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

Hazan‐Halevy

Barzilai

et al. 2015

Leukemia & Lymphoma

Self Cite

Alterations in 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 CLL cells’ metabolic needs. STAT3, known to be constitutively activated in CLL, increases the levels of lipoprotein lipase that mediates lipoprotein uptake and shifts 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 in CLL cells, and discuss possible therapeutic strategies to inhibit lipid metabolism pathways in patient with CLL.

Section: Altered Lipid Metabolism In Cllmentioning

confidence: 99%

Section: Altered Lipid Metabolism In Cllmentioning

confidence: 99%

Metabolism pathways in chronic lymphocytic leukemia

Hazan‐Halevy

Barzilai

et al. 2015

Leukemia & Lymphoma

Self Cite

“…To profile the expression of the NF-κB target genes, we used an RT 2 Profiler PCR Array kit (Qiagen Sciences, Germantown, MD) This 96-well assay profiles the expression of 83 NF-κB target genes and has wells for 3 different housekeeping genes, a genomic DNA contamination control, 3 replicate reverse transcription controls, and 3 replicates of positive polymerase chain reaction (PCR). Real-time PCR was performed according to the manufacturer's instructions.…”

Section: Methodsmentioning

confidence: 99%

Activation of the B‐cell receptor successively activates NF‐κB and STAT3 in chronic lymphocytic leukemia cells

Harris

et al. 2017

Intl Journal of Cancer

Self Cite

In chronic lymphocytic leukemia (CLL) cells, both interleukin-6 (IL-6) and the B-cell receptor (BCR) activate Janus kinase 2 (JAK2) and induce the phosphorylation of signal transduction and activator of transcription 3 (STAT3) on tyrosine 705 residues. However, whereas IL-6 phosphorylates STAT3 within 15 minutes, stimulation of the BCR with anti–immunoglobulin M (IgM) antibodies phosphorylates STAT3 in 2–4 hours. Here we show that this process takes longer because it requires transcriptional activity of NF-κB. Using an electromobility shift assay, we found that incubation with IgM antibodies for 4 or 18 hours, but not 15 minutes, increased NF-κB DNA-binding of CLL cells and increased binding was translated to increased transcriptional activity. Hence, 42% of the 83 NF-κB target genes were constitutively expressed in all CLL cells prior to any inducible stimuli. However, activation of the BCR increased the number of NF-κB target genes with detectable expression by 23%. Remarkably, prolonged incubation with anti-IgM antibodies induced a time-dependent transcription, production, and secretion of IL-6 protein. The IgM-induced production of IL-6 prompted the phosphorylation of STAT3 on tyrosine residues. This effect was inhibited by the JAK1/2 inhibitor of the JAK/STAT3 pathway ruxolitinib. Taken together, these results suggest that in CLL cells, constitutive tonic activation of NF-κB can be further enhanced by the BCR and that the BCR-induced activation of the JAK/STAT3 pathway depends on the NF-κB–induced production of IL-6.

“…Serine pSTAT3 has biologic activities similar to those of tyrosine pSTAT3: Serine pSTAT3 is shuttled to the nucleus, binds to DNA, activates genes known to be activated by tyrosine pSTAT3, and provides CLL cells with a survival advantage (5, 9–12) and proliferation capacity (12, 13). …”

Section: Introductionmentioning

confidence: 99%

Constitutive Phosphorylation of STAT3 by the CK2–BLNK–CD5 Complex

Molecular Cancer Research

Harris

et al. 2017

Self Cite

In chronic lymphocytic leukemia (CLL), STAT3 is constitutively phosphorylated on serine 727 and plays a role in the pathobiology of CLL. However, what induces constitutive phosphorylation of STAT3 is currently unknown. Mass spectrometry was used to identify casein kinase 2 (CK2), a serine/threonine kinase that co-immunoprecipitated with serine phosphorylated STAT3 (pSTAT3). Furthermore, activated CK2 incubated with recombinant STAT3 induced phosphorylation of STAT3 on serine 727. Although STAT3 and CK2 are present in normal B- and T-cells, STAT3 is not constitutively phosphorylated in these cells. Further study found that CD5 and BLNK co-expressed in CLL, but not in normal B- or T-cells, are required for STAT3 phosphorylation. To elucidate the relationship of CD5 and BLNK to CK2 and STAT3, STAT3 was immunoprecipitated from CLL cells and CK2, CD5, and BLNK were detected in the immunoprecipitate. Conversely, STAT3, CD5, and BLNK were in the immunoprecipitate of CLL cells immunoprecipitated with CK2 antibodies. Furthermore, siRNA knockdown of CD5 or BLNK, or treatment with CD5-neutralizing antibodies significantly reduced the levels of serine pSTAT3 in CLL cells. Finally, confocal microscopy determined that CD5 is cell membrane bound and fractionation studies revealed that the CK2/CD5/BLNK/STAT3 complex remains in the cytoplasm, whereas serine pSTAT3 is shuttled to the nucleus. Implications These data show that the cellular proteins CK2, CD5, and BLNK are required for constitutive phosphorylation of STAT3 in CLL. Whether this protein complex phosphorylates other proteins or inhibiting its activity would have clinical benefit in patients has yet to be determined.