2013 Genentech USA, Inc. All rights reserved.

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The Molecular Basis of Hematological Malignancies slide presentation is not an independent educational program, and no CME credits will

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BIO00020782001

2013 Genentech USA, Inc. All rights reserved.

Cellular origin of B-cell malignancies

Germinalcenter Mantle

zone

Marginalzone

B-CLL=B-cell chronic lymphocytic leukemia; DLBCL=diffuse large B-cell lymphoma; MALT=mucosa-associated lymphoid tissue.

B-cell differentiation step.

Proposed malignancy from normal counterpart.

Naïve B cell

B-CLL (unmutated V gene)

DLBCL (ABC type) Primary mediastinal

B-cell lymphoma

Follicular lymphomaDLBCL (GC type)

Burkitt’s lymphoma

Classical Hodgkin’s lymphoma

Mantle-cell lymphomaB-CLL (unmutated V-region genes)

Multiple myeloma

MALT lymphomaNodal marginal-zone lymphoma

B-CLL

GCB cell

MemoryB cell

Apoptosis

Adapted by permission from Küppers. Nat Rev Cancer. 2005;5:251-262. 2

2013 Genentech USA, Inc. All rights reserved. 3

BCR signaling is central to the pathogenesis of lymphoma

Ras

Raf

mTOR

Cell-cyclecontrol

Proliferation

Apoptosis

Survival

Angiogenesis

MAPK

MEK

MAPK

Ligand-activated receptors

Lyn

Syk

PKC

NFκB

BTKPDK1

AK

T

PI3K

The Cancer Genome Atlas (TCGA). The National Cancer Institute. 2007. http://cancergenome.nih.gov/media/images.asp. Accessed July 18, 2008.Jumaa et al. Ann Rev Immunol. 2005;23:415-445.

B-cell receptor (BCR) signaling drives many pathways that lead to activation of targeted genes within the nucleus, resulting in lymphomagenesis.

Reference:Jumaa H, Hendriks RW, Reth M. B cell signaling and tumorigenesis. Annu Rev Immunol. 2005;23:415-445.

Notes

2013 Genentech USA, Inc. All rights reserved.

Apoptosis is an emerging therapeutic target in lymphoma

Caspases

Cell-extrinsicpathway

Pro-apoptotic ligand

Death receptor

Apoptosis

Ashkenazi. Nat Rev Cancer. 2002;2:420-430.

Cellularstress

Cell-intrinsic pathway

Mitochondria

5