Genetics of diffuse large B-cell lymphoma.

Diffuse large B-cell lymphoma (DLBCL) represents a grouping of clinically and biologically heterogeneous tumors Application of advanced molecular technology has significantly expanded our knowledge of DLBCL pathobiology, allowing identification of subgroups with common, potentially targetable, biological themes Here, we review the recent molecular analyses that could provide a paradigm shift to a new taxonomy, foundational to the rational transition to precision medicine We discuss how classification systems may be synthesized into a common taxonomy, drawing strength from the relationships between genetic alterations, gene expression, and tumor microenvironment Finally, challenges to translating such a taxonomy to the clinic will be outlined

/pdf/toward-a-new-molecular-taxonomy-of-diffuse-large-b-cell-lmnhkkenpg.pdf

Toward a New Molecular Taxonomy of Diffuse Large B-cell Lymphoma.

Primary lymphomas of the central nervous system (PCNSL) are mainly diffuse large B-cell lymphomas (DLBCLs) confined to the central nervous system (CNS). Molecular drivers of PCNSL have not been fully elucidated. Here, we profile and compare the whole-genome and transcriptome landscape of 51 CNS lymphomas (CNSL) to 39 follicular lymphoma and 36 DLBCL cases outside the CNS. We find recurrent mutations in JAK-STAT, NFkB, and B-cell receptor signaling pathways, including hallmark mutations in MYD88 L265P (67%) and CD79B (63%), and CDKN2A deletions (83%). PCNSLs exhibit significantly more focal deletions of HLA-D (6p21) locus as a potential mechanism of immune evasion. Mutational signatures correlating with DNA replication and mitosis are significantly enriched in PCNSL. TERT gene expression is significantly higher in PCNSL compared to activated B-cell (ABC)-DLBCL. Transcriptome analysis clearly distinguishes PCNSL and systemic DLBCL into distinct molecular subtypes. Epstein-Barr virus (EBV)+ CNSL cases lack recurrent mutational hotspots apart from IG and HLA-DRB loci. We show that PCNSL can be clearly distinguished from DLBCL, having distinct expression profiles, IG expression and translocation patterns, as well as specific combinations of genetic alterations. 

/pdf/the-genomic-and-transcriptional-landscape-of-primary-central-2y1o866p.pdf

The genomic and transcriptional landscape of primary central nervous system lymphoma

More than 50 subtypes of B-cell non-Hodgkin lymphoma (B-NHL) are recognized in the most recent World Health Organization classification of 2016. The current treatment paradigm, however, is largely based on 'one-size-fits-all' immune-chemotherapy. Unfortunately, this therapeutic strategy is inadequate for a significant number of patients. As such, there is an indisputable need for novel, preferably targeted, therapies based on a biologically driven classification and risk stratification. Sequencing studies identified mutations in the MYD88 gene as an important oncogenic driver in B-cell lymphomas. MYD88 mutations constitutively activate NF-κB and its associated signaling pathways, thereby promoting B-cell proliferation and survival. High frequencies of the hotspot MYD88(L265P) mutation are observed in extranodal diffuse large B-cell lymphoma and Waldenstrom macroglobulinemia, thereby demonstrating this mutation's potential as a disease marker. In addition, the presence of mutant MYD88 predicts survival outcome in B-NHL subtypes and it provides a therapeutic target. Early clinical trials targeting MYD88 have shown encouraging results in relapsed/refractory B-NHL. Patients with these disorders can benefit from analysis for the MYD88 hotspot mutation in liquid biopsies, as a minimally invasive method to demonstrate treatment response or resistance. Given these clear clinical implications and the crucial role of MYD88 in lymphomagenesis, we expect that analysis of this gene will increasingly be used in routine clinical practice, not only as a diagnostic classifier, but also as a prognostic and therapeutic biomarker directing precision medicine. This review focuses on the pivotal mechanistic role of mutated MYD88 and its clinical implications in B-NHL.

/pdf/myd88-in-the-driver-s-seat-of-b-cell-lymphomagenesis-from-4ecz5yn57x.pdf

MYD88 in the driver's seat of B-cell lymphomagenesis: from molecular mechanisms to clinical implications.

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.

Molecular pathogenesis of germinal center-derived B cell lymphomas.

CD79B and MYD88 mutations are frequently and simultaneously detected in B cell malignancies. It is not known if these mutations cooperate or how crosstalk occurs. Here we analyze the consequences of CD79B and MYD88L265P mutations individually and combined in normal activated mouse B lymphocytes. CD79B mutations alone increased surface IgM but did not enhance B cell survival, proliferation, or altered NF-κB responsive markers. Conversely, B cells expressing MYD88L265P decreased surface IgM coupled with accumulation of endoglycosidase H-sensitive IgM intracellularly, resembling the trafficking block in anergic B cells repeatedly stimulated by self-antigen. Mutation or overexpression of CD79B counteracted the effect of MYD88L265P In B cells chronically stimulated by self-antigen, CD79B and MYD88L265P mutations in combination, but not individually, blocked peripheral deletion and triggered differentiation into autoantibody secreting plasmablasts. These results reveal that CD79B and surface IgM constitute a rate-limiting checkpoint against B cell dysregulation by MYD88L265P and provide an explanation for the co-occurrence of MYD88 and CD79B mutations in lymphomas.

/pdf/synergistic-cooperation-and-crosstalk-between-myd88-l265p-4pqx09zzuk.pdf

Synergistic cooperation and crosstalk between MYD88 L265P and mutations that dysregulate CD79B and surface IgM.

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Synergistic cooperation and crosstalk between MYD88 L265P and mutations that dysregulate CD79B and surface IgM.