Cell Collective12461000ModelsAudrey Crowtherhttps://cellcollective.org/#4783/-igvh-mutations-in-chronic-lymphocytic-leukemia.80.10071SBML1Cell Collectivehttps://cellcollective.org/#4783:1/-igvh-mutations-in-chronic-lymphocytic-leukemia.<h4>Background</h4>Chronic lymphocytic leukemia (CLL) is an incurable malignancy of mature B-lymphocytes, characterized as being a heterogeneous disease with variable clinical manifestation and survival. Mutational statuses of rearranged immunoglobulin heavy chain variable (IGVH) genes has been consider one of the most important prognostic factors in CLL, but despite of its proven value to predict the course of the disease, the regulatory programs and biological mechanisms responsible for the differences in clinical behavior are poorly understood.<h4>Methods</h4>In this study, (i) we performed differential gene expression analysis between the IGVH statuses using multiple and independent CLL cohorts in microarrays platforms, based on this information, (ii) we constructed a simplified protein-protein interaction (PPI) network and (iii) investigated its structure and critical genes. This provided the basis to (iv) develop a Boolean model, (v) infer biological regulatory mechanism and (vi) performed perturbation simulations in order to analyze the network in dynamic state.<h4>Results</h4>The result of topological analysis and the Boolean model showed that the transcriptional relationships of IGVH mutational status were determined by specific regulatory proteins (PTEN, FOS, EGR1, TNF, TGFBR3, IFGR2 and LPL). The dynamics of the network was controlled by attractors whose genes were involved in multiple and diverse signaling pathways, which may suggest a variety of mechanisms related with progression occurring over time in the disease. The overexpression of FOS and TNF fixed the fate of the system as they can activate important genes implicated in the regulation of process of adhesion, apoptosis, immune response, cell proliferation and other signaling pathways related with cancer.<h4>Conclusion</h4>The differences in prognosis prediction of the IGVH mutational status are related with several regulatory hubs that determine the dynamic of the system.Proteins interaction network and modeling of IGVH mutational status in chronic lymphocytic leukemia.Álvarez-Silva María Camila MC, Yepes Sally S, Torres Maria Mercedes MM, Barrios Andrés Fernando González AFNgf1, B Cells, CG33956, Materials, egr-1, Globulin, egr, DPTEN, LIPD, D-fos, Tumor, Long Term, Social Controls, rat, zif-268, Method, 3, TEP1, LC64P, 300kDa), FATE, CG12919, l-plastin, procedures, DIF, Social, Intrinsic Pathway Apoptosis, ch, adult chronic leukemia, TNFSF2, D-Fos, Homo sapiens disease, Ngfi, B Lymphocyte, KROX-24, single organism signaling, Tumors, dif, tnfa, anatomical protrusion, B Lymphocytes, e(Pc), TNFA, Longterm Effect, AF-1, Procedure, lymphoplasmacytic leukemia, Acceptance Processes, Benign, signaling (initiator) caspase activity, PTEN3, induction of apoptosis, PTEN1, FOS, Fos, Regg1, Cellular, chronic lymphatic leukemia, TGF-beta type III receptors, Caspase-Dependent, HDLCQ11, DmelCG7776, death rate, fos, Benign Neoplasms, Methodological, Controls, PTENa, ZNF225, human, Malignant Neoplasms, Intrinsic Pathway Apoptoses, IFNGT1, B-Lymphocyte, Material, Proliferation, DmelLcp3, G0S7, BG:DS02740.11, Extrinsic Pathway, Tnfa, Globulins, Fra, anatomical systems., 2310035O07Rik, Regulations, CLL, Cll, GH05739, Bursa-Dependent, g0s30, beta receptor III (betaglycan, Immunoglobulin, conformation, GLM2, Effects, Processes, TNF, Neoplasms, chronic LYMPHOCYTIC, fra, high weight, DmelCG33956, Prognostic Factors, protein-containing complex, PLS2, cll, Krox-1, CML, GH14582, AI463227, heavy, pls2, Gene Products, disease or disorder, Number Growth, Technique, DmelCG2043, anatomical systems, lcp3, cFos, Longterm, RATTNF, LCP-3, G0/G1 switch regulatory protein 7, Long-Term, A530045N19Rik, Expressions, DmelCG12919, DmelCG5671, TGF-beta type III, Neoplasias, Study, darth, CP3, Classic Apoptosis, at225, B430203M17Rik, Expression, transforming growth factor, CG7937, Cancer, Apoptosis, leukemia, Krox24, EGR-1-A, LcpIII, Malignant Neoplasm, PTEN, xtnf, Proteins, disorders, Chronic Lymphocytic Leukemia, lymphoplasmacytic leukaemia, 311, dPten, Factor, pten, chronic, Cell, dt1, dpten, MT, 93Bal, native protein, Social Control, CWS1, chemical analysis, Long Term Effects, Neoplasm, AW215636, condition, background, dPTEN, LCP3, Kay, cellular oncogene fos, primary cancer, c15, Mmac, c-Fos, DMLCP3, CG5671, dfos, apoptosis, l(2)28-28-12, DmelCG7937, IMD28, Cancers, malignant tumor, Longterm Effects, Classic Apoptoses, DmelCG5861, Gene Proteins, AP1, B-Cells, dAP-1, dFos, signalling process, c-fos, commitment to apoptosis, receptor, regulation, CG2043, DFos, DFOS, NGF1-A, Neoplasia, AU015626, determination, Bursa-Dependent Lymphocytes, AP-1, egr1, Immune Globulin, protein, TBRIII, Cell Growth in Number, Techniques, Dfos, diseases, Extrinsic Pathway Apoptoses, DFra, Cell Number Growth, diseases and disorders, protein aggregate, xtnf-alpha, Effect, Formal Social Controls, chronic lymphatic, dFra, dFRA, CG15507, CG15509, Immune Processes, human disease, Immune Responses, Growth, Prognoses, Gene Expressions, PPI, B-cell chronic lymphocytic leukemia, L-PLASTIN, reference sample, regg1, IFGR2, adult chronic leukaemia, Zenk, Immune, Methodological Studies, Egr-1, Zfp-6, malignant neoplasm, Classic, Classical Apoptosis, Malignancies, CG7776, d-fos, chronic lymphatic leukaemia, Long-Term Effects, Ifgr2, single-organism behavior, ngfi-a, lc64p, BGCAN, krox-24, Caspase-Dependent Apoptosis, Process, mouse, Lymphocyte B-Cell, L[[3]]CP3, results, Programs, Acceptance Process, Intrinsic Pathway, Extrinsic Pathway Apoptosis, Diseases, tnf-alpha, CT43, Genetic Materials, lymphocytic, fixed, Genetic Material, D-fos/kay, Factors, beta receptor III, Ifgt, MMAC1, Prognostic, Heterogeneity, Control, TNFalpha, BcDNA:RH51659, Methodological Study, disease, immunoglobulin, induction of apoptosis by p53, spine, E(PC), D12Rfj1, anon-48Ac, Cell Number, Cistron, chronic lymphocytic leukaemia, BZS, Regulation, Classical, Apoptoses, Prognostic Factor, other disease, TNF-alpha, transforming growth factor beta type III receptor, Procedures, caspase-dependent programmed cell death, Benign Neoplasm, p55, B-Cell, Gene, Caspase Dependent Apoptosis, ETR103, Malignant, Lymphocyte B-Cells, B-cell chronic lymphocytic leukaemia, protrusion, TGF beta type III receptor, antibody, MHAM, TNF-a, III, B-cell chronic lymphoid leukemia, Genetic heterogeneity, Studies, Krox-24, 1110036H20Rik, Type I, proto-oncogene protein c-fos, fbz, study, betaglycan, Genetic, LPL, Malignancy, dlhD, Bursa Dependent Lymphocytes, AT225, apoptosis activator activity, Ect1, TIS8, Ect5, non-neoplastic, cell proliferation, Immune Response, type III TGFbeta receptor, lpl, time of survival, tis8, znf225, disorder, Long-Term Effect, Behaviors, G0S30, Immune Process, Lymphocyte, Controlled, 3.1.1.34, Multiplication, Controlling, Cellular Proliferation, Formal Social Control, protein complex, HEL-S-37, ggr, medical condition, Zif268, Cistrons, Immune Globulins, tnfsf2, survival, Programmed Cell Death, Protein, TGFBR3, techniques, Xegr-1, TGFBR3 protein, opsonin activity, Acceptance, small lymphocytic lymphoma, cp64, Bursa-Dependent Lymphocyte, 10q23del, Tgfbr3 protein, NGFI-A, anon-35Fa, Lymphocytes, A130070J02Rik, beta-glycan, introduction, Protein Gene Products, DEC, Hox11-311, C-FOS, NGFIA, anon-35Fc, ZIF-268, Cell Multiplication, B cell receptor activity, Response, Egr, CP64, assay, variable, Tnfsf1a, methodologyLymphoplasmacytoid Lymphomas, CLL Lymphoplasmacytoid Lymphomas, CLL, Chronic B-Cell Leukemia, Chronic B-Cell, Lymphocytic Leukemia, B-Lymphocytic Leukemias, chronic LYMPHOCYTIC, Chronic B-Lymphocytic, Gene, B-Cell, Lymphatic Leukemia, B-cell chronic lymphocytic leukaemia, B Cell, Small, B-cell chronic lymphoid leukemia, Gene Products, Chronic B-Cell Leukemias, Well-Differentiated Lymphocytic, Lymphoplasmacytoid Lymphoma, Well Differentiated, Chronic Lymphocytic Leukemias, Lymphomas, chronic lymphatic, Low-Grade, Lymphocytic, Leukemia, B-cell chronic lymphocytic leukemia, Malignancy, Small-Cell Lymphomas, CLL Lymphoplasmacytoid Lymphoma, Plasmacytoid, Small Lymphocytic Lymphoma, Well-Differentiated Lymphocytic Lymphoma, Small-Cell Lymphoma, B-Lymphocytic Leukemia, B Cell., Diffuse, Lymphoblastic Leukemias, Chronic Lymphatic Leukemias, Disrupted In B Cell Malignancy, Chronic, Diffuse Well Differentiated Lymphocytic Lymphoma, Malignancies, Chronic B-Lymphocytic Leukemias, chronic lymphatic leukaemia, Chronic Lymphocytic, Diffuse Well-Differentiated Lymphocytic Lymphoma, Low Grade, leukemia, B-Cell Chronic Lymphocytic Leukemia, B Cell Malignancy, Small Cell, Proteins, Chronic Lymphocytic Leukemia, Chronic B-Lymphocytic Leukemia, lymphoplasmacytic leukaemia, B-Cell Malignancy, Low-Grade B-Cell Malignancies, Chronic Lymphoblastic Leukemia, lymphoplasmacytic leukemia, Leukemias, chronic, B-Cell Leukemia, Well-Differentiated, Chronic Lymphatic, Small Cell Lymphoma, Protein, Lymphocytic Leukemias, B-Cell Malignancies, B Lymphocytic Leukemia, B Cell Chronic Lymphocytic Leukemia, chronic lymphatic leukemia, B Cell Leukemia, lymphocytic, Low-Grade B-Cell, Lymphoblastic Leukemia, Chronic Lymphatic Leukemia, small lymphocytic lymphoma, Lymphatic Leukemias, Lymphocytic Lymphomas, Well-Differentiated Lymphocytic Lymphomas, B-Cell Leukemias, Disrupted In B-Cell Malignancy, Lymphoblastic, Chronic Lymphoblastic, Small Lymphocytic, Chronic Lymphoblastic Leukemias, Low-Grade B-Cell Malignancy, Protein Gene Products, Gene Proteins, Small-Cell, Lymphocytic Lymphoma, Lymphoplasmacytoid, CLL Lymphoplasmacytoid, Lymphoma, chronic lymphocytic leukaemia, Small Lymphocytic LymphomasLymphoplasmacytoid Lymphomas, leukemia, CLL Lymphoplasmacytoid Lymphomas, CLL, B-Cell Chronic Lymphocytic Leukemia, Chronic B-Cell Leukemia, Chronic B-Cell, Lymphocytic Leukemia, B-Lymphocytic Leukemias, B Cell Malignancy, Small Cell, Chronic Lymphocytic Leukemia, chronic LYMPHOCYTIC, Chronic B-Lymphocytic, Chronic B-Lymphocytic Leukemia, lymphoplasmacytic leukaemia, B-Cell Malignancy, B-Cell, Lymphatic Leukemia, Low-Grade B-Cell Malignancies, Chronic Lymphoblastic Leukemia, lymphoplasmacytic leukemia, B-cell chronic lymphocytic leukaemia, Leukemias, chronic, B-Cell Leukemia, Mutations, B Cell, Small, Well-Differentiated, Chronic Lymphatic, Small Cell Lymphoma, B-cell chronic lymphoid leukemia, Lymphocytic Leukemias, B-Cell Malignancies, B Lymphocytic Leukemia, Chronic B-Cell Leukemias, Well-Differentiated Lymphocytic, B Cell Chronic Lymphocytic Leukemia, chronic lymphatic leukemia, Lymphoplasmacytoid Lymphoma, B Cell Leukemia, Well Differentiated, Chronic Lymphocytic Leukemias, lymphocytic, Low-Grade B-Cell, Lymphomas, chronic lymphatic, Low-Grade, Lymphoblastic Leukemia, Chronic Lymphatic Leukemia, Lymphocytic, small lymphocytic lymphoma, Leukemia, Lymphatic Leukemias, B-cell chronic lymphocytic leukemia, Malignancy, Lymphocytic Lymphomas, Well-Differentiated Lymphocytic Lymphomas, Small-Cell Lymphomas, B-Cell Leukemias, CLL Lymphoplasmacytoid Lymphoma, Plasmacytoid, Disrupted In B-Cell Malignancy, Lymphoblastic, Chronic Lymphoblastic, Small Lymphocytic Lymphoma, Well-Differentiated Lymphocytic Lymphoma, Small Lymphocytic, Small-Cell Lymphoma, B-Lymphocytic Leukemia, B Cell., Chronic Lymphoblastic Leukemias, Low-Grade B-Cell Malignancy, Diffuse, Lymphoblastic Leukemias, Small-Cell, Chronic Lymphatic Leukemias, Lymphocytic Lymphoma, Disrupted In B Cell Malignancy, Lymphoplasmacytoid, CLL Lymphoplasmacytoid, Lymphoma, Chronic, Diffuse Well Differentiated Lymphocytic Lymphoma, chronic lymphocytic leukaemia, Malignancies, Chronic B-Lymphocytic Leukemias, chronic lymphatic leukaemia, Chronic Lymphocytic, Diffuse Well-Differentiated Lymphocytic Lymphoma, Low Grade, Small Lymphocytic LymphomasNgf1, B Cells, CG33956, Materials, egr-1, Globulin, egr, DPTEN, LIPD, D-fos, Tumor, Long Term, Social Controls, rat, zif-268, Method, 3, TEP1, LC64P, 300kDa), FATE, CG12919, l-plastin, procedures, DIF, Social, Intrinsic Pathway Apoptosis, ch, adult chronic leukemia, TNFSF2, D-Fos, Homo sapiens disease, Ngfi, B Lymphocyte, KROX-24, single organism signaling, Tumors, dif, tnfa, anatomical protrusion, B Lymphocytes, e(Pc), TNFA, Longterm Effect, AF-1, Procedure, lymphoplasmacytic leukemia, Acceptance Processes, Benign, signaling (initiator) caspase activity, PTEN3, induction of apoptosis, PTEN1, FOS, Fos, Regg1, Cellular, chronic lymphatic leukemia, TGF-beta type III receptors, Caspase-Dependent, HDLCQ11, DmelCG7776, death rate, fos, Benign Neoplasms, Methodological, Controls, PTENa, ZNF225, human, Malignant Neoplasms, Intrinsic Pathway Apoptoses, IFNGT1, B-Lymphocyte, Material, Proliferation, DmelLcp3, G0S7, BG:DS02740.11, Extrinsic Pathway, Tnfa, Globulins, Fra, anatomical systems., 2310035O07Rik, Regulations, CLL, Cll, GH05739, Bursa-Dependent, g0s30, beta receptor III (betaglycan, Immunoglobulin, conformation, GLM2, Effects, Processes, TNF, Neoplasms, chronic LYMPHOCYTIC, fra, high weight, DmelCG33956, Prognostic Factors, protein-containing complex, PLS2, cll, Krox-1, CML, GH14582, AI463227, heavy, pls2, Gene Products, disease or disorder, Number Growth, Technique, DmelCG2043, anatomical systems, lcp3, cFos, Longterm, RATTNF, LCP-3, G0/G1 switch regulatory protein 7, Long-Term, A530045N19Rik, Expressions, DmelCG12919, DmelCG5671, TGF-beta type III, Neoplasias, Study, darth, CP3, Classic Apoptosis, at225, B430203M17Rik, Expression, transforming growth factor, CG7937, Cancer, Apoptosis, leukemia, Krox24, EGR-1-A, LcpIII, Malignant Neoplasm, PTEN, xtnf, Proteins, disorders, Chronic Lymphocytic Leukemia, lymphoplasmacytic leukaemia, 311, dPten, Factor, pten, chronic, Cell, dt1, dpten, MT, 93Bal, native protein, Social Control, CWS1, chemical analysis, Long Term Effects, Neoplasm, AW215636, condition, background, dPTEN, LCP3, Kay, cellular oncogene fos, primary cancer, c15, Mmac, c-Fos, DMLCP3, CG5671, dfos, apoptosis, l(2)28-28-12, DmelCG7937, IMD28, Cancers, malignant tumor, Longterm Effects, Classic Apoptoses, DmelCG5861, Gene Proteins, AP1, B-Cells, dAP-1, dFos, signalling process, c-fos, commitment to apoptosis, receptor, regulation, CG2043, DFos, DFOS, NGF1-A, Neoplasia, AU015626, determination, Bursa-Dependent Lymphocytes, AP-1, egr1, Immune Globulin, protein, TBRIII, Cell Growth in Number, Techniques, Dfos, diseases, Extrinsic Pathway Apoptoses, DFra, Cell Number Growth, diseases and disorders, protein aggregate, xtnf-alpha, Effect, Formal Social Controls, chronic lymphatic, dFra, dFRA, CG15507, CG15509, Immune Processes, human disease, Immune Responses, Growth, Prognoses, Gene Expressions, PPI, B-cell chronic lymphocytic leukemia, L-PLASTIN, reference sample, regg1, IFGR2, adult chronic leukaemia, Zenk, Immune, Methodological Studies, Egr-1, Zfp-6, malignant neoplasm, Classic, Classical Apoptosis, Malignancies, CG7776, d-fos, chronic lymphatic leukaemia, Long-Term Effects, Ifgr2, single-organism behavior, ngfi-a, lc64p, BGCAN, krox-24, Caspase-Dependent Apoptosis, Process, mouse, Lymphocyte B-Cell, L[[3]]CP3, results, Programs, Acceptance Process, Intrinsic Pathway, Extrinsic Pathway Apoptosis, Diseases, tnf-alpha, CT43, Genetic Materials, lymphocytic, fixed, Genetic Material, D-fos/kay, Factors, beta receptor III, Ifgt, MMAC1, Prognostic, Heterogeneity, Control, TNFalpha, BcDNA:RH51659, Methodological Study, disease, immunoglobulin, induction of apoptosis by p53, spine, E(PC), D12Rfj1, anon-48Ac, Cell Number, Cistron, chronic lymphocytic leukaemia, BZS, Regulation, Classical, Apoptoses, Prognostic Factor, other disease, TNF-alpha, transforming growth factor beta type III receptor, Procedures, caspase-dependent programmed cell death, Benign Neoplasm, p55, B-Cell, Gene, Caspase Dependent Apoptosis, ETR103, Malignant, Lymphocyte B-Cells, B-cell chronic lymphocytic leukaemia, protrusion, TGF beta type III receptor, antibody, MHAM, TNF-a, III, B-cell chronic lymphoid leukemia, Genetic heterogeneity, Studies, Krox-24, 1110036H20Rik, Type I, proto-oncogene protein c-fos, fbz, study, betaglycan, Genetic, LPL, Malignancy, dlhD, Bursa Dependent Lymphocytes, AT225, apoptosis activator activity, Ect1, TIS8, Ect5, non-neoplastic, cell proliferation, Immune Response, type III TGFbeta receptor, lpl, time of survival, tis8, znf225, disorder, Long-Term Effect, Behaviors, G0S30, Immune Process, Lymphocyte, Controlled, 3.1.1.34, Multiplication, Controlling, Cellular Proliferation, Formal Social Control, protein complex, HEL-S-37, ggr, medical condition, Zif268, Cistrons, Immune Globulins, tnfsf2, survival, Programmed Cell Death, Protein, TGFBR3, techniques, Xegr-1, TGFBR3 protein, opsonin activity, Acceptance, small lymphocytic lymphoma, cp64, Bursa-Dependent Lymphocyte, 10q23del, Tgfbr3 protein, NGFI-A, anon-35Fa, Lymphocytes, A130070J02Rik, beta-glycan, introduction, Protein Gene Products, DEC, Hox11-311, C-FOS, NGFIA, anon-35Fc, ZIF-268, Cell Multiplication, B cell receptor activity, Response, Egr, CP64, assay, variable, Tnfsf1a, methodology12461false IGVH mutations in chronic lymphocytic leukemia.BACKGROUND: Chronic lymphocytic leukemia (CLL) is an incurable malignancy of mature B-lymphocytes, characterized as being a heterogeneous disease with variable clinical manifestation and survival. Mutational statuses of rearranged immunoglobulin heavy chain variable (IGVH) genes has been consider one of the most important prognostic factors in CLL, but despite of its proven value to predict the course of the disease, the regulatory programs and biological mechanisms responsible for the differences in clinical behavior are poorly understood. METHODS: In this study, (i) we performed differential gene expression analysis between the IGVH statuses using multiple and independent CLL cohorts in microarrays platforms, based on this information, (ii) we constructed a simplified protein-protein interaction (PPI) network and (iii) investigated its structure and critical genes. This provided the basis to (iv) develop a Boolean model, (v) infer biological regulatory mechanism and (vi) performed perturbation simulations in order to analyze the network in dynamic state. RESULTS: The result of topological analysis and the Boolean model showed that the transcriptional relationships of IGVH mutational status were determined by specific regulatory proteins (PTEN, FOS, EGR1, TNF, TGFBR3, IFGR2 and LPL). The dynamics of the network was controlled by attractors whose genes were involved in multiple and diverse signaling pathways, which may suggest a variety of mechanisms related with progression occurring over time in the disease. The overexpression of FOS and TNF fixed the fate of the system as they can activate important genes implicated in the regulation of process of adhesion, apoptosis, immune response, cell proliferation and other signaling pathways related with cancer. CONCLUSION: The differences in prognosis prediction of the IGVH mutational status are related with several regulatory hubs that determine the dynamic of the system.2016-08-232017-03-152017-03-15478326088082