Non-Hodgkin Lymphomas: Malignancies Arising from Mature B Cells

Abstract

Non-Hodgkin lymphomas (NHLs) are a diverse group of entities, both clinically and molecularly. Here, we review the evolution of classification schemes in B-cell lymphoma, noting the now standard WHO classification system that is based on immune cell-of-origin and molecular phenotypes. We review how lymphomas arise throughout the B-cell development process as well as the molecular and clinical features of prominent B-cell lymphomas. We provide an overview of the major progress that has occurred over the past decade in terms of our molecular understanding of these diseases. We discuss treatment options available and focus on a number of the diverse research tools that have been employed to improve our understanding of these diseases. We discuss the problem of heterogeneity in lymphomas and anticipate that the near future will bring significant advances that provide a measurable impact on NHL outcomes.

Figure 1.

B-cell development. Progenitor B cells undergo V(D)J recombination in the bone marrow before exiting at the immature B-cell stage. Upon antigen stimulation, mature B cells undergo somatic hypermutation (SHM) and class-switch recombination (CSR) in the germinal center before undergoing terminal differentiation into plasma or memory B cells. Examples of lymphomas that can arise at each B-cell stage are noted. HSC, hematopoietic stem cell; CLL, chronic lymphocytic leukemia; MCL, mantle cell lymphoma; GCB-DLBCL, germinal center B-cell diffuse large B-cell lymphoma; BL, Burkitt lymphoma; FL, follicular lymphoma; PCFCL, primary cutaneous follicle center lymphoma; PCLBCL, primary cutaneous large B-cell lymphoma; NMZL, nodal marginal zone lymphoma; SMZL, splenic marginal zone lymphoma; MALT, mucosa-associated lymphoid tissue; PCMZL, primary cutaneous marginal zone lymphoma; HCL, hairy cell leukemia; ABC-DLBCL, activated B-cell like DLBCL; LPL, lymphoplasmacytic lymphoma.

Figure 2.

Incidence of B-cell non-Hodgkin lymphomas. NOS, Not otherwise specified; WM, Waldenström's macroglobulinemia.

Figure 3.

Targetable signaling pathways in non-Hodgkin lymphoma. Targetable nodes with clinically available small molecule inhibitors are ringed in red. BCR, B-cell receptor; SYK, spleen tyrosine kinase; BTK, Bruton's tyrosine kinase; PI3Kδ, phosphoinositide 3-kinases delta; NICD, Notch intracellular domain; JAK, Janus kinase; IKK, IκB kinase; HDAC, histone deacetylase.

Figure 4.

Lymphoma models. Cell culture, patient-derived xenograft (PDX), and transgenic mouse models are used to model lymphomas in the research and clinical settings.