Owen A. O’Connor, M.D., Ph.D. is an American Cancer Society Research Professor at the University of Virginia Comprehensive Cancer Center. He completed his training in Internal Medicine at the New York Presbyterian Hospital at Weill Cornell University Medical School, a Fellowship in Hematology and Oncology at Memorial Sloan Kettering Cancer Center and a Fellowship in Clinical Pharmacology at Weill Cornell. He has been recognized as one of the Top Physicians in Cancer in the U.S. and is recognized by the Irish Government as one of the top 50 Irish Americans in Science and Medicine. Stephen M. Ansell, M.D., Ph.D. is the Dorotha W. and Grant L. Sundquist Professor of Hematologic Malignancies Research and the Chair of the Division of Hematology at Mayo Clinic. He received his medical degree from the University of Pretoria, South Africa and then completed a fellowship in Hematology and Medical Oncology at Mayo Clinic. His research focuses on optimizing antitumor immune function in B-cell malignancies. He received the Ernst Beutler Award from the American Society of Hematology in 2021 in recognition of his work. John F. Seymour MBBS Ph.D. heads the Department of Haematology of the Peter MacCallum Cancer Centre & the Royal Melbourne Hospital and is Professor of Medicine at the University of Melbourne. He completed a translational research fellowship at the MD Anderson Cancer Center in Houston, and has received their Distinguished Alumnus award. His work is focused on new drug development in lymphoid malignancies. He was awarded Membership of the Order of Australia, and elected to the Australian Academy of Health and Medical Sciences for his contributions to the field.

• List of Contributors xixVolume Foreword xxivVolume Preface xxviSeries Preface xxviiiSection I Biological Basis of the Lymphoid Malignancies 11 Fundamental Principles of Lymphomagenesis 3Pierre Sujobert, Philippe Gaulard, and Laurence de Leval2 Identifying Molecular Drivers of Lymphomagenesis 12Jennifer Shingleton and Sandeep S. Dave3 Characterizing the Spectrum of Epigenetic Dysregulation Across Lymphoid Malignancies 25Sean Harrop, Michael Dickinson, Ricky Johnstone, and Henry Miles Prince4 Animal Models of Lymphoid Malignancies 40Anjali MishraSection II Targeting the PI3 Kinase-AKT-mTOR Pathway 535 Principles of PI3K Biology and Its Role in Lymphoma 55Ralitsa R. Madsen6 Pharmacologic Differentiation of Drugs Targeting the PI3K-AKT-mTOR Signaling Pathway 71Inhye E. Ahn, Jennifer R. Brown, and Matthew S. Davids7 Clinical Experience with Phosphatidylinositol 3-Kinase Inhibitors in Hematologic Malignancies 86Alessandro Broccoli and Pier Luigi Zinzani9 PI3 Kinase, AKT, and mTOR Inhibitors 113Joel McCay and John G. GribbenSection III Targeting Programmed Cell Death 13110 Principles for Understanding Mechanisms of Cell Death and Their Role in Cancer Biology 133Sarah T. Diepstraten, John E. La Marca, David C.S. Huang, and Gemma L. Kelly11 Pharmacologic Features of Drugs Targeting BCL2 Family Members 151Jennifer K. Lue and Owen A. O’Connor12 Clinical Experience with Pro-Apoptotic Agents 165Thomas E. Lew and John F. Seymour13 Promising Combinations of Drugs Targeting Apoptosis 186William G. WierdaSection IV Targeting the Cancer Epigenome 19714 The Role of Epigenetic Dysregulation in Lymphoma Biology 199Qing Deng and Michael R. Green15 Quantitating and Characterizing the Effects of Epigenetic Targeted Drugs 209Emily Gruber, Alexander C. Lewis, and Lev M. Kats16 Clinical Experience with Epigenetic Drugs in Lymphoid Malignancies 225Enrica Marchi, Ipsita Pal, and John Sanil Manavalan17 Future Prospects for Targeting the Epigenome in Lymphomas 236Yusuke Isshiki and Ari MelnickSection V Targeting the B-cell Receptor (BCR) 24918 The Pathologic Role of BCR Dysregulation in Lymphoid Malignancies 251Jan A. Burger19 Pharmacologic Features of Drugs Targeting Bruton’s Tyrosine Kinase (BTK) 268Joel McCay and John G. Gribben20 Clinical Experience with Drugs Targeting Bruton’s Tyrosine Kinase (BTK) 278Julia Aronson, Anthony R. Mato, Catherine C. Coombs, Prioty Islam, Lindsey E. Roeker, and Toby Eyre21 Promising Combinations of BTK Inhibitors with Other Targeted Agents 287Nicholas J. Schmidt, Michael E. Williams, and Craig A. PortellSection VI Protein Degraders and Membrane Transport Inhibitors 30122 The Biological Basis for Targeting Protein Turnover in Malignant Cells 303Robert Z. Orlowski23 Preclinical Overview of Drugs Affecting Protein Turnover in Multiple Myeloma 313Giada Bianchi, Matthew Ho, and Kenneth C. Anderson24 Clinical Experience on Proteasome Inhibitors in Cancer 331Noa Biran, Pooja Phull, and Andre Goy25 Targeting Nuclear Protein Transport with XPO Inhibitors in Lymphoma 361Farheen Manji, Kyla Trkulja, Rob C. Laister, and John Kuruvilla26 Heterobifunctional Degraders for the Treatment of Lymphoid Malignancies 372Ashwin Gollerkeri, Jared Gollob, and Nello MainolfiSection VII Novel Targets and Therapeutic Prospects in Development 38127 Strategies for Targeting the JAK-STAT Pathway in Lymphoid Malignancies 383David J. Feith, Johnson Ung, Omar Elghawy, Peibin Yue, James Turkson, and Thomas P. Loughran Jr28 Strategies for Targeting MYC 402Jemma Longley and Andrew Davies29 Targeting NOTCH in Lymphoid Malignancies 411Deborah Piffaretti, Georgia Alice Galimberti, and Davide Rossi30 Targeting NF-κB in Oncology, an Untapped Therapeutic Potential 428Matko Kalac31 Targeting the Cell Cycle and Cyclin-dependent Kinases 444Chiara Tarantelli and Francesco BertoniReferences 452Index 457

Owen A. O’Connor, M.D., Ph.D. is an American Cancer Society Research Professor at the University of Virginia Comprehensive Cancer Center. He completed his training in Internal Medicine at the New York Presbyterian Hospital at Weill Cornell University Medical School, a Fellowship in Hematology and Oncology at Memorial Sloan Kettering Cancer Center and a Fellowship in Clinical Pharmacology at Weill Cornell. He has been recognized as one of the Top Physicians in Cancer in the U.S. and is recognized by the Irish Government as one of the top 50 Irish Americans in Science and Medicine. Stephen M. Ansell, M.D., Ph.D. is the Dorotha W. and Grant L. Sundquist Professor of Hematologic Malignancies Research and the Chair of the Division of Hematology at Mayo Clinic. He received his medical degree from the University of Pretoria, South Africa and then completed a fellowship in Hematology and Medical Oncology at Mayo Clinic. His research focuses on optimizing antitumor immune function in B-cell malignancies. He received the Ernst Beutler Award from the American Society of Hematology in 2021 in recognition of his work. John F. Seymour MBBS Ph.D. heads the Department of Haematology of the Peter MacCallum Cancer Centre & the Royal Melbourne Hospital and is Professor of Medicine at the University of Melbourne. He completed a translational research fellowship at the MD Anderson Cancer Center in Houston, and has received their Distinguished Alumnus award. His work is focused on new drug development in lymphoid malignancies. He was awarded Membership of the Order of Australia, and elected to the Australian Academy of Health and Medical Sciences for his contributions to the field.

• List of Contributors xixVolume Foreword xxivVolume Preface xxviSeries Preface xxviiiSection I Biological Basis of the Lymphoid Malignancies 11 Fundamental Principles of Lymphomagenesis 3Pierre Sujobert, Philippe Gaulard, and Laurence de Leval2 Identifying Molecular Drivers of Lymphomagenesis 12Jennifer Shingleton and Sandeep S. Dave3 Characterizing the Spectrum of Epigenetic Dysregulation Across Lymphoid Malignancies 25Sean Harrop, Michael Dickinson, Ricky Johnstone, and Henry Miles Prince4 Animal Models of Lymphoid Malignancies 40Anjali MishraSection II Targeting the PI3 Kinase-AKT-mTOR Pathway 535 Principles of PI3K Biology and Its Role in Lymphoma 55Ralitsa R. Madsen6 Pharmacologic Differentiation of Drugs Targeting the PI3K-AKT-mTOR Signaling Pathway 71Inhye E. Ahn, Jennifer R. Brown, and Matthew S. Davids7 Clinical Experience with Phosphatidylinositol 3-Kinase Inhibitors in Hematologic Malignancies 86Alessandro Broccoli and Pier Luigi Zinzani9 PI3 Kinase, AKT, and mTOR Inhibitors 113Joel McCay and John G. GribbenSection III Targeting Programmed Cell Death 13110 Principles for Understanding Mechanisms of Cell Death and Their Role in Cancer Biology 133Sarah T. Diepstraten, John E. La Marca, David C.S. Huang, and Gemma L. Kelly11 Pharmacologic Features of Drugs Targeting BCL2 Family Members 151Jennifer K. Lue and Owen A. O’Connor12 Clinical Experience with Pro-Apoptotic Agents 165Thomas E. Lew and John F. Seymour13 Promising Combinations of Drugs Targeting Apoptosis 186William G. WierdaSection IV Targeting the Cancer Epigenome 19714 The Role of Epigenetic Dysregulation in Lymphoma Biology 199Qing Deng and Michael R. Green15 Quantitating and Characterizing the Effects of Epigenetic Targeted Drugs 209Emily Gruber, Alexander C. Lewis, and Lev M. Kats16 Clinical Experience with Epigenetic Drugs in Lymphoid Malignancies 225Enrica Marchi, Ipsita Pal, and John Sanil Manavalan17 Future Prospects for Targeting the Epigenome in Lymphomas 236Yusuke Isshiki and Ari MelnickSection V Targeting the B-cell Receptor (BCR) 24918 The Pathologic Role of BCR Dysregulation in Lymphoid Malignancies 251Jan A. Burger19 Pharmacologic Features of Drugs Targeting Bruton’s Tyrosine Kinase (BTK) 268Joel McCay and John G. Gribben20 Clinical Experience with Drugs Targeting Bruton’s Tyrosine Kinase (BTK) 278Julia Aronson, Anthony R. Mato, Catherine C. Coombs, Prioty Islam, Lindsey E. Roeker, and Toby Eyre21 Promising Combinations of BTK Inhibitors with Other Targeted Agents 287Nicholas J. Schmidt, Michael E. Williams, and Craig A. PortellSection VI Protein Degraders and Membrane Transport Inhibitors 30122 The Biological Basis for Targeting Protein Turnover in Malignant Cells 303Robert Z. Orlowski23 Preclinical Overview of Drugs Affecting Protein Turnover in Multiple Myeloma 313Giada Bianchi, Matthew Ho, and Kenneth C. Anderson24 Clinical Experience on Proteasome Inhibitors in Cancer 331Noa Biran, Pooja Phull, and Andre Goy25 Targeting Nuclear Protein Transport with XPO Inhibitors in Lymphoma 361Farheen Manji, Kyla Trkulja, Rob C. Laister, and John Kuruvilla26 Heterobifunctional Degraders for the Treatment of Lymphoid Malignancies 372Ashwin Gollerkeri, Jared Gollob, and Nello MainolfiSection VII Novel Targets and Therapeutic Prospects in Development 38127 Strategies for Targeting the JAK-STAT Pathway in Lymphoid Malignancies 383David J. Feith, Johnson Ung, Omar Elghawy, Peibin Yue, James Turkson, and Thomas P. Loughran Jr28 Strategies for Targeting MYC 402Jemma Longley and Andrew Davies29 Targeting NOTCH in Lymphoid Malignancies 411Deborah Piffaretti, Georgia Alice Galimberti, and Davide Rossi30 Targeting NF-κB in Oncology, an Untapped Therapeutic Potential 428Matko Kalac31 Targeting the Cell Cycle and Cyclin-dependent Kinases 444Chiara Tarantelli and Francesco BertoniReferences 452Index 457

Owen A. O’Connor, M.D., Ph.D. is an American Cancer Society Research Professor at the University of Virginia Comprehensive Cancer Center. He completed his training in Internal Medicine at the New York Presbyterian Hospital at Weill Cornell University Medical School, a Fellowship in Hematology and Oncology at Memorial Sloan Kettering Cancer Center and a Fellowship in Clinical Pharmacology at Weill Cornell. He has been recognized as one of the Top Physicians in Cancer in the U.S. and is recognized by the Irish Government as one of the top 50 Irish Americans in Science and Medicine. Stephen M. Ansell, M.D., Ph.D. is the Dorotha W. and Grant L. Sundquist Professor of Hematologic Malignancies Research and the Chair of the Division of Hematology at Mayo Clinic. He received his medical degree from the University of Pretoria, South Africa and then completed a fellowship in Hematology and Medical Oncology at Mayo Clinic. His research focuses on optimizing antitumor immune function in B-cell malignancies. He received the Ernst Beutler Award from the American Society of Hematology in 2021 in recognition of his work. John F. Seymour MBBS Ph.D. heads the Department of Haematology of the Peter MacCallum Cancer Centre & the Royal Melbourne Hospital and is Professor of Medicine at the University of Melbourne. He completed a translational research fellowship at the MD Anderson Cancer Center in Houston, and has received their Distinguished Alumnus award. His work is focused on new drug development in lymphoid malignancies. He was awarded Membership of the Order of Australia, and elected to the Australian Academy of Health and Medical Sciences for his contributions to the field.

• List of Contributors xixVolume Foreword xxivVolume Preface xxviSeries Preface xxviiiSection I Biological Basis of the Lymphoid Malignancies 11 Fundamental Principles of Lymphomagenesis 3Pierre Sujobert, Philippe Gaulard, and Laurence de Leval2 Identifying Molecular Drivers of Lymphomagenesis 12Jennifer Shingleton and Sandeep S. Dave3 Characterizing the Spectrum of Epigenetic Dysregulation Across Lymphoid Malignancies 25Sean Harrop, Michael Dickinson, Ricky Johnstone, and Henry Miles Prince4 Animal Models of Lymphoid Malignancies 40Anjali MishraSection II Targeting the PI3 Kinase-AKT-mTOR Pathway 535 Principles of PI3K Biology and Its Role in Lymphoma 55Ralitsa R. Madsen6 Pharmacologic Differentiation of Drugs Targeting the PI3K-AKT-mTOR Signaling Pathway 71Inhye E. Ahn, Jennifer R. Brown, and Matthew S. Davids7 Clinical Experience with Phosphatidylinositol 3-Kinase Inhibitors in Hematologic Malignancies 86Alessandro Broccoli and Pier Luigi Zinzani9 PI3 Kinase, AKT, and mTOR Inhibitors 113Joel McCay and John G. GribbenSection III Targeting Programmed Cell Death 13110 Principles for Understanding Mechanisms of Cell Death and Their Role in Cancer Biology 133Sarah T. Diepstraten, John E. La Marca, David C.S. Huang, and Gemma L. Kelly11 Pharmacologic Features of Drugs Targeting BCL2 Family Members 151Jennifer K. Lue and Owen A. O’Connor12 Clinical Experience with Pro-Apoptotic Agents 165Thomas E. Lew and John F. Seymour13 Promising Combinations of Drugs Targeting Apoptosis 186William G. WierdaSection IV Targeting the Cancer Epigenome 19714 The Role of Epigenetic Dysregulation in Lymphoma Biology 199Qing Deng and Michael R. Green15 Quantitating and Characterizing the Effects of Epigenetic Targeted Drugs 209Emily Gruber, Alexander C. Lewis, and Lev M. Kats16 Clinical Experience with Epigenetic Drugs in Lymphoid Malignancies 225Enrica Marchi, Ipsita Pal, and John Sanil Manavalan17 Future Prospects for Targeting the Epigenome in Lymphomas 236Yusuke Isshiki and Ari MelnickSection V Targeting the B-cell Receptor (BCR) 24918 The Pathologic Role of BCR Dysregulation in Lymphoid Malignancies 251Jan A. Burger19 Pharmacologic Features of Drugs Targeting Bruton’s Tyrosine Kinase (BTK) 268Joel McCay and John G. Gribben20 Clinical Experience with Drugs Targeting Bruton’s Tyrosine Kinase (BTK) 278Julia Aronson, Anthony R. Mato, Catherine C. Coombs, Prioty Islam, Lindsey E. Roeker, and Toby Eyre21 Promising Combinations of BTK Inhibitors with Other Targeted Agents 287Nicholas J. Schmidt, Michael E. Williams, and Craig A. PortellSection VI Protein Degraders and Membrane Transport Inhibitors 30122 The Biological Basis for Targeting Protein Turnover in Malignant Cells 303Robert Z. Orlowski23 Preclinical Overview of Drugs Affecting Protein Turnover in Multiple Myeloma 313Giada Bianchi, Matthew Ho, and Kenneth C. Anderson24 Clinical Experience on Proteasome Inhibitors in Cancer 331Noa Biran, Pooja Phull, and Andre Goy25 Targeting Nuclear Protein Transport with XPO Inhibitors in Lymphoma 361Farheen Manji, Kyla Trkulja, Rob C. Laister, and John Kuruvilla26 Heterobifunctional Degraders for the Treatment of Lymphoid Malignancies 372Ashwin Gollerkeri, Jared Gollob, and Nello MainolfiSection VII Novel Targets and Therapeutic Prospects in Development 38127 Strategies for Targeting the JAK-STAT Pathway in Lymphoid Malignancies 383David J. Feith, Johnson Ung, Omar Elghawy, Peibin Yue, James Turkson, and Thomas P. Loughran Jr28 Strategies for Targeting MYC 402Jemma Longley and Andrew Davies29 Targeting NOTCH in Lymphoid Malignancies 411Deborah Piffaretti, Georgia Alice Galimberti, and Davide Rossi30 Targeting NF-κB in Oncology, an Untapped Therapeutic Potential 428Matko Kalac31 Targeting the Cell Cycle and Cyclin-dependent Kinases 444Chiara Tarantelli and Francesco BertoniReferences 452Index 457