Diffuse large B-cell lymphoma (DLBCL), the most frequent subtype of lymphoid malignancy, remains a significant clinical challenge, as ∼30% of patients are not cured. Over the past decade, remarkable ...progress has been made in the understanding of the pathogenesis of this disease, spurred by the implementation of powerful genomic technologies that enabled the definition of its genetic and epigenetic landscape. These studies have uncovered a multitude of genomic alterations that contribute to the initiation and maintenance of the tumor clone by disrupting biological functions known to be critical for the normal biology of its cells of origin, germinal center B cells. The identified alterations involve epigenetic remodeling, block of differentiation, escape from immune surveillance, and the constitutive activation of several signal transduction pathways. This wealth of new information offers unique opportunities for the development of improved diagnostic and prognostic tools that could help guide the clinical management of DLBCL patients. Furthermore, a number of the mutated genes identified are potentially actionable targets that are currently being explored for the development of novel therapeutic strategies. This review summarizes current knowledge of the most common genetic alterations associated with DLBCL in relation to their functional impact on the malignant transformation process, and discusses their clinical implications for mechanism-based therapeutics.
Diffuse large B-cell lymphoma (DLBCL), the most common lymphoid malignancy in the western world, is an aggressive disease that remains incurable in approximately 30% of patients. Over the past ...decade, the rapid expansion of sequencing technologies allowing the genome-wide assessment of genomic and transcriptional changes has revolutionized our understanding of the genetic basis of DLBCL by providing a comprehensive and unbiased view of the genes/pathways that are disrupted by genetic alterations in this disease, and may contribute to tumor initiation and expansion. These studies uncovered the existence of several previously unappreciated alterations in key cellular pathways that may also influence treatment outcome. Indeed, a number of newly identified genetic lesions are currently being explored as markers for improved diagnosis and risk stratification, or are entering clinical trials as promising therapeutic targets. This review focuses on recent advances in the genomic characterization of DLBCL and discusses how information gained from these efforts has provided new insights into its biology, uncovering potential targets of prognostic and therapeutic relevance.
In response to T cell-dependent antigens, mature B cells are stimulated to form germinal centers (GCs), the sites of B cell affinity maturation and the cell of origin (COO) of most B cell lymphomas. ...To explore the dynamics of GC B cell development beyond the known dark zone and light zone compartments, we performed single-cell (sc) transcriptomic analysis on human GC B cells and identified multiple functionally linked subpopulations, including the distinct precursors of memory B cells and plasma cells. The gene expression signatures associated with these GC subpopulations were effective in providing a sc-COO for ∼80% of diffuse large B cell lymphomas (DLBCLs) and identified novel prognostic subgroups of DLBCL.
Summary
B cell lymphomas comprise a heterogeneous group of genetically, biologically, and clinically distinct neoplasms that, in most cases, originate from the clonal expansion of B cells in the ...germinal center (GC). In recent years, the advent of novel genomics technologies has revolutionized our understanding of the molecular pathogenesis of lymphoid malignancies as a multistep process that requires the progressive accumulation of multiple genetic and epigenetic alterations. A common theme that emerged from these studies is the ability of lymphoma cells to co‐opt the same biological programs and signal transduction networks that operate during the normal GC reaction, and misuse them for their own survival advantage. This review summarizes recent progress in the understanding of the genetic and epigenetic mechanisms that drive the malignant transformation of GC B cells. These insights provide a conceptual framework for the identification of cellular pathways that may be explored for precision medicine approaches.
Inactivating mutations of the CREBBP and EP300 acetyltransferases are among the most common genetic alterations in diffuse large B cell lymphoma (DLBCL) and follicular lymphoma (FL). Here, we ...examined the relationship between these two enzymes in germinal center (GC) B cells, the normal counterpart of FL and DLBCL, and in lymphomagenesis by using conditional GC-directed deletion mouse models targeting Crebbp or Ep300. We found that CREBBP and EP300 modulate common as well as distinct transcriptional programs implicated in separate anatomic and functional GC compartments. Consistently, deletion of Ep300 but not Crebbp impaired the fitness of GC B cells in vivo. Combined loss of Crebbp and Ep300 completely abrogated GC formation, suggesting that these proteins partially compensate for each other through common transcriptional targets. This synthetic lethal interaction was retained in CREBBP-mutant DLBCL cells and could be pharmacologically targeted with selective small molecule inhibitors of CREBBP and EP300 function. These data provide proof-of-principle for the clinical development of EP300-specific inhibitors in FL and DLBCL.
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•CREBBP and EP300 control distinct as well as shared transcriptional targets in the GC•Deletion of Crebbp and Ep300 in B cells abrogates GC formation, revealing paralog lethality•CREBBP-mutant DLBCL cells are preferentially sensitive to EP300 deletion•EP300-dependency can be pharmacologically targeted by CREBBP and EP300 inhibitors
Loss-of-function mutations of CREBBP and EP300 are frequent and early events in the pathogenesis of FL and DLBCL, the two most common lymphoma subtypes. Meyer et al. uncover distinct as well as compensatory roles for these acetyltransferases in separate compartments of the germinal center and exploit this notion to document an EP300-dependency in CREBBP-deficient lymphoma cells that can be targeted therapeutically.
Diffuse large B-cell lymphoma (DLBCL) is the most common form of human lymphoma. Although a number of structural alterations have been associated with the pathogenesis of this malignancy, the full ...spectrum of genetic lesions that are present in the DLBCL genome, and therefore the identity of dysregulated cellular pathways, remains unknown. By combining next-generation sequencing and copy number analysis, we show that the DLBCL coding genome contains, on average, more than 30 clonally represented gene alterations per case. This analysis also revealed mutations in genes not previously implicated in DLBCL pathogenesis, including those regulating chromatin methylation (MLL2; 24% of samples) and immune recognition by T cells. These results provide initial data on the complexity of the DLBCL coding genome and identify novel dysregulated pathways underlying its pathogenesis.
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Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Dissecting the pathogenesis of classical Hodgkin lymphoma (cHL), a common cancer in young adults, remains challenging because of the rarity of tumor cells in involved tissues (usually <5%). Here, we ...analyzed the coding genome of cHL by microdissecting tumor and normal cells from 34 patient biopsies for a total of ∼50 000 singly isolated lymphoma cells. We uncovered several recurrently mutated genes, namely, STAT6 (32% of cases), GNA13 (24%), XPO1 (18%), and ITPKB (16%), and document the functional role of mutant STAT6 in sustaining tumor cell viability. Mutations of STAT6 genetically and functionally cooperated with disruption of SOCS1, a JAK-STAT pathway inhibitor, to promote cHL growth. Overall, 87% of cases showed dysregulation of the JAK-STAT pathway by genetic alterations in multiple genes (also including STAT3, STAT5B, JAK1, JAK2, and PTPN1), attesting to the pivotal role of this pathway in cHL pathogenesis and highlighting its potential as a new therapeutic target in this disease.
•Identification of genes frequently mutated in cHL, fostering tumor growth in a manner amenable to pharmacological targeting.•Mutated genes include the almost ubiquitous targeting of JAK-STAT pathway members, as well as GNA13, XPO1, and ITPKB.
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We report that diffuse large B cell lymphoma (DLBCL) commonly fails to express cell-surface molecules necessary for the recognition of tumor cells by immune-effector cells. In 29% of cases, mutations ...and deletions inactivate the
β2-Microglobulin gene, thus preventing the cell-surface expression of the HLA class-I (HLA-I) complex that is necessary for recognition by CD8
+ cytotoxic T cells. In 21% of cases, analogous lesions involve the
CD58 gene, which encodes a molecule involved in T and natural killer cell-mediated responses. In addition to gene inactivation, alternative mechanisms lead to aberrant expression of HLA-I and CD58 in >60% of DLBCL. These two events are significantly associated in this disease, suggesting that they are coselected during lymphomagenesis for their combined role in escape from immune-surveillance.
► Disruption of B2M and CD58 by genetic lesions is a frequent event in DLBCL ► Multiple mechanisms lead to combined loss of surface B2M, HLA-I, and CD58 expression ► Evasion of immune surveillance plays a central role in DLBCL pathogenesis
Most B cell lymphomas arise from the oncogenic transformation of B cells that have undergone the germinal center (GC) reaction of the T cell-dependent immune response, where high-affinity memory B ...cells and plasma cells are generated. The high proliferation of GC B cells coupled with occasional errors in the DNA-modifying processes of somatic hypermutation and class switch recombination put the cell at a risk to obtain transforming genetic aberrations, which may activate proto-oncogenes or inactivate tumour suppressor genes. Several subtypes of GC lymphomas harbor genetic mutations leading to constitutive, aberrant activation of the nuclear factor-κB (NF-κB) signaling pathway. In normal B cells, NF-κB has crucial biological roles in development and physiology. GC lymphomas highjack these activities to promote tumour-cell growth and survival. It has become increasingly clear that the separate canonical and non-canonical routes of the NF-κB pathway and the five downstream NF-κB transcription factors have distinct functions in the successive stages of GC B-cell development. These findings may have direct implications for understanding how aberrant NF-κB activation promotes the genesis of various GC lymphomas corresponding to the developmentally distinct GC B-cell subsets. The knowledge arising from these studies may be explored for the development of precision medicine approaches aimed at more effective treatments of the corresponding tumours with specific NF-κB inhibitors, thus reducing systemic toxicity. We here provide an overview on the patterns of genetic NF-κB mutations encountered in the various GC lymphomas and discuss the consequences of aberrant NF-κB activation in those malignancies as related to the biology of NF-κB in their putative normal cellular counterparts.
Inactivating mutations of the CREBBP acetyltransferase are highly frequent in diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL), the two most common germinal center (GC)-derived ...cancers. However, the role of CREBBP inactivation in lymphomagenesis remains unclear. Here, we show that CREBBP regulates enhancer/super-enhancer networks with central roles in GC/post-GC cell fate decisions, including genes involved in signal transduction by the B-cell receptor and CD40 receptor, transcriptional control of GC and plasma cell development, and antigen presentation. Consistently,
-deficient B cells exhibit enhanced response to mitogenic stimuli and perturbed plasma cell differentiation. Although GC-specific loss of
was insufficient to initiate malignant transformation, compound
-haploinsufficient/BCL2-transgenic mice, mimicking the genetics of FL and DLBCL, develop clonal lymphomas recapitulating the features of the human diseases. These findings establish
as a haploinsufficient tumor-suppressor gene in GC B cells and provide insights into the mechanisms by which its loss contributes to lymphomagenesis.
Loss-of-function mutations of
are common and early lesions in FL and DLBCL, suggesting a prominent role in lymphoma initiation. Our studies identify the cellular program by which reduced CREBBP dosage facilitates malignant transformation, and have direct implications for targeted lymphoma therapy based on drugs affecting CREBBP-mediated chromatin acetylation.
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