About B–Cell Lymphomas - Computational Diagnostics...

About B–Cell Lymphomas

Groupmeeting Klipp/Spang, December 09 2002

Dennis KostkaMax-Planck-Institute for Molecular Genetics

– Computational Molecular Biology –Berlin

1

Overview

• Short History of Lymphoma Classification

Overview


• About Healthy B–CellsBlood CellsImmune SystemImmunoglobulinsLymphatic SystemB–Cell Differentiation

Overview



• WHO Classification

Overview



• WHO Classification

• MicroarraysAlizadeh et. al.Shipp et. al.

2

Short History of Classification

• > 1970’sHenry Rappaport

Dennis Kostka About B-cell Lymphoma, MPI for Molecular Genetics, 2002 Dec 09 3



• 1970’sLukes, CollinsLennert, ’Kiel Group’





• 1980’sWorking Formulation






• 1994Revised European American Lymphoma Scheme






• 1994Revised European American Lymphoma Scheme

• 2001WHO comprehensive classification of neoplasmsof haematopietic and lymphoid tissues


Blood Cells

Blood Cells

Erytrocytes Leucocytes


Blood Cells

Blood Cells


Lymphocytes Granulocytes Monocytes


Blood Cells

Blood Cells


Lymphocytes Granulocytes Monocytes

T CellsB Cells NK Cells


Immune System

Pathogens

Innate ImmuneResponses

Adaptive ImmuneResponses

• innate response

• adaptive response


Immune System

Pathogens



• innate response

• adaptive responsecellular mediated


Immune System

Pathogens



• innate response

• adaptive responsecellular mediatedantibody mediated


Antibodies

how they work

how they look like


The Lymphatic System

Human Lymphoid Organs

Lymphnode

Secondary Follicle


V(D)J – Joining


Class Switch / Somatic Hypermutation

Class Switches

Somatic Hypermutation

• 1 / V region coding sequence / generation

• aim : enlargen affinity to antigen

• place: germinal center


B Cell Differentiation


B Cell Differentiation ctd.

Naive B cell



Naive B cell

B Immunoblast



Naive B cell

B Immunoblast Plasmacytoid Lymphocyte



Naive B cell


Mantle cell



Naive B cell


Mantle cell

Follicular B blast



Naive B cell


Mantle cell

Follicular B blast

Centroblast



Naive B cell


Mantle cell

Follicular B blast

Centroblast

Centrocyte



Naive B cell


Mantle cell

Follicular B blast

Centroblast

Centrocyte

Marginal zone & Monocytoid B cell



Naive B cell


Mantle cell

Follicular B blast

Centroblast

Centrocyte

Marginal zone & Monocytoid B cell

Plasma cell


Blood Cancer

Blood Cancer

LeukemiaLymphoma Myeloma

CLL can beChronic Lymphatic LeukemiaSmall Lymphocytic Lymphoma

ALL can beAcute Lymphoblastic Leukemia (B-ALL)

if >25 % Lymphoblasts in bonemarrowLymphoblastic Lymphoma (B-LBL)

else


Blood Cancer

Blood Cancer

LeukemiaLymphoma Myeloma

CLL can beChronic Lymphatic LeukemiaSmall Lymphocytic Lymphoma

ALL can beAcute Lymphoblastic Leukemia (B-ALL)

if >25 % Lymphoblasts in bonemarrowLymphoblastic Lymphoma (B-LBL)

else

each case: same biological entity


WHO Classification

Haematological Malignancies

MyeloidLymphoid Histocytic / Dendritic

T Cells / NK Cells Hodkin Lymphomas

Precursor Mature

B Cells


WHO Classification




Precursor Mature

ALL CLL

B Cells


WHO Classification




Precursor Mature

ALL CLL

B Cells

85%15%

30%


WHO Classification ctd.

Criteria:

• Clinical Presentation· dissaminated?· leuekemic?· extranodal/nodal?

• Morpholgy· ’structure’ of cells involved

• Immunophenotype· CD surface markers, Immunoglobulins

• Cytogenetics· translocations


Translocations

• deregulate oncogene by placing it e. g. near IG locioncogenes have been found that way

• create new fusion proteins


WHO B–Cell Neoplasms

I. Precursor B-cell neoplasm:A. precursor B-acute lymphoblastic leukemia/lymphoblastic lymphoma (B-ALL, LBL)

II. Peripheral B-cell neoplasmsA. B-cell chronic lymphocytic leukemia/small lymphocytic lymphomaB. B-cell prolymphocytic leukemiaC. Lymphoplasmacytic lymphoma/immunocytomaD. Mantle cell lymphomaE. Follicular lymphoma (22%)F. Extranodal marginal zone B-cell lymphoma of MALT typeG. Nodal marginal zone B-cell lymphoma (+/- monocytoid B-cells)H. Splenic marginal zone lymphoma (+/- villous lymphocytes)I. Hairy cell leukemiaJ. Plasmacytoma/plasma cell myelomaK. Diffuse large B-cell lymphoma (30%)L. Burkitt’s lymphoma

(subtypes are missing)


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)




• Two variants (morphological)· Immunoblastic· Centroblastic

• Highly variable clinical course (independent of subtype)

use microarrays for further classification


Microarrays: Alizadeh et al.

Lymphochip· 17 856 cDNA clones· 96 tissue-samples· DLBCL, FL, CLL· 128 chips

Alizadeh, A. et.al Distinct types of dif-fuse large B-cell lymphoma identified bygene expression profiling. Nature 4051,503-511 (2000)

OCI Ly3OCI Ly10DLCL-0042DLCL-0007DLCL-0031DLCL-0036DLCL-0030DLCL-0004DLCL-0029Tonsil Germinal Center BTonsil Germinal Center CentroblastsSUDHL6DLCL-0008DLCL-0052DLCL-0034DLCL-0051DLCL-0011DLCL-0032DLCL-0006DLCL-0049TonsilDLCL-0039Lymph NodeDLCL-0001DLCL-0018DLCL-0037DLCL-0010DLCL-0015DLCL-0026DLCL-0005DLCL-0023DLCL-0027DLCL-0024DLCL-0013DLCL-0002DLCL-0016DLCL-0020DLCL-0003DLCL-0014DLCL-0048DLCL-0033DLCL-0025DLCL-0040DLCL-0017DLCL-0028DLCL-0012DLCL-0021Blood B;anti-IgM+CD40L low 48hBlood B;anti-IgM+CD40L high 48hBlood B;anti-IgM+CD40L 24hBlood B;anti-IgM 24hBlood B;anti-IgM+IL-4 24hBlood B;anti-IgM+CD40L+IL-4 24hBlood B;anti-IgM+IL-4 6hBlood B;anti-IgM 6hBlood B;anti-IgM+CD40L 6hBlood B;anti-IgM+CD40L+IL-4 6hBlood 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 Ly1WSU1JurkatU937OCI Ly12OCI Ly13.2SUDHL5DLCL-0041FL-9FL-9;CD19+FL-12;CD19+FL-10;CD19+FL-10FL-11FL-11;CD19+FL-6;CD19+FL-5;CD19+Blood B;memoryBlood B;naiveBlood BCord Blood BCLL-60CLL-68CLL-9CLL-14CLL-51CLL-65CLL-71#2CLL-71#1CLL-13CLL-39CLL-52DLCL-0009

2 1 0–1–2

4.0002.0001.0000.5000.250

DLBCLGerminal centre BNl. lymph node/tonsilActivated blood BResting/activated TTransformed cell linesFLResting blood BCLL

Germinal CentreB cell

Lymph node

T cell

Pan B cell

Activated B cell

Proliferation

A

G


Alizadeh ctd.

a b c

GC B-like DLBCL Activated B-like DLBCL

DLC

L-00

12D

LCL-

0024

DLC

L-00

03D

LCL-

0026

DLC

L-00

23D

LCL-

0015

DLC

L-00

10D

LCL-

0030

DLC

L-00

34S

UD

HL6

DLC

L-00

18D

LCL-

0032

DLC

L-00

52D

LCL-

0037

DLC

L-00

01D

LCL-

0008

GC

BG

C c

entr

obla

sts

DLC

L-00

04D

LCL-

0029

DLC

L-00

09D

LCL-

0020

DLC

L-00

51D

LCL-

0033

DLC

L-00

05D

LCL-

0011

DLC

L-00

48D

LCL-

0027

DLC

L-00

13D

LCL-

0007

DLC

L-00

28D

LCL-

0025

DLC

L-00

21D

LCL-

0016

DLC

L-00

02D

LCL-

0017

OC

I Ly3

DLC

L-00

40D

LCL-

0014

DLC

L-00

31D

LCL-

0036

DLC

L-00

39D

LCL-

0042

OC

I Ly1

0D

LCL-

0041

DLC

L-00

49D

LCL-

0006

10 12

1.0

0.5

0.00 2 4 6 8

G C B -like

Activated B -likePro

bab

ility

19 patients , 6 deaths


P =0.01

12

1.0

0.5

0.00 2 4 6 8 10

Pro

bab

ility

P =0.002

Overall survival (years )

Low clinical risk


High clinical risk


All patients

All patients

a

b

c

12

1.0

0.5

0.0

0 2 4 6 8 10

Pro

bab

ility

P =0.05

G C B -like


Activated B -like


Low clinical risk patients


Microarrays: Shipp et al.

Affy HU 6800· 6 800 genes· 77 tissue samples· DLBCL, FL

Shipp, M.A. et al. Diffuse large B-celllymphoma outcome predition by geneexpression profiling using supervisedmachine learning. Nature Medicine 8,68-74 (2002)


Shipp ctd.


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