Over-expression of BACH2 is related to ongoing somatic hypermutation of the immunoglobulin heavy chain gene variable region of de novo diffuse large B-cell lymphoma.

The basic region-leucine zipper (bZip) factor BTB, CNC homology 2 (BACH2) is known to have important roles in class switch recombination and somatic hypermutation (SHM) of the immunoglobulin (Ig) gene. In this study, we investigated the relationship between the expression of BACH2 and the status of SHM of the Ig heavy chain gene variable region (IgHV) for SHM in diffuse large B-cell lymphoma (DLBCL). We examined 20 cases of DLBCL, 13 of which were germinal center B-cell (GCB) DLBCL and 7 were non-GCB DLBCL. Seven cases were negative, 6 were positive (cytoplasmic expression) and 7 were strongly positive (both nuclear and cytoplasmic expression) for BACH2. Confirmed mutation (CM) was identified in 8 cases and the CM index (number of confirmed mutations per 10 subclones) was distributed from 0 to 5. A CM index of 7 strongly positive (over-expression) cases with BACH2 were distributed from 0 to 5, and that of 7 negative and 6 positive cases were distributed from 0 to 1. Over-expression of BACH2 was statistically related to CM index (P = 0.008). In conclusion, over-expression of BACH2 is critical for ongoing SHM of IgHV in DLBCL, and our data suggest that BACH2 may play an essential role for SHM of the Ig gene in B-cell lymphoma.

Kikuchi T ，Tokunaka M ，Kikuti YY ，Carreras J ，Ogura G ，Takekoshi S ，Kojima M ，Ando K ，Hashimoto Y ，Abe M ，Takata K ，Yoshino T ，Muto A ，Igarashi K ，Nakamura N ... -  《-》

Molecular characterization of immunoglobulin gene rearrangements in diffuse large B-cell lymphoma: antigen-driven origin and IGHV4-34 as a particular subgroup of the non-GCB subtype.

The pathogenesis of diffuse large B-cell lymphoma (DLBCL) remains partially unknown. The analysis of the B-cell receptor of the malignant cells could contribute to a better understanding of the DLBCL biology. We studied the molecular features of the immunoglobulin heavy chain (IGH) rearrangements in 165 patients diagnosed with DLBCL not otherwise specified. Clonal IGH rearrangements were amplified according to the BIOMED-2 protocol and PCR products were sequenced directly. We also analyzed the criteria for stereotyped patterns in all complete IGHV-IGHD-IGHJ (V-D-J) sequences. Complete V-D-J rearrangements were identified in 130 of 165 patients. Most cases (89%) were highly mutated, but 12 sequences were truly unmutated or minimally mutated. Three genes, IGHV4-34, IGHV3-23, and IGHV4-39, accounted for one third of the whole cohort, including an overrepresentation of IGHV4-34 (15.5% overall). Interestingly, all IGHV4-34 rearrangements and all unmutated sequences belonged to the nongerminal center B-cell-like (non-GCB) subtype. Overall, we found three cases following the current criteria for stereotyped heavy chain VH CDR3 sequences, two of them belonging to subsets previously described in CLL. IGHV gene repertoire is remarkably biased, implying an antigen-driven origin in DLBCL. The particular features in the sequence of the immunoglobulins suggest the existence of particular subgroups within the non-GCB subtype.

Sebastián E ，Alcoceba M ，Balanzategui A ，Marín L ，Montes-Moreno S ，Flores T ，González D ，Sarasquete ME ，Chillón MC ，Puig N ，Corral R ，Pardal E ，Martín A ，González-Barca E ，Caballero MD ，San Miguel JF ，García-Sanz R ，González M ... -  《-》

Analysis of the immunoglobulin heavy chain gene variable region of CD5-positive diffuse large B-cell lymphoma.

Nakamura N ，Hashimoto Y ，Kuze T ，Tasaki K ，Sasaki Y ，Sato M ，Abe M ... -  《LABORATORY INVESTIGATION》

Immunoglobulin somatic hypermutation has clinical impact in DLBCL and potential implications for immune checkpoint blockade and neoantigen-based immunotherapies.

Xu-Monette ZY ，Li J ，Xia Y ，Crossley B ，Bremel RD ，Miao Y ，Xiao M ，Snyder T ，Manyam GC ，Tan X ，Zhang H ，Visco C ，Tzankov A ，Dybkaer K ，Bhagat G ，Tam W ，You H ，Hsi ED ，van Krieken JH ，Huh J ，Ponzoni M ，Ferreri AJM ，Møller MB ，Piris MA ，Winter JN ，Medeiros JT ，Xu B ，Li Y ，Kirsch I ，Young KH ... -  《Journal for ImmunoTherapy of Cancer》

AID is expressed in germinal center B-cell-like and activated B-cell-like diffuse large-cell lymphomas and is not correlated with intraclonal heterogeneity.

Lossos IS ，Levy R ，Alizadeh AA 《-》