 2013 Genentech USA, Inc. All rights reserved. Disclosure/Disclaimer The Molecular Basis of Hematological Malignancies slide presentation is not an independent educational program, and no CME credits will be provided. This program is not intended to promote any cancer agent or class approved by the FDA/EMA or currently under clinical development. The contents of this slide presentation are owned solely by Genentech; any unauthorized uses are prohibited. This program is presented on behalf of Genentech and the information presented is consistent with FDA guidelines. The following slides are selected samples from a complete presentation. They are for educational purposes only. BIO

 2013 Genentech USA, Inc. All rights reserved. Cellular origin of B-cell malignancies Germinal center Mantle zone Marginal zone 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 lymphoma DLBCL (GC type) Burkitt’s lymphoma Classical Hodgkin’s lymphoma Mantle-cell lymphoma B-CLL (unmutated V-region genes) Multiple myeloma MALT lymphoma Nodal marginal-zone lymphoma B-CLL GC B cell Memory B cell Apoptosis Adapted by permission from Küppers. Nat Rev Cancer. 2005;5:

 2013 Genentech USA, Inc. All rights reserved. 3 BCR signaling is central to the pathogenesis of lymphoma Ras Raf mTOR Cell-cycle control Proliferation  Apoptosis  Survival Angiogenesis MAPK MEK MAPK Ligand-activated receptors LynSyk PKC NFκB BTK PDK1 AKT PI3K The Cancer Genome Atlas (TCGA). The National Cancer Institute Accessed July 18, Jumaa et al. Ann Rev Immunol. 2005;23: 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: Notes

 2013 Genentech USA, Inc. All rights reserved. Apoptosis is an emerging therapeutic target in lymphoma Caspases Cell-extrinsic pathway Pro-apoptotic ligand Death receptor Apoptosis Ashkenazi. Nat Rev Cancer. 2002;2: Cellular stress Cell-intrinsic pathway Mitochondria 5