Distinct IL-4-induced gene expression, proliferation, and intracellular signaling in germinal center B-cell-like and activated B-cell-like diffuse large-cell lymphomas

Lu, Xiaoyan; Nechushtan, Hovav; Ding, Feiying; Rosado, Marcos; Singal, Rakesh; Alizadeh, Ash A.; Lossos, Izidore S.

doi:10.1182/blood-2004-10-3820

Cited by 65 publications

(79 citation statements)

References 46 publications

(68 reference statements)

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“…A likely source of IL-4 and CD40L in vivo is CD4 + T lymphocytes of the Th2 effector type infiltrating the lymphoma tissue. A potential role of T-cell-derived IL-4 has been discussed in the context of DLBCL (44), which is frequently associated with an overrepresentation of IL-4-producing Th2-polarized T lymphocytes in the peripheral blood (45). On the other hand, tumor-infiltrating CD4 + T cells may be too few or display an inappropriate phenotype in most PMBL that do not exhibit CSR activity.…”

Section: Discussionmentioning

confidence: 99%

Target Sequence Accessibility Limits Activation-Induced Cytidine Deaminase Activity in Primary Mediastinal B-Cell Lymphoma

Popov

Moldenhauer²,

Wotschke³

et al. 2007

Cancer Research

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Activation-induced cytidine deaminase (AID) initiates somatic hypermutation (SHM) and class switch recombination (CSR) in activated B lymphocytes and is potentially implicated in genomic instability of B-cell malignancies. For unknown reasons, B-cell neoplasms often lack SHM and CSR in spite of high AID expression. Here, we show that primary mediastinal B-cell lymphoma (PMBL), an immunoglobulin (Ig)-negative lymphoma that possesses hypermutated, class-switched Ig genes, expresses high levels of AID with an intact primary structure but does not do CSR in 14 of 16 cases analyzed.

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Section: Discussionmentioning

confidence: 99%

Target Sequence Accessibility Limits Activation-Induced Cytidine Deaminase Activity in Primary Mediastinal B-Cell Lymphoma

Popov

Moldenhauer²,

Wotschke³

et al. 2007

Cancer Research

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“…The enriched pathways included two gene sets consisting of genes found differentially expressed between multiple myeloma subclasses (gene set 1 and 5, Table 7), 17,18 one gene set involved in B-cell lymphoma (gene set 2, Table 7), 19 a gene set involved in the B-cell lymphocyte immune function (BCR pathway, gene set 3, Table 7) and one gene set consisting of genes induced in B cells when exposed to interleukin-4 cytokine (gene set 4, Table 7). 20 The analyses of grouping B showed that no pathways were recognized as enriched for the non-fatigued group, but one pathway, nucleotide sugars metabolism, was found enriched in the fatigued group (Tables 6 and 7).…”

Section: Alterations Of Gene Expression In Blood Cells Associated Witmentioning

confidence: 99%

Alterations of gene expression in blood cells associated with chronic fatigue in breast cancer survivors

et al. 2009

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Fatigue is one of the most frequent complaints among breast cancer survivors. However, mechanisms underlying persisting fatigue after end of treatment are poorly understood. To explore whether biological processes underlying persistent fatigue can affect gene expression of blood cells, genome-wide expression analyses were performed on whole blood samples from breast cancer survivors classified as chronic fatigued 2-6 years after diagnosis. Non-fatigued survivors served as controls. Several gene sets involved in plasma-and B-cell pathways differed between the chronic fatigued and the non-fatigued, suggesting that a dysregulation in these pathways is associated with chronic fatigue and that a B-cell-mediated inflammatory process might underlie fatigue. The chronic fatigued also had a higher level of leucocytes, lymphocytes and neutrophiles compared with the non-fatigued, thus further indicating that an activation of the immune system plays a role in the biology of chronic fatigue in breast cancer survivors.

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“…We have recently demonstrated qualitatively different IL-4 effects on germinal center B-cell (GCB)-like and activated-B-cell (ABC)-like diffuse large B-cell lymphoma (DLBCL) cell lines derived from primary tumors (24). In GCB-like DLBCL cells, IL-4 induced the activation of STAT6 and expression of IL-4 target genes.…”

mentioning

confidence: 99%

“…Defective JAK-STAT6 signaling in the ABC-like cell lines was attributed to increased cytoplasmic and nuclear STAT6 dephosphorylation (24). Dephosphorylation of activated STAT6 is fundamental to the control of IL-4 signaling and serves to prevent allergic responses and may underlie at least some changes in gene expression and the biology of DLBCL subtypes (24). However, only a few studies have focused on the mechanisms of STAT6 dephosphorylation, and currently STAT6 nuclear PTP is unknown.…”

mentioning

confidence: 99%

“…In contrast, in ABC-like DLBCL cells, IL-4 neither induced the expression of IL-4 target genes nor did it induce sustained increases in nuclear phosphorylated STAT6. Defective JAK-STAT6 signaling in the ABC-like cell lines was attributed to increased cytoplasmic and nuclear STAT6 dephosphorylation (24). Dephosphorylation of activated STAT6 is fundamental to the control of IL-4 signaling and serves to prevent allergic responses and may underlie at least some changes in gene expression and the biology of DLBCL subtypes (24).…”

mentioning

confidence: 99%

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T-Cell Protein Tyrosine Phosphatase, Distinctively Expressed in Activated-B-Cell-Like Diffuse Large B-Cell Lymphomas, Is the Nuclear Phosphatase of STAT6

Sasmono

Hsi

et al. 2007

Molecular and Cellular Biology

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Diffuse large B-cell lymphomas (DLBCLs) consist of clinically distinct subtypes: germinal center B-cell (GCB)-like and activated-B-cell (ABC)-like tumors, characterized by long and short survival, respectively. We reported distinct interleukin 4 (IL-4) responsiveness and STAT6 signaling in these DLBCL subtypes. Increased nuclear dephosphorylation of phospho-STAT6 (pSTAT6) was observed in ABC-like tumors, which exhibited a different expression profile of protein tyrosine phosphatases (PTPs). Among the differentially expressed PTPs, only T-cell PTP (TCPTP) localizes to the nucleus. Herein, we report that the elevated expression of TCPTP in ABC-versus GCB-like DLBCL tumors is not due to the distinct ontogeny of these neoplasms but rather may be an acquired feature of the tumors. Moreover, we report that STAT6 may serve as a physiological nuclear substrate for TCPTP. We demonstrate interactions between endogenous TCPTP and STAT6 and delineate the domains responsible for the interaction. Overexpression of TCPTP ameliorates IL-4-induced STAT6 phosphorylation and associated gene transcription, whereas knockdown of endogenous TCPTP results in increased IL-4-induced STAT6 signaling. Moreover, we report that TCPTP protein levels may be increased in response to IL-4 and that TCPTP may serve in a negative feedback loop for the suppression of IL-4-induced signaling. Taken together, these results identify TCPTP as a physiological regulator of STAT6 phosphorylation and suggest that specific increases in TCPTP expression in ABC-like DLBCLs may contribute to the different biological characteristics of these tumors.Tyrosine phosphorylation is fundamental to the control of numerous important physiological processes, and its dysregulation can contribute to the pathogenesis of varied inherited and acquired human diseases, from immune deficiencies to cancer. Protein tyrosine phosphatases (PTPs) are a large family of enzymes that catalyze the dephosphorylation of tyrosylphosphorylated proteins, and their actions are integral to the maintenance of homeostasis and health (2, 3). T-cell PTP (TCPTP), also known as protein tyrosine phosphatase nonreceptor type 2 (PTPN2), is a classical tyrosine-specific PTP expressed predominantly in cells of hematopoietic origin. TCPTP mRNA can be alternatively spliced to generate 48-kDa and 45-kDa TCPTP variant proteins with distinct subcellular localizations: 48-kDa TCPTP is targeted to the endoplasmic reticulum by a hydrophobic C terminus (8, 16), whereas 45-kDa TCPTP (TCPTP-45) lacks the hydrophobic C terminus and is targeted to the nucleus by a bipartite nuclear localization sequence (39). Despite TCPTP-45 having an apparently exclusively nuclear localization in resting cells, specific stimuli can induce TCPTP-45 shuttling to the cytoplasm (20) where it can access cytoplasmic substrates that include the epidermal growth factor receptor (18), the insulin receptor (12), Src family protein tyrosine kinases (41), the adaptor protein p52 Shc (38), and Janus family protein tyrosine kinases 1 and 3 (JAK1 an...

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Distinct IL-4-induced gene expression, proliferation, and intracellular signaling in germinal center B-cell-like and activated B-cell-like diffuse large-cell lymphomas

Cited by 65 publications

References 46 publications

Target Sequence Accessibility Limits Activation-Induced Cytidine Deaminase Activity in Primary Mediastinal B-Cell Lymphoma

Target Sequence Accessibility Limits Activation-Induced Cytidine Deaminase Activity in Primary Mediastinal B-Cell Lymphoma

Alterations of gene expression in blood cells associated with chronic fatigue in breast cancer survivors

T-Cell Protein Tyrosine Phosphatase, Distinctively Expressed in Activated-B-Cell-Like Diffuse Large B-Cell Lymphomas, Is the Nuclear Phosphatase of STAT6

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