabine–cyclophosphamide regimen
Ahmed M. Bedewy (2019)
Metabolic rewiring beyond Warburg in chronic lymphocytic leukemia: How much do we actually know?
G. Galicia-Vázquez (2019)
The use of inexpensive broad spectrum lower toxicity therapeutics in chronic lymphocytic leukemia.
G. Marjanović (2017)
Role of purines in regulation of metabolic reprogramming
Zhenwei Tang (2019)
Effects of PSMA1 on the differentiation and lipid deposition of bovine preadipocytes
Sheng Li (2019)
Endocytosis of very low-density lipoprotein particles: an unexpected mechanism for lipid acquisition by breast cancer cells
Leslie E. Lupien (2019)
B1a B cells require autophagy for metabolic homeostasis and self-renewal
A. Clarke (2018)
Lipoprotein Lipase as a Prognostic Marker in Chronic Lymphocytic Leukemia
Zoltán Mátrai (2016)
Laser flow cytometry as a tool for the advancement of clinical medicine.
David Aebisher (2017)
Lipoprotein Lipase Expression in Chronic Lymphocytic Leukemia: New Insights into Leukemic Progression
Daniel Prieto (2017)
LPL deletion is associated with poorer response to ibrutinib-based treatments and overall survival in TP53-deleted chronic lymphocytic leukemia
W. Liu (2020)
Ibrutinib Resistance Is Reduced by an Inhibitor of Fatty Acid Oxidation in Primary CLL Lymphocytes
G. Galicia-Vázquez (2018)
Altered Metabolism of Leukemic Cells: New Therapeutic Opportunity.
J. Starkova (2018)
An Inhibitor of Fatty Acid Synthase Thioesterase Domain with Improved Cytotoxicity against Breast Cancer Cells and Stability in Plasma
Leslie E. Lupien (2019)
Change of COMT Val158Met Genotype in Tumoral B Cells of a Chronic Lymphocytic Leukemia Patient: A Case Report
Role of bone marrow adipocytes in leukemia and chemotherapy challenges
A. Samimi (2019)
Lipid metabolism: An alternative Achille’s heel in lymphomas?
Pier Paolo Piccaluga (2017)
Telomere fusions associate with coding sequence and copy number alterations in CLL
Laura Escudero (2019)
Oxidative stress in chronic lymphocytic leukemia: still a matter of debate
G. D'Arena (2019)
Ibrutinib inhibits free fatty acid metabolism in chronic lymphocytic leukemia
U. Rozovski (2018)
Proteomics and metabolomics identify molecular mechanisms of aging potentially predisposing for chronic lymphocytic leukemia*
R. Mayer (2017)
Zinc-chitosan nanoparticles induced apoptosis in human acute T-lymphocyte leukemia through activation of tumor necrosis factor receptor CD95 and apoptosis-related genes.
K. Saravanakumar (2018)