ZAP-70 expression is associated with enhanced ability to respond to migratory and survival signals in B-cell chronic lymphocytic leukemia (B-CLL)

Richardson, Sarah J.; Matthews, Christine; Catherwood, Mark; Alexander, H. Denis; Carey, Barbara; Farrugia, Joanna; Gardiner, Anne; Mould, Sarah; Oscier, David; Copplestone, J. A.; Prentice, A. G.

doi:10.1182/blood-2005-04-1718

Cited by 162 publications

(169 citation statements)

References 52 publications

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“…28 The ERK pathway is activated in CLL cells by nurse-like cells through B-cell activating factor of the tumor necrosis factor family (BAFF) or a proliferation inducing ligand (APRIL) receptors or B-cell receptor (BCR) stimulation. 36,37 This pathway appears to be more activated in ZAP-70 þ than in ZAP-70 -CLL cells, 40 which may account for the observed differences in levels of phosphorylated BCL-2 between these two sets of CLL patients. On the basis of these studies, we have demonstrated that the MEK1/ ERK inhibitor PD98059 is able to reduce BCL-2 phosphorylation levels and increase GX15-070 activity in CLL primary cells.…”

Section: Discussionmentioning

confidence: 90%

BCL-2 phosphorylation modulates sensitivity to the BH3 mimetic GX15-070 (Obatoclax) and reduces its synergistic interaction with bortezomib in chronic lymphocytic leukemia cells

et al. 2008

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Chronic lymphocytic leukemia (CLL) is a B-cell lymphoid neoplasm with deregulated apoptosis and overexpression of several antiapoptotic BCL-2 proteins. GX15-070/Obatoclax is a small-molecule BH3 mimetic compound that has shown activity against several hematologic malignancies and solid tumors. In the present work, we report that GX15-070 led to the disruption of BCL-2/BIM and MCL-1/BAK complexes in CLL cells, followed by the activation of the mitochondrial apoptotic pathway. CLL cells showed lower sensitivity to GX15-070 than primary mantle cell lymphoma (MCL) ones, in correlation with higher levels of phosphorylated BCL-2 at serine 70 residue (pBCL-2(Ser70)) in CLL cells. Decrease in BCL-2 phosphorylation by extracellular signal-regulated kinase (ERK)1/2 inhibition increased CLL sensitivity to GX15-070, while blocking BCL-2 dephosphorylation using a PP2A antagonist reduced the activity of this BH3 mimetic. GX15-070 activity was increased by cotreatment with the proteasome inhibitor bortezomib. However, as proteasome inhibition led to the accumulation of phosphorylated BCL-2, the degree of interaction between GX15-070 and bortezomib was regulated by basal pBCL-2(Ser70) levels. These results support the role of BCL-2 phosphorylation as a mechanism of resistance to BH3 mimetic compounds, and demonstrate that combination approaches including ERK inhibitors could enhance BH3 mimetics activity both alone or in combination with proteasome inhibitors.

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Section: Discussionmentioning

confidence: 90%

BCL-2 phosphorylation modulates sensitivity to the BH3 mimetic GX15-070 (Obatoclax) and reduces its synergistic interaction with bortezomib in chronic lymphocytic leukemia cells

et al. 2008

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“…This chemokine receptor is known to regulate trafficking of normal B, T and dendritic cells into the lymph node, and an increased expression of CCR7 has been invoked as a mechanism through which the CLL B cells can move from PB to BM and lymph nodes. [23][24][25] The seven genes (ID3, SFMBT1, PBX3, HIVEP2, ZFP64, RXRA, LEF1) involved in the regulation of transcription category were upregulated in CLL. LEF1 was the most significant overexpressed gene in CLL-BL samples compared with WM-BL and NBL.…”

Section: Resultsmentioning

confidence: 99%

Gene expression profiling of B lymphocytes and plasma cells from Waldenström's macroglobulinemia: comparison with expression patterns of the same cell counterparts from chronic lymphocytic leukemia, multiple myeloma and normal individuals

et al. 2007

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The tumoral clone of Waldenströ m's macroglobulinemia (WM) shows a wide morphological heterogeneity, which ranges from B lymphocytes (BL) to plasma cells (PC). By means of genomewide expression profiling we have been able to identify genes exclusively deregulated in BL and PC from WM, but with a similar expression pattern in their corresponding cell counterparts from chronic lymphocytic leukemia (CLL) and multiple myeloma (MM), as well as normal individuals. The differentially expressed genes have important functions in B-cell differentiation and oncogenesis. Thus, two of the genes downregulated in WM-BL were IL4R, which plays a relevant role in CLL B-cell survival, and BACH2, which participates in the development of class-switched PC. Interestingly, one of the upregulated genes in WM-BL was IL6. A set of four genes was able to discriminate clonal BL from WM and CLL: LEF1 (WNT/b-catenin pathway), MARCKS, ATXN1 and FMOD. We also found deregulation of genes involved in plasma cell differentiation such as PAX5, which was overexpressed in WM-PC, and IRF4 and BLIMP1, which were underexpressed. In addition, three of the target genes activated by PAX5 -CD79, BLNK and SYK -were upregulated in WM-PC. In summary, these results indicate that both PC and BL from WM are genetically different from the MM and CLL cell counterpart.

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“…Importantly, CLL cells expressing ZAP-70 have been shown to be more responsive to B-cell receptor stimulation in vitro than CLL cells without ZAP-70, indicating that ZAP-70 could enhance B-cell receptor signaling for survival and proliferation and thereby contribute to disease progression (14). Recently, differences in the responses to chemokines have been described between ZAP-70 positive and negative CLL cells (15). This could affect the ability of CLL cells to interact with the stroma microenvironment in lymph node and bone marrow where proliferation of the leukemic cells occurs.…”

Section: Zap-70 a Prognostic Markermentioning

confidence: 99%

Flow cytometry for ZAP‐70: New colors for chronic lymphocytic leukemia

Wiestner

2006

Cytometry Part B Clinical

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ZAP-70 expression is associated with enhanced ability to respond to migratory and survival signals in B-cell chronic lymphocytic leukemia (B-CLL)

Cited by 162 publications

References 52 publications

BCL-2 phosphorylation modulates sensitivity to the BH3 mimetic GX15-070 (Obatoclax) and reduces its synergistic interaction with bortezomib in chronic lymphocytic leukemia cells

BCL-2 phosphorylation modulates sensitivity to the BH3 mimetic GX15-070 (Obatoclax) and reduces its synergistic interaction with bortezomib in chronic lymphocytic leukemia cells

Gene expression profiling of B lymphocytes and plasma cells from Waldenström's macroglobulinemia: comparison with expression patterns of the same cell counterparts from chronic lymphocytic leukemia, multiple myeloma and normal individuals

Flow cytometry for ZAP‐70: New colors for chronic lymphocytic leukemia

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