Impact of a Faulty Germinal Center Reaction on the Pathogenesis of Primary Diffuse Large B Cell Lymphoma of the Central Nervous System

Abstract

Primary lymphoma of the central nervous system (PCNSL, CNS) is a specific diffuse large B cell lymphoma (DLBCL) entity confined to the CNS. Key to its pathogenesis is a failure of B cell differentiation and a lack of appropriate control at differentiation stages before entrance and within the germinal center (GC). Self-/polyreactive B cells rescued from apoptosis by MYD88 and/or CD79B mutations accumulate a high load of somatic mutations in their rearranged immunoglobulin (IG) genes, with ongoing somatic hypermutation (SHM). Furthermore, the targeting of oncogenes by aberrant SHM (e.g., PIM1, PAX5, RHOH, MYC, BTG2, KLHL14, SUSD2), translocations of the IG and BCL6 genes, and genomic instability (e.g., gains of 18q21; losses of 9p21, 8q12, 6q21) occur in these cells in the course of their malignant transformation. Activated Toll-like receptor, B cell receptor (BCR), and NF-κB signaling pathways foster lymphoma cell proliferation. Hence, tumor cells are arrested in a late B cell differentiation stage, corresponding to late GC exit B cells, which are genetically related to IgM+ memory cells. Paradoxically, the GC reaction increases self-/polyreactivity, yielding increased tumor BCR reactivity for multiple CNS proteins, which likely contributes to CNS tropism of the lymphoma. The loss of MHC class I antigen expression supports tumor cell immune escape. Thus, specific and unique interactions of the tumor cells with resident CNS cells determine the hallmarks of PCNSL.

Two cases of primary diffuse large B-cell lymphoma of the CNS associated with t(8;14)(q24;q32) or t(3;14)(q27;q32) identified by G-banding and fluorescence <i>in situ</i> hybridization applied to metaphase spreads

“…BCL6 rearrangements have been observed in 17 to 38% of PCNS-DLBCL cases by FISH using the BCL6 BA probe applied to tissue sections or single cells, 2,6,10,11,[16][17][18][19] and associated with worse progression-free and overall survivals of PCNS-DLBCL patients, 10,18 potentially accounting for the poor treatment outcome in case 2. The gene is rearranged with not only IG genes but also a variety of non-IG genes, resulting from translocations with other chromosomal loci or deletions of upstream sequences, and juxtaposed to the regulatory sequences of each partner gene.…”

“…Lymphoma cells were aseptically prepared from the excised specimens and incubated overnight in RPMI 1640 medium supplemented with 15% heat-inactivated fetal bovine serum at 37°C under a CO 2 concentration of 5%. The cells were then cultured in the presence of 0.1 μg/mL colcemid for 2 hr.…”

“…Two cases of primary diffuse large B-cell lymphoma of the CNS associated with t(8;14)(q24;q32) or t(3;14)(q27;q32) identified by G-banding and fluorescence in situ hybridization applied to metaphase spreads Hitoshi Ohno, 1,2) Fumiyo Maekawa, 1) Misumi Nakagawa, 1) Yoshinari Chagi, 1) Miho Nakagawa, 1) Chiyuki Kishimori, 1) Katsuhiro Fukutsuka, 1) Masahiko Hayashida, 1) Kayo Takeoka, 1) Wataru Maruyama, 2) Naoya Ukyo, 2) Shinji Sumiyoshi 3) We describe two patients with primary diffuse large B-cell lymphoma of the central nervous system (PCNS-DLBCL). The first patient (case 1) was a woman in her late 70s who presented with a tumor in the left frontal lobe, whereas the second patient (case 2) was a man in his early 70s who presented with a left frontal lobe tumor associated with intratumoral hemorrhage.…”

“…Because the vast majority of malignant lymphomas that primarily develop in the central nervous system (CNS) exhibit features of diffuse large B-cell lymphoma (DLBCL), the WHO 2017 Classification of Tumours of Haematopoietic and Lymphoid Tissues listed primary DLBCL of CNS (PCNS-DLBCL) as a distinctive category. 1 , 2 Tumor cells tend to infiltrate along the perivascular space within the brain, and dissemination to extra-CNS sites is very rare. 1 Treatment consists of high-dose methotrexate-based chemotherapy with or without whole-brain radiotherapy (WBRT), and only in Japan, a novel Bruton’s tyrosine kinase inhibitor, tirabrutinib, has been approved for relapsed/refractory cases.…”

Effect of glaucocalyxin B on the protein expressions of PTEN, Beclin1 and LC3 in a mouse model of transplanted cervical cancer, and its significance

“…Therefore, it is important to identify more efficient and low-toxicity antitumor drugs for treatment of cervical cancer. Glaucocalyxin B (GLB) is extracted from cymbidium blue, and it exerts anti-inflammatory, antioxidant and anti-tumor effects [9]. A study has demonstrated that GLB inhibited the proliferation and apoptosis of tongue squamous cell carcinoma cells, possibly via inhibition of the activation of NF-κB signaling pathway [10].…”