The Experts below are selected from a list of 15654 Experts worldwide ranked by ideXlab platform
Hye Ra Lee - One of the best experts on this subject based on the ideXlab platform.
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KSHV-encoded viral Interferon Regulatory factor 4 (vIRF4) interacts with IRF7 and inhibits Interferon alpha production
Biochemical and Biophysical Research Communications, 2017Co-Authors: Sung-woo Hwang, Jae U Jung, Dongik Kim, Hye Ra LeeAbstract:Before an infection can be completely established, the host immediately turns on the innate immune system through activating the Interferon (IFN)-mediated antiviral pathway. Kaposi's sarcoma-associated herpesvirus (KSHV) utilizes a unique antagonistic mechanism of type I IFN-mediated host antiviral immunity by incorporating four viral Interferon Regulatory factors (vIRF1-4). Herein, we characterized novel immune evasion strategies of vIRF4 to inhibit the IRF7-mediated IFN-α production. KSHV vIRF4 specifically interacts with IRF7, resulting in inhibition of IRF7 dimerization and ultimately suppresses IRF7-mediated activation of type I IFN. These results suggest that each of the KSHV vIRFs, including vIRF4, subvert IFN-mediated anti-viral response via different mechanisms. Therefore, it is indicated that KSHV vIRFs are indeed a crucial immunomodulatory component of their life cycles.
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kaposi s sarcoma associated herpesvirus viral Interferon Regulatory factor 4 virf4 perturbs the g1 s cell cycle progression via deregulation of the cyclin d1 gene
Journal of Virology, 2016Co-Authors: Hye Ra Lee, Jaba Mitra, Stacy Lee, Shoujiang Gao, Myung Hee Kim, Jae U JungAbstract:Kaposi's sarcoma-associated herpesvirus (KSHV) infection modulates the host cell cycle to create an environment optimal for its viral-DNA replication during the lytic life cycle. We report here that KSHV vIRF4 targets the β-catenin/CBP cofactor and blocks its occupancy on the cyclin D1 promoter, suppressing the G1-S cell cycle progression and enhancing KSHV replication. This shows that KSHV vIRF4 suppresses host G1-S transition, possibly providing an intracellular milieu favorable for its replication.
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kaposi s sarcoma associated herpesvirus viral Interferon Regulatory factor 4 virf4 targets expression of cellular irf4 and the myc gene to facilitate lytic replication
Journal of Virology, 2014Co-Authors: Hye Ra Lee, Stacy Lee, Sultan Doganay, Brian Chung, Zsolt Toth, Kevin Brulois, Zhansaya Kanketayeva, Pinghui Feng, Jae U JungAbstract:Besides an essential transcriptional factor for B cell development and function, cellular Interferon Regulatory factor 4 (c-IRF4) directly regulates expression of the c-Myc gene, which is not only associated with various B cell lymphomas but also required for herpesvirus latency and pathogenesis. Kaposi's sarcoma-associated herpesvirus (KSHV), the etiological agent of Kaposi's sarcoma and primary effusion lymphoma, has developed a unique mechanism to deregulate host antiviral innate immunity and growth control by incorporating four viral homologs (vIRF1 to -4) of cellular IRFs into its genome. Previous studies have shown that several KSHV latent proteins, including vIRF3, vFLIP, and LANA, target the expression, function, and stability of c-Myc to establish and maintain viral latency. Here we report that the KSHV vIRF4 lytic protein robustly suppresses expression of c-IRF4 and c-Myc, reshaping host gene expression profiles to facilitate viral lytic replication. Genomewide gene expression analysis revealed that KSHV vIRF4 grossly affects host gene expression by upregulating and downregulating 118 genes and 166 genes, respectively, by at least 2-fold. Remarkably, vIRF4 suppressed c-Myc expression by 11-fold, which was directed primarily by the deregulation of c-IRF4 expression. Real-time quantitative PCR (RT-qPCR), single-molecule in situ hybridization, and chromatin immunoprecipitation assays showed that vIRF4 not only reduces c-IRF4 expression but also competes with c-IRF4 for binding to the specific promoter region of the c-Myc gene, resulting in drastic suppression of c-Myc expression. Consequently, the loss of vIRF4 function in the suppression of c-IRF4 and c-Myc expression ultimately led to a reduction of KSHV lytic replication capacity. These results indicate that the KSHV vIRF4 lytic protein comprehensively targets the expression and function of c-IRF4 to downregulate c-Myc expression, generating a favorable environment for viral lytic replication. Finally, this study further reinforces the important role of the c-Myc gene in KSHV lytic replication and latency.
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kaposi s sarcoma associated herpesvirus viral Interferon Regulatory factor 4 targets mdm2 to deregulate the p53 tumor suppressor pathway
Journal of Virology, 2009Co-Authors: Hye Ra Lee, Myung Hee Kim, Zsolt Toth, Young C Shin, Jongsoo Lee, Heesoon Chang, Jae U JungAbstract:Cells infected by viruses utilize Interferon (IFN)-mediated and p53-mediated irreversible cell cycle arrest and apoptosis as part of the overall host surveillance mechanism to ultimately block viral replication and dissemination. Viruses, in turn, have evolved elaborate mechanisms to subvert IFN- and p53-mediated host innate immune responses. Kaposi's sarcoma-associated herpesvirus (KSHV) encodes several viral IFN Regulatory factors (vIRF1 to vIRF4) within a cluster of loci, their functions being primarily to inhibit host IFN-mediated innate immunity and deregulate p53-mediated cell growth control. Despite its significant homology and similar genomic location to other vIRFs, vIRF4 is distinctive, as it does not target and antagonize host IFN-mediated signal transduction. Here, we show that KSHV vIRF4 interacts with the murine double minute 2 (MDM2) E3 ubiquitin ligase, leading to the reduction of p53, a tumor suppressor, via proteasome-mediated degradation. The central region of vIRF4 is required for its interaction with MDM2, which led to the suppression of MDM2 autoubiquitination and, thereby, a dramatic increase in MDM2 stability. Consequently, vIRF4 expression markedly enhanced p53 ubiquitination and degradation, effectively suppressing p53-mediated apoptosis. These results indicate that KSHV vIRF4 targets and stabilizes the MDM2 E3 ubiquitin ligase to facilitate the proteasome-mediated degradation of p53, perhaps to circumvent host growth surveillance and facilitate viral replication in infected cells. Taken together, the indications are that the downregulation of p53-mediated cell growth control is a common characteristic of the four KSHV vIRFs and that p53 is indeed a key factor in the host's immune surveillance program against viral infections.
Jae U Jung - One of the best experts on this subject based on the ideXlab platform.
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KSHV-encoded viral Interferon Regulatory factor 4 (vIRF4) interacts with IRF7 and inhibits Interferon alpha production
Biochemical and Biophysical Research Communications, 2017Co-Authors: Sung-woo Hwang, Jae U Jung, Dongik Kim, Hye Ra LeeAbstract:Before an infection can be completely established, the host immediately turns on the innate immune system through activating the Interferon (IFN)-mediated antiviral pathway. Kaposi's sarcoma-associated herpesvirus (KSHV) utilizes a unique antagonistic mechanism of type I IFN-mediated host antiviral immunity by incorporating four viral Interferon Regulatory factors (vIRF1-4). Herein, we characterized novel immune evasion strategies of vIRF4 to inhibit the IRF7-mediated IFN-α production. KSHV vIRF4 specifically interacts with IRF7, resulting in inhibition of IRF7 dimerization and ultimately suppresses IRF7-mediated activation of type I IFN. These results suggest that each of the KSHV vIRFs, including vIRF4, subvert IFN-mediated anti-viral response via different mechanisms. Therefore, it is indicated that KSHV vIRFs are indeed a crucial immunomodulatory component of their life cycles.
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kaposi s sarcoma associated herpesvirus viral Interferon Regulatory factor 4 virf4 perturbs the g1 s cell cycle progression via deregulation of the cyclin d1 gene
Journal of Virology, 2016Co-Authors: Hye Ra Lee, Jaba Mitra, Stacy Lee, Shoujiang Gao, Myung Hee Kim, Jae U JungAbstract:Kaposi's sarcoma-associated herpesvirus (KSHV) infection modulates the host cell cycle to create an environment optimal for its viral-DNA replication during the lytic life cycle. We report here that KSHV vIRF4 targets the β-catenin/CBP cofactor and blocks its occupancy on the cyclin D1 promoter, suppressing the G1-S cell cycle progression and enhancing KSHV replication. This shows that KSHV vIRF4 suppresses host G1-S transition, possibly providing an intracellular milieu favorable for its replication.
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kaposi s sarcoma associated herpesvirus viral Interferon Regulatory factor 4 virf4 targets expression of cellular irf4 and the myc gene to facilitate lytic replication
Journal of Virology, 2014Co-Authors: Hye Ra Lee, Stacy Lee, Sultan Doganay, Brian Chung, Zsolt Toth, Kevin Brulois, Zhansaya Kanketayeva, Pinghui Feng, Jae U JungAbstract:Besides an essential transcriptional factor for B cell development and function, cellular Interferon Regulatory factor 4 (c-IRF4) directly regulates expression of the c-Myc gene, which is not only associated with various B cell lymphomas but also required for herpesvirus latency and pathogenesis. Kaposi's sarcoma-associated herpesvirus (KSHV), the etiological agent of Kaposi's sarcoma and primary effusion lymphoma, has developed a unique mechanism to deregulate host antiviral innate immunity and growth control by incorporating four viral homologs (vIRF1 to -4) of cellular IRFs into its genome. Previous studies have shown that several KSHV latent proteins, including vIRF3, vFLIP, and LANA, target the expression, function, and stability of c-Myc to establish and maintain viral latency. Here we report that the KSHV vIRF4 lytic protein robustly suppresses expression of c-IRF4 and c-Myc, reshaping host gene expression profiles to facilitate viral lytic replication. Genomewide gene expression analysis revealed that KSHV vIRF4 grossly affects host gene expression by upregulating and downregulating 118 genes and 166 genes, respectively, by at least 2-fold. Remarkably, vIRF4 suppressed c-Myc expression by 11-fold, which was directed primarily by the deregulation of c-IRF4 expression. Real-time quantitative PCR (RT-qPCR), single-molecule in situ hybridization, and chromatin immunoprecipitation assays showed that vIRF4 not only reduces c-IRF4 expression but also competes with c-IRF4 for binding to the specific promoter region of the c-Myc gene, resulting in drastic suppression of c-Myc expression. Consequently, the loss of vIRF4 function in the suppression of c-IRF4 and c-Myc expression ultimately led to a reduction of KSHV lytic replication capacity. These results indicate that the KSHV vIRF4 lytic protein comprehensively targets the expression and function of c-IRF4 to downregulate c-Myc expression, generating a favorable environment for viral lytic replication. Finally, this study further reinforces the important role of the c-Myc gene in KSHV lytic replication and latency.
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kaposi s sarcoma associated herpesvirus viral Interferon Regulatory factor 4 targets mdm2 to deregulate the p53 tumor suppressor pathway
Journal of Virology, 2009Co-Authors: Hye Ra Lee, Myung Hee Kim, Zsolt Toth, Young C Shin, Jongsoo Lee, Heesoon Chang, Jae U JungAbstract:Cells infected by viruses utilize Interferon (IFN)-mediated and p53-mediated irreversible cell cycle arrest and apoptosis as part of the overall host surveillance mechanism to ultimately block viral replication and dissemination. Viruses, in turn, have evolved elaborate mechanisms to subvert IFN- and p53-mediated host innate immune responses. Kaposi's sarcoma-associated herpesvirus (KSHV) encodes several viral IFN Regulatory factors (vIRF1 to vIRF4) within a cluster of loci, their functions being primarily to inhibit host IFN-mediated innate immunity and deregulate p53-mediated cell growth control. Despite its significant homology and similar genomic location to other vIRFs, vIRF4 is distinctive, as it does not target and antagonize host IFN-mediated signal transduction. Here, we show that KSHV vIRF4 interacts with the murine double minute 2 (MDM2) E3 ubiquitin ligase, leading to the reduction of p53, a tumor suppressor, via proteasome-mediated degradation. The central region of vIRF4 is required for its interaction with MDM2, which led to the suppression of MDM2 autoubiquitination and, thereby, a dramatic increase in MDM2 stability. Consequently, vIRF4 expression markedly enhanced p53 ubiquitination and degradation, effectively suppressing p53-mediated apoptosis. These results indicate that KSHV vIRF4 targets and stabilizes the MDM2 E3 ubiquitin ligase to facilitate the proteasome-mediated degradation of p53, perhaps to circumvent host growth surveillance and facilitate viral replication in infected cells. Taken together, the indications are that the downregulation of p53-mediated cell growth control is a common characteristic of the four KSHV vIRFs and that p53 is indeed a key factor in the host's immune surveillance program against viral infections.
Michael Cullen - One of the best experts on this subject based on the ideXlab platform.
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the d2 and d3 sublineages of human papillomavirus 16 positive cervical cancer in guatemala differ in integration rate and age of diagnosis
Cancer Research, 2020Co-Authors: Hong Lou, Joseph Boland, Edmundo Torresgonzalez, Anaseidy Albanez, Weiyin Zhou, Mia Steinberg, Lena Diaw, Jason Mitchell, David Roberson, Michael CullenAbstract:Human papillomavirus (HPV) 16 displays substantial sequence variation: four HPV16 lineages (A, B, C, D) have been described as well as multiple sublineages. To identify molecular events associated with HPV16 carcinogenesis, we evaluated viral variation, the integration of HPV16, and somatic mutation in 96 cervical cancer samples from Guatemala. A total of 65% (62/96) of the samples had integrated HPV16 sequences and integration was associated with an earlier age of diagnosis and pre-menopausal disease. HPV16 integration sites were broadly distributed in the genome, but in one tumor, HPV16 integrated into the promoter of the Interferon Regulatory factor 4 (IRF4) gene, which plays an important role in the regulation of the Interferon response to viral infection. The HPV16 D2 and D3 sublineages were found in 23% and 30% of the tumors, respectively, and were significantly associated with adenocarcinoma. D2-positive tumors had a higher rate of integration, earlier age of diagnosis, and a lower rate of somatic mutation, whereas D3-positive tumors were less likely to integrate, had later age of diagnosis, and exhibited a higher rate of somatic mutation. In conclusion, Guatemalan cervical tumors have a high frequency of very high-risk HPV16 D2 and D3 sublineages harboring distinct histology, which may help guide future therapeutic strategies to target the tumor and reduce recurrence.
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human papillomavirus 16 positive cervical cancer in guatemala the d2 and d3 sublineages differ in integration rate and age of diagnosis
bioRxiv, 2020Co-Authors: Hong Lou, Joseph Boland, Edmundo Torresgonzalez, Anaseidy Albanez, Weiyin Zhou, Mia Steinberg, Lena Diaw, Jason Mitchell, David Roberson, Michael CullenAbstract:Human papillomavirus (HPV) 16 displays substantial sequence variation; four HPV16 lineages (A, B, C, D) have been described, as well as multiple sub-lineages. To identify molecular events associated with HPV16 carcinogenesis we evaluated viral variation, the integration of HPV16, and somatic mutation in 96 cervical cancer samples from Guatemala. A total of 64% (60/94) of the samples had integrated HPV16 sequences, and integration was associated with an earlier age of diagnosis (P=0.0007) and pre-menopausal disease. HPV16 integration sites were broadly distributed in the genome but in one tumor, HPV16 integrated into the promoter of the Interferon Regulatory factor 4 (IRF4) gene, which plays an important role in the regulation of the Interferon response to viral infection. The HPV16 D2 and D3 sub-lineages were found in 23% and 30% of the tumors, respectively and were significantly associated with adenocarcinoma. D2-positive tumors had a higher rate of integration (P=0.011), earlier age of diagnosis (P=0.012), and a lower rate of somatic mutation (P=0.03). Whereas D3-positive tumors are less likely to integrate, have later age-of-diagnosis, and a higher rate of somatic mutation. In conclusion, Guatemalan cervical tumors have a high frequency of the very high-risk HPV16 D2 and D3 sub-lineages and cervical cancer patients with these variants of HPV16 differ in histology, age-of-diagnosis, integration, and somatic mutation frequency. In summary, related lineages of HPV16 have different features of oncogenicity.
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the d2 and d3 sublineages of human papilloma virus 16 positive cervical cancer in guatemala differ in integration rate and age of diagnosis
Cancer Research, 2020Co-Authors: Hong Lou, Joseph Boland, Edmundo Torresgonzalez, Anaseidy Albanez, Weiyin Zhou, Mia Steinberg, Lena Diaw, Jason Mitchell, David Roberson, Michael CullenAbstract:Human papillomavirus (HPV) 16 displays substantial sequence variation: four HPV16 lineages (A, B, C, D) have been described as well as multiple sublineages. To identify molecular events associated with HPV16 carcinogenesis, we evaluated viral variation, the integration of HPV16, and somatic mutation in 96 cervical cancer samples from Guatemala. A total of 65% (62/96) of the samples had integrated HPV16 sequences and integration was associated with an earlier age of diagnosis and pre-menopausal disease. HPV16 integration sites were broadly distributed in the genome, but in one tumor, HPV16 integrated into the promoter of the Interferon Regulatory factor 4 (IRF4) gene, which plays an important role in the regulation of the Interferon response to viral infection. The HPV16 D2 and D3 sublineages were found in 23% and 30% of the tumors, respectively, and were significantly associated with adenocarcinoma. D2-positive tumors had a higher rate of integration, earlier age of diagnosis, and a lower rate of somatic mutation, whereas D3-positive tumors were less likely to integrate, had later age of diagnosis, and exhibited a higher rate of somatic mutation. In conclusion, Guatemalan cervical tumors have a high frequency of very high-risk HPV16 D2 and D3 sublineages harboring distinct histology, which may help guide future therapeutic strategies to target the tumor and reduce recurrence.
Karolien De Bosscher - One of the best experts on this subject based on the ideXlab platform.
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Epicutaneous sensitization to house dust mite allergen requires Interferon Regulatory factor 4-dependent dermal dendritic cells
Journal of Allergy and Clinical Immunology, 2017Co-Authors: Julie Deckers, Dorine Sichien, Maud Plantinga, Justine Van Moorleghem, Manon Vanheerswynghels, Esther Hoste, Bernard Malissen, David Dombrowicz, Martin Guilliams, Karolien De BosscherAbstract:Background: Exposure to allergens, such as house dust mite (HDM), through the skin often precedes allergic inflammation in the lung. It was proposed that T(H)2 sensitization through the skin occurs when skin barrier function is disrupted by, for example, genetic predisposition, mechanical damage, or the enzymatic activity of allergens. Objective: We sought to study how HDM applied to unmanipulated skin leads to T(H)2 sensitization and to study which antigen-presenting cells mediate this process. Methods: HDM was applied epicutaneously by painting HDM on unmanipulated ear skin or under an occlusive tape. HDM challenge was through the nose. Mouse strains lacking different dendritic cell (DC) populations were used, and 1-DER T cells carrying a transgenic T-cell receptor reactive to Der p 1 allergen were used as a readout for antigen presentation. The T(H)2-inducing capacity of sorted skin-derived DC subsets was determined by means of adoptive transfer to naive mice. Results: Epicutaneous HDM application led to T(H)2 sensitization and eosinophilic airway inflammation upon intranasal HDM challenge. Skin sensitization did not require prior skin damage or enzymatic activity within HDM extract, yet was facilitated by applying the allergen under an occlusive tape. Primary proliferation of 1-DER T cells occurred only in the regional skin-draining lymph nodes. Epicutaneous sensitization was found to be driven by 2 variants of Interferon Regulatory factor 4-dependent dermal type 2 conventional DC subsets and not by epidermal Langerhans cells. Conclusion: These findings identify skin type 2 conventional DCs as crucial players in T(H)2 sensitization to common inhaled allergens that enter the body through the skin and can provoke features of allergic asthma.
Ryuzo Ueda - One of the best experts on this subject based on the ideXlab platform.
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multiple myeloma oncogene 1 mum1 Interferon Regulatory factor 4 irf4 upregulates monokine induced by Interferon gamma mig gene expression in b cell malignancy
Leukemia, 2005Co-Authors: Miyuki Uranishi, Shinsuke Iida, Takaomi Sanda, Takashi Ishida, Emi Tajima, Masato Ito, Hirokazu Komatsu, Hiroshi Inagaki, Ryuzo UedaAbstract:MUM1 (multiple myeloma oncogene 1)/IRF4 (Interferon Regulatory factor 4) is a transcription factor that is activated as a result of t(6;14)(p25;q32) in multiple myeloma. MUM1 expression is seen in various B-cell lymphomas and predicts an unfavorable outcome in some lymphoma subtypes. To elucidate its role in B-cell malignancies, we prepared MUM1-expressing Ba/F3 cells, which proliferated until higher cellular density than the parental cells, and performed cDNA microarray analysis to identify genes whose expression is regulated by MUM1. We found that the expression of four genes including FK506-binding protein 3 (FKBP3), the monokine induced by Interferon-gamma(MIG), Fas apoptotic inhibitory molecule (Faim) and Zinc-finger protein 94 was altered in the MUM1-expressing cells. We then focused on MIG since its expression was immediately upregulated by MUM1. In reporter assays, MUM1 activated the MIG promoter in cooperation with PU.1, and the interaction between MUM1 and the MIG promoter sequence was confirmed. The expression of MIG was correlated with that of MUM1 in B-CLL cell lines, and treatment with neutralizing antibodies against MIG and its receptor, CXCR3, slightly inhibited the proliferation of two MUM1-expressing lines. These results suggest that MUM1 plays roles in the progression of B-cell lymphoma/leukemia by regulating the expression of various genes including MIG. Leukemia (2005) 19, 1471-1478. doi:10.1038/sj.leu.2403833; published online 16 June 2005.
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multiple myeloma oncogene 1 mum1 Interferon Regulatory factor 4 irf4 upregulates monokine induced by Interferon gamma mig gene expression in b cell malignancy
Blood, 2004Co-Authors: Shinsuke Iida, Miyuki Uranishi, Takaomi Sanda, Takashi Ishida, Emi Tajima, Masato Ito, Hirokazu Komatsu, Hiroshi Inagaki, Ryuzo UedaAbstract:MUM1(multiple myeloma oncogene 1)/IRF4(Interferon Regulatory factor 4) is a transcription Regulatory factor that is activated as a result of t(6;14)(p25;q32) in multiple myeloma. MUM1 expression is seen in various B-cell lymphomas/leukemias and has been reported to predict an unfavorable outcome in some lymphoma subtypes including diffuse large B-cell lymphoma (DLBCL) and B-cell chronic lymphocytic leukemia (B-CLL). To elucidate its role in B-cell malignancies, we prepared stably MUM1-expressing Ba/F3 cells, which proliferated at a higher rate than the parental cells, and performed cDNA microarray analysis to identify genes whose expression is regulated by MUM1. We found that the expression of four genes including FK506-binding protein 3 (FKBP3), the Monokine induced by Interferon-gamma (MIG), Fas apoptotic inhibitory molecule (Faim) and Zinc finger protein 94 was altered in the MUM1-expressing cells. We then focused on MIG since its expression was immediately upregulated by MUM1 in inducible MUM1 expressing system. In reporter assays, MUM1 activated the MIG promoter in cooperation with PU.1, and the interaction between MUM1 and the MIG promoter sequence was confirmed in chromatin immunoprecipitation assay. The expression of MIG was correlated with that of MUM1 in B-CLL cell lines, and its receptor CXCR3 was also coexpressed in B-CLL cell lines that were positive for MUM1. Interestingly, treatment with neutralizing antibodies against MIG and its receptor, CXCR3, partially inhibited the proliferation of two MUM1-expressing B-CLL cell lines. These results suggest that MUM1 plays certain roles in the progression of B-cell lymphomas/leukemias by regulating the expression of various genes including MIG.