Disruption of the IFN-γ cytokine network in chronic lymphocytic leukemia contributes to resistance of leukemic B cells to apoptosis

Zaki, Mohamed H.; Douglas, Raymond S.; Patten, Nancy; Bachinsky, Margaret; Lamb, Roberta J.; Nowell̀, Peter C.; Moore, Jonni S.

doi:10.1016/s0145-2126(00)00022-9

Cited by 30 publications

(19 citation statements)

References 34 publications

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“…Interestingly, six of these 37 differentially regulated genes, that is, interferon-induced protein 35 (IFI35), myxovirus resistance 1 (MX1), bone marrow stromal cell antigen 2 (BST2), signal transducer and activator of transcription 1 (STAT1), polymerase (RNA) II (DNA directed) polypeptide J (POLR2J) and CD38, are known interferon-stimulated genes 29 that were coordinately upregulated in the ZAP-70 þ CD38 þ samples. This finding in combination with data from the literature 30 showing that interferons secreted by dysregulated accessory T cells exert an antiapoptotic effect on CLL cells raises the possibility that interferon signaling may play a prominent role in the pathogenesis of ZAP-70 þ CD38 þ CLL cases. Furthermore, given that expression and aberrant phosphorylation of STAT1 has also been linked to apoptosis resistance in B-CLL cells, 31,32 overexpression of this molecule may contribute to the more aggressive clinical behavior of ZAP-70 þ CD38 þ CLL cases.…”

Section: Discussionsupporting

confidence: 55%

Combined analysis of ZAP-70 and CD38 expression as a predictor of disease progression in B-cell chronic lymphocytic leukemia

et al. 2005

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Prognostic predictions in B-cell chronic lymphocytic leukemia (B-CLL) at early clinical stage are based on biological disease parameters, such as ZAP-70 and CD38 protein levels, genomic aberrations as well as immunoglobulin variable heavy chain gene (IgV H ) mutation status. In the current study, ZAP-70 and CD38 expressions were examined by flow cytometry in 252 patients with B-CLL. Cytoplasmic ZAP-70 expression in more than 20% (ZAP-70 þ ) and surface CD38 expression on more than 30% (CD38 þ ) of B-CLL cells were associated with an unfavorable clinical course. The levels of ZAP-70 and CD38 did not change over time in the majority of patients where sequential samples were available for analysis. Combined analysis of ZAP-70 and CD38 yielded discordant results in 73 patients (29.0%), whereas 120 patients (47.6%) were concordantly negative and 59 patients (23.4%) were concordantly positive for ZAP-70 and CD38 expression. Median treatment-free survival times in patients whose leukemic cells were ZAP-70 þ CD38 þ was 30 months as compared to 130 months in patients with a ZAP-70À status. In patients with discordant ZAP-70/CD38 results, the median treatment-free survival time was 43 months. Thus, ZAP-70 and CD38 expression analyses provided complementary prognostic information identifying three patient subgroups with good, intermediate and poor prognosis. Over-representation of high-risk genomic aberrations such as 17p deletion or 11q deletion and distribution of the IgV H mutation status in B-CLL discordant for ZAP-70/ CD38 pointed toward a distinct biologic background of the observed disease subgroups. This finding was also supported by microarray-based gene expression profiling in a subset of 35 patients. The expression of 37 genes differed significantly between the three groups defined by their expression of ZAP-70 and CD38, including genes that are involved in regulation of cell survival and chemotherapy resistance.

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Section: Discussionsupporting

confidence: 55%

Combined analysis of ZAP-70 and CD38 expression as a predictor of disease progression in B-cell chronic lymphocytic leukemia

et al. 2005

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“…Hence, the decreased degranulation capacity may possibly be associated with a shift of circulating CD56 dim NK cells in CLL patients from cytolytic effectors to cytokine production, which may actually benefit tumor survival, since IFNg can reportedly protect CLL cells from apoptosis. 50,51 Reduced expression of NKp30 and NKp44 activating receptors has been reported on NK cells in CLL patients with high tumor burden, while expression of NKp46 was unchanged. 18,19 A recent report found reduced expression of CD16, DNAM-1, NKp30, and NKp46 activating receptors on NK cells from CLL patients.…”

Section: Discussionmentioning

confidence: 97%

NK cell dysfunction in chronic lymphocytic leukemia is associated with loss of the mature cells expressing inhibitory killer cell Ig-like receptors

et al. 2017

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A prospective analysis of natural killer (NK) cell phenotype and function was performed on fresh peripheral blood samples from untreated patients with B-cell chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). Compared to healthy controls, CD56 dim NK cells in CLL patients displayed reduced expression of the NKG2D activating receptor and increased CD27 expression, which indicates declines in mature cells. In addition, NK cells from CLL patients showed reduced degranulation responses toward transformed B cells alone or with rituximab and were more sensitive to activation-induced cell death. We further noted a striking reduction in the frequency and viability of NK cells expressing the inhibitory killer cell Ig-like receptors (KIR)2DL1 and/or KIR3DL1, which progressed over time in most patients. Comparisons between a CLL patient and healthy monozygotic twin were consistent with our results in the larger cohorts. Functional and biomarker alterations were less pronounced on NK cells from SLL patients, which have lower tumor burden in peripheral blood than CLL, but significant reduction in degranulation under ADCC conditions and lower frequency and viability of KIR-expressing NK cells were still evident in SLL. We conclude that mature KIR-expressing NK cells respond to the high circulating B cell tumor burden in CLL, but undergo activation-induced apoptosis. Consequently, CLL patients may benefit from therapies that augment NK cell survival and function.

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“…21 Attempts have been made to elucidate these type 1 and type 2 responses in patients with leukaemia. Whereas immune activity with respect to cytokine profiles has been evaluated in patients with chronic lymphocytic leukaemia (CLL), [24][25][26] acute lymphocytic leukaemia (ALL), 19,27 and chronic myelogenous leukaemia Percentage of cells in each subset producing intracellular cytokine IL-4, IL-10, IL-12 and IFN-g in normal controls and in AML patients before and after chemotherapy. There were significantly more leukaemic blasts making IFN-g compared with the normal precursor population.…”

Section: Discussionmentioning

confidence: 99%

Quantification and cytokine production of circulating lymphoid and myeloid cells in acute myelogenous leukaemia

2003

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A simple assay was developed to assess the potential of patients with acute myelogenous leukaemia (AML) to respond to immunotherapy. Lymphocytes, monocytes and leukaemic blasts with their corresponding intracellular cytokine profiles were evaluated by four-colour flow cytometry. In 50 ll samples of whole blood, surface labelling for CD45, CD8 and CD3 was used for cell identification prior to intracellular staining for interleukin (IL)-4, IL-10, IL-12 and interferon (IFN)-c. Absolute numbers of CD8 + and CD8 À (putative CD4 + ) T-cells, NK cells (CD8 + /CD3 À ) and monocytes were determined by reference to a fixed number of added fluorescent beads. The absolute numbers of CD8 À and CD8 + T-cells in the blood of patients with AML were similar to those of normal controls. More of the lymphocytes in the blood of leukaemic patients spontaneously produced cytokines compared with those of controls. Furthermore, primary AML blasts secreted predominantly IFN-c. After recovery from chemotherapy, lymphocyte counts tended to be lower than in normals and reduction of NK cells reached significance after the second chemotherapy (P ¼ 0.01). A prominent CD8 lo /CD3 lo-int lymphocyte subset appeared after recovery in some patients. This laboratory application of the study of cell subsets and intracellular cytokines in patients undergoing treatment may be helpful in monitoring immunological responses in AML.

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Disruption of the IFN-γ cytokine network in chronic lymphocytic leukemia contributes to resistance of leukemic B cells to apoptosis

Cited by 30 publications

References 34 publications

Combined analysis of ZAP-70 and CD38 expression as a predictor of disease progression in B-cell chronic lymphocytic leukemia

Combined analysis of ZAP-70 and CD38 expression as a predictor of disease progression in B-cell chronic lymphocytic leukemia

NK cell dysfunction in chronic lymphocytic leukemia is associated with loss of the mature cells expressing inhibitory killer cell Ig-like receptors

Quantification and cytokine production of circulating lymphoid and myeloid cells in acute myelogenous leukaemia

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