Session Descriptions for the ASH Meeting on Lymphoma Biology
The following sessions will take place at the 2020 ASH Meeting on Lymphoma Biology.
Germinal Center Biology
Bertrand Nadel, PhD
Klaus Rajewsky, MD
Most adult B cell lymphomas originate from germinal-center (GC) B cells. GCs are specialized micro-anatomical structures involved in T-dependent B-cell responses, in which antigen-activated B cells proliferate and mutate their B-cell antigen receptor. The ultimate function of GCs is to select and produce high-affinity antibody-secreting plasma cells and memory B cells. B cells expanding in GCs are at increased risk of acquiring oncogenic genomic lesions, through the derailment of a very specific (epi)genetic program combining intense proliferation, somatic DNA rearrangement, and mutagenesis.
Dr. Klaus Rajewsky will discuss how anti-apoptotic mechanisms in MYC-driven B-cells lymphomas play a crucial role in the control of the competitive fitness of the transformed cells in the germinal centers. He will present examples of this principle and discuss their therapeutic implications.
Dr. Dinis Calado will discuss processes of differentiation of GC B cells and lymphomagenesis. In the germinal center, reaction B cells undergo affinity maturation and differentiation into plasma cells and memory B cells, which are key for long-term protection from infection. In GCs, B cells cyclically migrate between a dark-zone area, where somatic hypermutation occurs, and a light-zone area, in which B cells are considered to be selected based on their B-cell receptor affinity for antigen and subsequent T-cell help. He will discuss insights on the processes of selection and differentiation in the light zone and how these could translate to an understanding of lymphomagenesis.
Dr. Jagan Muppidi will discuss signaling pathways mediating cell death in GC B cells. He will discuss how these cell-death pathways contribute to germinal-center homeostasis and support selection of B cells within the germinal center. Finally, he will discuss how evasion of these pathways contributes to the development of germinal center–derived malignancies.
Novel Genetic and Epigenetic Mechanisms in Lymphomagenesis
Dan A. Landau, MD
Ari Melnick, MD
Epigenetic modifications are a central hallmark of lymphoma biology. Indeed, lymphomas show frequent genetic mutations to epigenetic modifiers as central drivers of this disease.
Dr. Ari Melnick’s laboratory has led the discovery of how mutations in CREBBP, KMT2D, EZH2, and TET2 drive lymphomagenesis and serve as potential therapeutic targets. Dr. Melnick will review emerging discoveries that explain how these mutations reprogram the immune system to set the stage for malignant transformation of B cells and discuss novel findings that go beyond epigenetics to explain how mutations that affect the topology of the genome can lead to lymphomagenesis.
Dr. Hans-Guido Wendel will report on a systematic interrogation of the genetic targets of the chromosome 12 amplicon, which is seen in about 30% of follicular and diffuse large B-cell lymphomas. Serine hydroxylmethyltransferase-2 (SHMT2) emerged as a surprising oncogenic driver that acts, at least in large part, through an epigenetic mechanism, emphasizing the link between metabolic disruption and epigenetic patterning.
Dr. Jude Fitzgibbon will discuss the efforts of targeting KMT2D mutations in follicular lymphomas. These mutations are present in an overwhelming proportion of follicular lymphomas as well as diffuse large B-cell lymphomas. To target these loss-of-function events, the Fitzgibbon lab has developed the inhibition of KDM5, an epigenetic actuator that normally opposes KMT2D in regulating histone methylation.
Dr. Dan Landau will discuss the role of epigenetic diversification in the evolution of chronic lymphocytic leukemia (CLL). He will provide an overview on the concept of stochastic epigenetic variation as drivers of CLL diversity, from DNA methylation changes to histone modifications, charted at both the bulk and single-cell level, leveraging unique multi-omics technology. Finally, Dr. Landau will discuss a novel analytic framework to define epidrivers of disease progression and relapse that identifies unique methylation changes that are validated to increase cellular fitness and are closely associated with adverse outcome.
Disrupted Signaling Pathways and Microenvironment in Lymphoma
Christian Steidl, MD
Margot Thome-Miazza, PhD
It is a hallmark of lymphomas that particular signaling pathways, which are normally only transiently activated or inhibited in lymphocytes, are deregulated and often constitutively activated or silenced in malignant B cells. This can be caused by genetic and epigenetic mechanisms but also through interactions with other cells in the microenvironment. Indeed, microenvironmental interactions of various kinds play a major role in lymphoma biology.
Dr. Margot Thome will discuss the role of the CBM signaling complex in the pathogenesis of B-cell malignancy and natural B-cell function. Somatic mutations in the CBM component CARD11/CARMA1 and its upstream regulators, such as CD79, have been identified as recurrent genetic alterations in diffuse large B-cell lymphoma of the activated B-cell subtype and a variety of other B- and T-cell malignancies. Dr. Thome will describe the molecular mechanisms by which constitutive CBM activity promotes activation of the protease MALT1 and how MALT1-dependent cleavage of cellular substrates promotes lymphomagenesis.
Dr. Karin Tarte will discuss the functional heterogeneity of follicular lymphoma (FL) cell niches. FL is the paradigm of a tumor in which malignant cells are dependent on a dynamic crosstalk with a complex surrounding microenvironment, and FL genetic alterations were recently demonstrated to directly affect the heterogeneity and commitment of the pro-tumoral niche. Dr Tarte will discuss the mechanisms by which the main cell components of FL microenvironment support directly and indirectly neoplastic growth and will discuss recent data on how the understanding of FL-niche specific differentiation pathways could be translated to therapeutic applications.
Dr. Margaret Shipp will discuss emerging data regarding genetically defined subtypes of diffuse large B-cell lymphoma with distinct deregulated signaling and survival pathways and associated therapeutic vulnerabilities. She will also describe the shared and unique genetic features of recognized large B-cell lymphoma subtypes and potential approaches to treatment.
Dr. Martina Seiffert will discuss novel insights into the role of the tumor microenvironment in CLL. Interactions between malignant B cells and their surrounding cells and factors in the lymphoid niche are known to be essential for survival and proliferation of CLL cells. This crosstalk is also the basis for an immunosuppressive milieu with myeloid-derived suppressor cells and exhausted effector T cells contributing to immune escape in CLL. Dr. Seiffert will present novel molecular mechanisms of immune escape and T-cell exhaustion in CLL and discuss their potential in innovative immunotherapy approaches.
Understanding Mechanisms of Sensitivity and Resistance to Novel Therapies in Lymphoma
Ari Melnick, MD
Ash A. Alizadeh, MD, PhD
In recent years there has been a proliferation of new targeted therapies with potential relevance to the treatment of B-cell lymphomas. This affords the opportunity to provide patients with more precise and impactful therapies with reduced reliance on toxic chemotherapy drugs. However, there is the danger of missing the mark when these drugs are tested in clinical trials if the following factors are not taken into consideration: the genetic and biological features of individual lymphomas; the populations of patients who are most likely to respond to a given therapeutic approach; or the ways in which resistance might develop to these compounds.
Dr. Ash Alizadeh will discuss the application of ctDNA for detection and monitoring of diverse B-cell lymphomas, including during therapy with novel agents such as CAR T cells. He will also address the use of this technology for classification of lymphomas, which include cell of origin as well as the use of newly proposed classification schemes. Dr. Alizadeh will also discuss how novel features of lymphomas – including epigenetic features informative for cellular derivation and circulating viromes derived from cell-free DNA studies – could be translated into targeted therapeutic intervention for these diseases.
Dr. Louis Staudt will discuss the development of improved classification schemes based on genomic studies and how these may predict the success of targeted therapy regimens, with a special focus on chronic active B-cell receptor signaling in lymphoma. Dr. Staudt will explain how multiple independent survival pathways cooperate to sustain the viability of lymphoma cells, prompting the development of combination regimens that target several survival pathways simultaneously, which are showing great promise in early-phase clinical trials.
Dr. Anas Younes will discuss the development of novel agents for the treatment of lymphoma, focusing on new targets. Mechanism-based and biomarker selection clinical trials, including combination strategies to intercept oncogenic cooperation, will be discussed. He will place these studies in the context of new and emerging molecular classification schemes.
Wing “John” C. Chan, MD
Seishi Ogawa, MD, PhD
Kojo S. J. Elenitoba-Johnson, MD
Peripheral T-cell lymphoma (PTCL) consists of a highly heterogeneous group of diseases that constitute approximately 10-15% of all non-Hodgkin lymphomas (NHLs). The understanding of the pathogenesis of this group of disorders is far behind B-cell NHL, and the prognosis of PTCL is also generally poorer. With the publication of a number of key genomic studies in the past decade, there is increasing understanding of the pathogenesis and biology of PTCL, which could be translated to novel treatment approaches to improve the outcome of these patients.
Dr. Seishi Ogawa will present the molecular genetics of peripheral T-cell lymphomas. While different subtypes of PTCL have distinctive profiles of genetic abnormalities, there are some common themes. Dr. Ogawa will provide an overview of important genetic drivers in PTCL with special emphasis on certain key lesions with broad biological implications.
Dr. Teresa Palomero will speak on the role and mechanisms of VAV1 translocations in PTCL. She will discuss the role of genomic alterations affecting the VAV1 oncogene in the pathogenesis of PTCL. Genomic alterations, including gene fusions and in-frame deletions, affect almost 10% of the patients with angioimmunoblastic T-cell lymphoma (AITL) and PTCL not otherwise specified. Dr. Palomero will describe the molecular mechanisms by which genomic aberrations leading to increased activity of VAV1 affect T-cell differentiation and lead to malignant transformation in PTCL and how mouse models can improve our understanding of the process of transformation.
Dr. Kojo S.J. Elenitoba-Johnson will speak on novel insights in the role of ubiquitin ligases in T-cell function and neoplasia. Proper regulation of protein stability is increasingly being recognized to play a significant role in the control of immune processes. Autoimmune disorders and abnormal lymphoid proliferations are moreover representing a significant cause of morbidity in the Western hemisphere. The biologic events underlying these disorders are not completely understood. He has investigated new roles for E3 ubiquitin ligases in the regulation of T-cell function and in the pathogenesis of atypical T-cell proliferations. In this presentation, he will describe in vitro and in vivo studies that support a prominent role for deregulated ubiquitination in the pathogenesis of atypical T-cell proliferations with implications for T-cell neoplasia.
Germinal Center B-cell–Derived Lymphomas
Laura Pasqualucci, MD
Sandrine Roulland, PhD
The majority of B-cell lymphomas arise from the neoplastic transformation of B cells at different stages of germinal-center B-cell differentiation. This session will focus on recent advances in the genetics and biology of this group of lymphoid malignancies. In particular, the session will highlight novel observations related to the evolutionary history of follicular lymphoma (FL) and the mechanisms by which genetic alterations can influence the immune microenvironment. These discussions are poised to offer new perspectives on the pathogenesis of these tumors and to form the basis for the development of more effective targeted treatments.
Dr. Sandrine Roulland will discuss the natural history of FL progression and describe the mutational landscape of the FL common precursor cell (CPC) in pre-diagnostic blood from healthy individuals, years before disease onset. She will present novel insights leveraging single-cell transcriptomics to describe how early FL mutations progressively build up lymphomagenesis through perturbation of the B-cell differentiation dynamics in a mouse model phenocopying various stages of FL progression. Finally, Dr. Roulland will explore how early loss of epigenetic modifiers during lymphomagenesis influences B-cell behaviors but also affects the crosstalk between the FL CPC/tumor cells and their microenvironment.
Dr. Reiner Siebert will present data on multi-omics sequence-based analyses of different types of Burkitt lymphomas and related diseases, as compared with other germinal center–derived B-cell lymphomas. The mechanisms leading to MYC deregulation will be discussed, as well as the landscape of genetic and epigenetic changes in this group of neoplasms. Examples of dysregulated key cellular pathways will also be presented.
Dr. Christian Steidl will review the genomic landscape of primary mediastinal large B-cell lymphoma (PMBCL) and classical Hodgkin lymphoma (HL) with a specific focus on alterations that shape the crosstalk of the malignant cells with their tumor microenvironment. He will discuss discoveries obtained by using next-generation sequencing and tissue imaging technologies that have the potential to translate into novel biomarkers and therapeutic approaches.
Chronic Lymphocytic Leukemia and other Small B-cell Neoplasms
Elias Campo, MD, PhD
Davide Rossi, MD, PhD
Small B-cell neoplasms encompass several entities arising from different stages of the B-cell differentiation process with very heterogeneous clinical presentation, biological evolution, and response to therapies. The recent large-scale genomic and epigenomic analyses, integrated with biological and clinical studies of these entities, are providing novel insights into the mechanisms that generate this diversity with implications in the clinical practice.
Dr. Davide Rossi will discuss novel findings from the genomic analysis of splenic marginal zone lymphoma that clarify the heterogeneous evolution of this disease, emphasizing the role of the common NOTCH2 and KLF2 mutations that favor the growth of tumor cells and their overall role in the biology of this lymphoma. Dr Rossi will also emphasize the translation of these novel observations into the clinical practice.
Dr. Catherine Wu will address recent integrative analyses of genetic and clinical information and studies on the tumor growth dynamics that provide a conceptual framework to understand the vast variation in the clinical evolution of small B-cell neoplasms. These results provide a conceptual and quantitative framework of cancer growth based on the direct observation on primary patient samples.
Dr. Iñaki Martin-Subero will present a comprehensive perspective of the epigenome modifications in chronic lymphocytic leukemia and mantle cell lymphoma departing from the configuration of the epigenome in normal B-cells. This perspective provides a novel view of the heterogeneity of these neoplasms, describing novel epigenetic subtypes related to different cells of origin that have relevant clinical and biological implications. These studies also illuminate novel mechanisms involved in the transformation and progression of the tumors.
Immunotherapies of Lymphomas
Margaret A. Shipp, MD
Stephen M. Ansell, MD, PhD
Lymphoid malignancies represent promising targets from immunotherapeutic approaches dependent upon the activity of T-cells, innate immune cells, and an optimal cytokine microenvironment and antigen recognition.
Dr. Stephen Ansell will discuss the role of immune checkpoints in lymphoma beyond PD-1 and its ligands. He will address the relevance of TIM-3, LAG3, and TIGIT in T-cell suppression and exhaustion. He will also discuss the role of innate immune checkpoints and how this information is being translated into clinical practice.
Dr. Catherine Bollard will discuss the different cell-based strategies to overcome TGF–mediated immune evasion in lymphomas and other human cancers. She will describe the use of antigen-specific T cells targeting viral and non-viral tumor-associated antigens expressed by lymphomas and how these T cells can be rendered resistant to TGF using a dominant-negative TGF receptor II (TGFRII). Finally, Dr. Bollard will discuss how NK cells can be engineered to be resistant to TGF in the tumor microenvironment.
Dr. Ranjana Advani will discuss a novel target, CD47, an antiphagocytic “don’t eat me" signal that is overexpressed in lymphoid malignancies. She will describe the results of clinical trials in relapsed/refractory lymphoma using anti CD47 antibodies, which induce phagocytosis of tumor cells by blocking the interaction of CD47 with its receptor, signal regulatory protein α(SIRP-α).
Dr. Ronald Levy will review recent progress in the use of in situ vaccination for the treatment of lymphoma, including single-cell sequencing of serial biopsy samples as a way of monitoring the local and global effects of this therapy.