loading...| Preferred Name |
Mantle Cell Lymphoma |
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| Synonyms |
PathwayType: signaling PMID: 19880776 CellType: cancer cell PMID: 18410453 Notes: Headnote: Mantle cell lymphoma (MCL) represents approximately 4-10% of all cases of non-Hodgkin lymphoma. It occurs primarily among elderly individuals with a median age of approximately 60 years (range 29-85). Most MCL patients have disseminated disease including generalized lymphadenopathies and bone marrow involvement. The clinical behavior of MCL patients is aggressive with a median overall survival of approximately 3-4 years. MCL is a mature B-cell neoplasm arising from antigen-experienced B cells. Signaling description:The genetic hallmark of MCL is the translocation t(11;14)(q13;q32) leading to the formation of a fusion gene and protein, IGH-CCND1 and aberrant expression of cyclin D1 (CCND1) which is not typically expressed in normal lymphocytes. At the same time, several observations suggest that CCND1 dysregulation is not sufficient for cell transformation, nor does it explain the aggressive behavior of MCL. Therefore, secondary chromosome alterations are necessary. MCL has the highest degree of genomic instability among B-cell malignances and many secondary chromosomal alterations of cell-cycle regulation genes have been described in MCL. TP53, RB1, ATM, BCL2L11, SOCS1, CDKN2A, CDKN2C, HIC1, FAF1, TNFAIP3, and CHEK2 genes are frequently inactivated by point mutations or gene deletions. In addition, gene amplifications deregulate additional genes including CDK4, BMI1, MDM2, BCL2, MYC, SYK, and PIK3CA while point mutations may activate NOTCH1. Furthermore, several signaling pathways contribute to MCL pathogenesis including constitutively activated PI3K/AKT1/MTOR, NF-kB, WNT, Hedgehog (SHH), Notch, and JAK/STAT pathways. Further, there are some indications that tumor-host interactions may be more important in MCL than currently believed. It has been shown that IL6, IL10, and CXCL12 may activate JAK/STAT3 pathway. The expression of CD40 and responsiveness to CD40LG suggest that MCL cells can interact with CD40LG-positive T cells. Furthermore, epigenetic changes in MCL are currently under investigation. Several hypomethylated and thereby upregulated genes including NOTCH1, CDK5, and HDAC1 could play a pathogenic role in disease development and progression. MCL is one of the most difficult B-cell lymphomas to treat. Although conventional chemotherapy induces high remission rates in previously untreated patients, relapse within a few years is common contributing to a rather short median survival of 3-4 years. Proteasome inhibitors (bortezomib), MTOR inhibitors (temsirolimus), immunomodulatory drugs (lenalidomide) and new alkylating agents (bendamustine) have recently been added to the treatment options for MCL. Outcome effects: In general, all of the described MCL-related signaling routes promote tumor cell proliferation and survival. The role of CCND1 in MCL lymphomagenesis is related to its function as a regulator of cyclin-dependent kinases, CDK4 and CDK6 during the cell cycle. The binding of CCND1 to CDK4/6 activates the transcription factor, E2F by phosphorylating its inhibitor, RB1, and further promoting cyclin E/CDK2 activation to trigger entry into the S phase of the cell cycle. In addition, the microenvironment most likely plays an important role in the biology of MCL. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and proteins with decreased expression or activity are highlighted in blue. Mutated genes: Mutated genes are shown in white-out style. CellType: B-cell Organ_System: lymphatic system Description: Mantle cell lymphoma (MCL) represents approximately 4-10? of all cases of non-Hodgkin lymphoma. MCL is a mature B-cell neoplasm arising from antigen-experienced B cells. Pathway is built manually using published studies. PMID: 22224767 PMID: 23023712 PMID: 20940415 Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-26ce00f6-56f5-4e8c-b1e5-a4d7293b1385 NodeType: Pathway Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin PMID: 19362399 Organ: lymph node Source: Diseases |
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| ID |
urn:agi-pathway:uuid-26ce00f6-56f5-4e8c-b1e5-a4d7293b1385 |
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| database_cross_reference |
PS:PathwayType PS:Description PS:Pathway_Author PS:Link PS:CellType PS:Organ_System PS:PMID PS:NodeType PS:Notes PS:Organ PS:Source |
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| has_exact_synonym |
PathwayType: signaling PMID: 19880776 CellType: cancer cell PMID: 18410453 Notes: Headnote: Mantle cell lymphoma (MCL) represents approximately 4-10% of all cases of non-Hodgkin lymphoma. It occurs primarily among elderly individuals with a median age of approximately 60 years (range 29-85). Most MCL patients have disseminated disease including generalized lymphadenopathies and bone marrow involvement. The clinical behavior of MCL patients is aggressive with a median overall survival of approximately 3-4 years. MCL is a mature B-cell neoplasm arising from antigen-experienced B cells. Signaling description:The genetic hallmark of MCL is the translocation t(11;14)(q13;q32) leading to the formation of a fusion gene and protein, IGH-CCND1 and aberrant expression of cyclin D1 (CCND1) which is not typically expressed in normal lymphocytes. At the same time, several observations suggest that CCND1 dysregulation is not sufficient for cell transformation, nor does it explain the aggressive behavior of MCL. Therefore, secondary chromosome alterations are necessary. MCL has the highest degree of genomic instability among B-cell malignances and many secondary chromosomal alterations of cell-cycle regulation genes have been described in MCL. TP53, RB1, ATM, BCL2L11, SOCS1, CDKN2A, CDKN2C, HIC1, FAF1, TNFAIP3, and CHEK2 genes are frequently inactivated by point mutations or gene deletions. In addition, gene amplifications deregulate additional genes including CDK4, BMI1, MDM2, BCL2, MYC, SYK, and PIK3CA while point mutations may activate NOTCH1. Furthermore, several signaling pathways contribute to MCL pathogenesis including constitutively activated PI3K/AKT1/MTOR, NF-kB, WNT, Hedgehog (SHH), Notch, and JAK/STAT pathways. Further, there are some indications that tumor-host interactions may be more important in MCL than currently believed. It has been shown that IL6, IL10, and CXCL12 may activate JAK/STAT3 pathway. The expression of CD40 and responsiveness to CD40LG suggest that MCL cells can interact with CD40LG-positive T cells. Furthermore, epigenetic changes in MCL are currently under investigation. Several hypomethylated and thereby upregulated genes including NOTCH1, CDK5, and HDAC1 could play a pathogenic role in disease development and progression. MCL is one of the most difficult B-cell lymphomas to treat. Although conventional chemotherapy induces high remission rates in previously untreated patients, relapse within a few years is common contributing to a rather short median survival of 3-4 years. Proteasome inhibitors (bortezomib), MTOR inhibitors (temsirolimus), immunomodulatory drugs (lenalidomide) and new alkylating agents (bendamustine) have recently been added to the treatment options for MCL. Outcome effects: In general, all of the described MCL-related signaling routes promote tumor cell proliferation and survival. The role of CCND1 in MCL lymphomagenesis is related to its function as a regulator of cyclin-dependent kinases, CDK4 and CDK6 during the cell cycle. The binding of CCND1 to CDK4/6 activates the transcription factor, E2F by phosphorylating its inhibitor, RB1, and further promoting cyclin E/CDK2 activation to trigger entry into the S phase of the cell cycle. In addition, the microenvironment most likely plays an important role in the biology of MCL. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and proteins with decreased expression or activity are highlighted in blue. Mutated genes: Mutated genes are shown in white-out style. CellType: B-cell Organ_System: lymphatic system Description: Mantle cell lymphoma (MCL) represents approximately 4-10? of all cases of non-Hodgkin lymphoma. MCL is a mature B-cell neoplasm arising from antigen-experienced B cells. Pathway is built manually using published studies. PMID: 22224767 PMID: 23023712 PMID: 20940415 NodeType: Pathway Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin PMID: 19362399 Organ: lymph node Source: Diseases |
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| id |
urn:agi-pathway:uuid-26ce00f6-56f5-4e8c-b1e5-a4d7293b1385 |
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| label |
Mantle Cell Lymphoma |
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| notation |
uuid-26ce00f6-56f5-4e8c-b1e5-a4d7293b1385 |
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| prefLabel |
Mantle Cell Lymphoma |
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| treeView |
urn:agi-folder:m urn:agi-folder:mantle_cell_lymphoma urn:agi-folder:lymphatic_system |
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| subClassOf |
urn:agi-folder:m urn:agi-folder:mantle_cell_lymphoma urn:agi-folder:lymphatic_system |