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1 About B Cell Lymphomas Groupmeeting Klipp/Spang, December Dennis Kostka Max-Planck-Institute for Molecular Genetics Computational Molecular Biology Berlin 1
2 Overview Short History of Lymphoma Classification
3 Overview Short History of Lymphoma Classification About Healthy B Cells Blood Cells Immune System Immunoglobulins Lymphatic System B Cell Differentiation
4 Overview Short History of Lymphoma Classification About Healthy B Cells Blood Cells Immune System Immunoglobulins Lymphatic System B Cell Differentiation WHO Classification
5 Overview Short History of Lymphoma Classification About Healthy B Cells Blood Cells Immune System Immunoglobulins Lymphatic System B Cell Differentiation WHO Classification Microarrays Alizadeh et. al. Shipp et. al. 2
6 Short History of Classification > 1970 s Henry Rappaport Dennis Kostka About B-cell Lymphoma, MPI for Molecular Genetics, 2002 Dec 09 3
7 Short History of Classification > 1970 s Henry Rappaport 1970 s Lukes, Collins Lennert, Kiel Group Dennis Kostka About B-cell Lymphoma, MPI for Molecular Genetics, 2002 Dec 09 3
8 Short History of Classification > 1970 s Henry Rappaport 1970 s Lukes, Collins Lennert, Kiel Group 1980 s Working Formulation Dennis Kostka About B-cell Lymphoma, MPI for Molecular Genetics, 2002 Dec 09 3
9 Short History of Classification > 1970 s Henry Rappaport 1970 s Lukes, Collins Lennert, Kiel Group 1980 s Working Formulation 1994 Revised European American Lymphoma Scheme Dennis Kostka About B-cell Lymphoma, MPI for Molecular Genetics, 2002 Dec 09 3
10 Short History of Classification > 1970 s Henry Rappaport 1970 s Lukes, Collins Lennert, Kiel Group 1980 s Working Formulation 1994 Revised European American Lymphoma Scheme 2001 WHO comprehensive classification of neoplasms of haematopietic and lymphoid tissues Dennis Kostka About B-cell Lymphoma, MPI for Molecular Genetics, 2002 Dec 09 3
11 Blood Cells Blood Cells Erytrocytes Leucocytes Dennis Kostka About B-cell Lymphoma, MPI for Molecular Genetics, 2002 Dec 09 4
12 Blood Cells Blood Cells Erytrocytes Leucocytes Lymphocytes Granulocytes Monocytes Dennis Kostka About B-cell Lymphoma, MPI for Molecular Genetics, 2002 Dec 09 4
13 Blood Cells Blood Cells Erytrocytes Leucocytes Lymphocytes Granulocytes Monocytes B Cells T Cells NK Cells Dennis Kostka About B-cell Lymphoma, MPI for Molecular Genetics, 2002 Dec 09 4
14 Immune System Pathogens Adaptive Immune Responses Innate Immune Responses innate response adaptive response Dennis Kostka About B-cell Lymphoma, MPI for Molecular Genetics, 2002 Dec 09 5
15 Immune System Pathogens Adaptive Immune Responses Innate Immune Responses innate response adaptive response cellular mediated Dennis Kostka About B-cell Lymphoma, MPI for Molecular Genetics, 2002 Dec 09 5
16 Immune System Pathogens Adaptive Immune Responses Innate Immune Responses innate response adaptive response cellular mediated antibody mediated Dennis Kostka About B-cell Lymphoma, MPI for Molecular Genetics, 2002 Dec 09 5
17 Antibodies how they work how they look like Dennis Kostka About B-cell Lymphoma, MPI for Molecular Genetics, 2002 Dec 09 6
18 The Lymphatic System Lymphnode Human Lymphoid Organs Secondary Follicle Dennis Kostka About B-cell Lymphoma, MPI for Molecular Genetics, 2002 Dec 09 7
19 V(D)J Joining Dennis Kostka About B-cell Lymphoma, MPI for Molecular Genetics, 2002 Dec 09 8
20 Class Switch / Somatic Hypermutation Class Switches Somatic Hypermutation 1 / V region coding sequence / generation aim : enlargen affinity to antigen place: germinal center Dennis Kostka About B-cell Lymphoma, MPI for Molecular Genetics, 2002 Dec 09 9
21 B Cell Differentiation Dennis Kostka About B-cell Lymphoma, MPI for Molecular Genetics, 2002 Dec 09 10
22 B Cell Differentiation ctd. Naive B cell Dennis Kostka About B-cell Lymphoma, MPI for Molecular Genetics, 2002 Dec 09 11
23 B Cell Differentiation ctd. B Immunoblast Naive B cell Dennis Kostka About B-cell Lymphoma, MPI for Molecular Genetics, 2002 Dec 09 11
24 B Cell Differentiation ctd. B Immunoblast Plasmacytoid Lymphocyte Naive B cell Dennis Kostka About B-cell Lymphoma, MPI for Molecular Genetics, 2002 Dec 09 11
25 B Cell Differentiation ctd. B Immunoblast Plasmacytoid Lymphocyte Naive B cell Mantle cell Dennis Kostka About B-cell Lymphoma, MPI for Molecular Genetics, 2002 Dec 09 11
26 B Cell Differentiation ctd. B Immunoblast Plasmacytoid Lymphocyte Naive B cell Follicular B blast Mantle cell Dennis Kostka About B-cell Lymphoma, MPI for Molecular Genetics, 2002 Dec 09 11
27 B Cell Differentiation ctd. B Immunoblast Plasmacytoid Lymphocyte Naive B cell Follicular B blast Mantle cell Centroblast Dennis Kostka About B-cell Lymphoma, MPI for Molecular Genetics, 2002 Dec 09 11
28 B Cell Differentiation ctd. B Immunoblast Plasmacytoid Lymphocyte Naive B cell Follicular B blast Centrocyte Mantle cell Centroblast Dennis Kostka About B-cell Lymphoma, MPI for Molecular Genetics, 2002 Dec 09 11
29 B Cell Differentiation ctd. B Immunoblast Plasmacytoid Lymphocyte Naive B cell Follicular B blast Centrocyte Mantle cell Centroblast Marginal zone & Monocytoid B cell Dennis Kostka About B-cell Lymphoma, MPI for Molecular Genetics, 2002 Dec 09 11
30 B Cell Differentiation ctd. B Immunoblast Plasmacytoid Lymphocyte Naive B cell Follicular B blast Centrocyte Mantle cell Centroblast Marginal zone & Monocytoid B cell Dennis Kostka About B-cell Lymphoma, MPI for Molecular Genetics, 2002 Dec 09 11
31 B Cell Differentiation ctd. B Immunoblast Plasmacytoid Lymphocyte Naive B cell Follicular B blast Centrocyte Plasma cell Mantle cell Centroblast Marginal zone & Monocytoid B cell Dennis Kostka About B-cell Lymphoma, MPI for Molecular Genetics, 2002 Dec 09 11
32 Blood Cancer Blood Cancer Leukemia Lymphoma Myeloma CLL can be Chronic Lymphatic Leukemia Small Lymphocytic Lymphoma ALL can be Acute Lymphoblastic Leukemia (B-ALL) if >25 % Lymphoblasts in bonemarrow Lymphoblastic Lymphoma (B-LBL) else Dennis Kostka About B-cell Lymphoma, MPI for Molecular Genetics, 2002 Dec 09 12
33 Blood Cancer Blood Cancer Leukemia Lymphoma Myeloma CLL can be Chronic Lymphatic Leukemia Small Lymphocytic Lymphoma ALL can be Acute Lymphoblastic Leukemia (B-ALL) if >25 % Lymphoblasts in bonemarrow Lymphoblastic Lymphoma (B-LBL) else each case: same biological entity Dennis Kostka About B-cell Lymphoma, MPI for Molecular Genetics, 2002 Dec 09 12
34 WHO Classification Haematological Malignancies Lymphoid Myeloid Histocytic / Dendritic T Cells / NK Cells B Cells Hodkin Lymphomas Precursor Mature Dennis Kostka About B-cell Lymphoma, MPI for Molecular Genetics, 2002 Dec 09 13
35 WHO Classification Haematological Malignancies Lymphoid Myeloid Histocytic / Dendritic T Cells / NK Cells B Cells Hodkin Lymphomas Precursor Mature ALL CLL Dennis Kostka About B-cell Lymphoma, MPI for Molecular Genetics, 2002 Dec 09 13
36 WHO Classification Haematological Malignancies Lymphoid 30% Myeloid Histocytic / Dendritic T Cells / NK Cells 15% B Cells 85% Hodkin Lymphomas Precursor Mature ALL CLL Dennis Kostka About B-cell Lymphoma, MPI for Molecular Genetics, 2002 Dec 09 13
37 WHO Classification ctd. Criteria: Clinical Presentation dissaminated? leuekemic? extranodal/nodal? Morpholgy structure of cells involved Immunophenotype CD surface markers, Immunoglobulins Cytogenetics translocations Dennis Kostka About B-cell Lymphoma, MPI for Molecular Genetics, 2002 Dec 09 14
38 Translocations deregulate oncogene by placing it e. g. near IG loci oncogenes have been found that way create new fusion proteins Dennis Kostka About B-cell Lymphoma, MPI for Molecular Genetics, 2002 Dec 09 15
39 WHO B Cell Neoplasms I. Precursor B-cell neoplasm: A. precursor B-acute lymphoblastic leukemia/lymphoblastic lymphoma (B-ALL, LBL) II. Peripheral B-cell neoplasms A. B-cell chronic lymphocytic leukemia/small lymphocytic lymphoma B. B-cell prolymphocytic leukemia C. Lymphoplasmacytic lymphoma/immunocytoma D. Mantle cell lymphoma E. Follicular lymphoma (22%) F. Extranodal marginal zone B-cell lymphoma of MALT type G. Nodal marginal zone B-cell lymphoma (+/- monocytoid B-cells) H. Splenic marginal zone lymphoma (+/- villous lymphocytes) I. Hairy cell leukemia J. Plasmacytoma/plasma cell myeloma K. Diffuse large B-cell lymphoma (30%) L. Burkitt s lymphoma (subtypes are missing) Dennis Kostka About B-cell Lymphoma, MPI for Molecular Genetics, 2002 Dec 09 16
40 Diffuse Large B Cell Lymphoma Dennis Kostka About B-cell Lymphoma, MPI for Molecular Genetics, 2002 Dec 09 17
41 Diffuse Large B Cell Lymphoma Account for about 30% of B cell neoplasms Dennis Kostka About B-cell Lymphoma, MPI for Molecular Genetics, 2002 Dec 09 17
42 Diffuse Large B Cell Lymphoma Account for about 30% of B cell neoplasms Two variants (morphological) Immunoblastic Centroblastic Highly variable clinical course (independent of subtype) Dennis Kostka About B-cell Lymphoma, MPI for Molecular Genetics, 2002 Dec 09 17
43 Diffuse Large B Cell Lymphoma Account for about 30% of B cell neoplasms Two variants (morphological) Immunoblastic Centroblastic Highly variable clinical course (independent of subtype) use microarrays for further classification Dennis Kostka About B-cell Lymphoma, MPI for Molecular Genetics, 2002 Dec 09 17
44 Microarrays: Alizadeh et al. Lymphochip cdna clones 96 tissue-samples DLBCL, FL, CLL 128 chips Alizadeh, A. et.al Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature 4051, (2000) A G OCI Ly3 OCI Ly10 DLCL-0042 DLCL-0007 DLCL-0031 DLCL-0036 DLCL-0030 DLCL-0004 DLCL-0029 Tonsil Germinal Center B Tonsil Germinal Center Centroblasts SUDHL6 DLCL-0008 DLCL-0052 DLCL-0034 DLCL-0051 DLCL-0011 DLCL-0032 DLCL-0006 DLCL-0049 Tonsil DLCL-0039 Lymph Node DLCL-0001 DLCL-0018 DLCL-0037 DLCL-0010 DLCL-0015 DLCL-0026 DLCL-0005 DLCL-0023 DLCL-0027 DLCL-0024 DLCL-0013 DLCL-0002 DLCL-0016 DLCL-0020 DLCL-0003 DLCL-0014 DLCL-0048 DLCL-0033 DLCL-0025 DLCL-0040 DLCL-0017 DLCL-0028 DLCL-0012 DLCL-0021 Blood B;anti-IgM+CD40L low 48h Blood B;anti-IgM+CD40L high 48h Blood B;anti-IgM+CD40L 24h Blood B;anti-IgM 24h Blood B;anti-IgM+IL-4 24h Blood B;anti-IgM+CD40L+IL-4 24h Blood B;anti-IgM+IL-4 6h Blood B;anti-IgM 6h Blood B;anti-IgM+CD40L 6h Blood B;anti-IgM+CD40L+IL-4 6h Blood T;Adult CD4+ Unstim. Blood T;Adult CD4+ I+P Stim. Cord Blood T;CD4+ I+P Stim. Blood T;Neonatal CD4+ Unstim. Thymic T;Fetal CD4+ Unstim. Thymic T;Fetal CD4+ I+P Stim. OCI Ly1 WSU1 Jurkat U937 OCI Ly12 OCI Ly13.2 SUDHL5 DLCL-0041 FL-9 FL-9;CD19+ FL-12;CD19+ FL-10;CD19+ FL-10 FL-11 FL-11;CD19+ FL-6;CD19+ FL-5;CD19+ Blood B;memory Blood B;naive Blood B Cord Blood B CLL-60 CLL-68 CLL-9 CLL-14 CLL-51 CLL-65 CLL-71#2 CLL-71#1 CLL-13 CLL-39 CLL-52 DLCL DLBCL Germinal centre B Nl. lymph node/tonsil Activated blood B Resting/activated T Transformed cell lines FL Resting blood B CLL Pan B cell Germinal Centre B cell T cell Activated B cell Proliferation Lymph node Dennis Kostka About B-cell Lymphoma, MPI for Molecular Genetics, 2002 Dec 09 18
45 Alizadeh ctd. a b c c 1.0 Low clinical risk patients GC B -like P robability patients, 3 deaths Activated B -like 10 patients, 6 deaths 0.0 P = b 1.0 All patients Low clinical risk P robability 24 patients, 9 deaths 0.5 High clinical risk 14 patients, 11 deaths P = GC B-like DLBCL Activated B-like DLBCL a 1.0 All patients GC B -like DLCL-0012 DLCL-0024 DLCL-0003 DLCL-0026 DLCL-0023 DLCL-0015 DLCL-0010 DLCL-0030 DLCL-0034 SUDHL6 DLCL-0018 DLCL-0032 DLCL-0052 DLCL-0037 DLCL-0001 DLCL-0008 GC B GC centroblasts DLCL-0004 DLCL-0029 DLCL-0009 DLCL-0020 DLCL-0051 DLCL-0033 DLCL-0005 DLCL-0011 DLCL-0048 DLCL-0027 DLCL-0013 DLCL-0007 DLCL-0028 DLCL-0025 DLCL-0021 DLCL-0016 DLCL-0002 DLCL-0017 OCI Ly3 DLCL-0040 DLCL-0014 DLCL-0031 DLCL-0036 DLCL-0039 DLCL-0042 OCI Ly10 DLCL-0041 DLCL-0049 DLCL-0006 P robability 19 patients, 6 deaths 0.5 Activated B -like 21 patients, 16 deaths P = Overall survival (years) Dennis Kostka About B-cell Lymphoma, MPI for Molecular Genetics, 2002 Dec 09 19
46 Microarrays: Shipp et al. Affy HU genes 77 tissue samples DLBCL, FL Shipp, M.A. et al. Diffuse large B-cell lymphoma outcome predition by gene expression profiling using supervised machine learning. Nature Medicine 8, (2002) Dennis Kostka About B-cell Lymphoma, MPI for Molecular Genetics, 2002 Dec 09 20
47 Shipp ctd. Dennis Kostka About B-cell Lymphoma, MPI for Molecular Genetics, 2002 Dec 09 21
48 Shipp ctd. Dennis Kostka About B-cell Lymphoma, MPI for Molecular Genetics, 2002 Dec 09 22
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