PREVALENCE OF MYD88 L265P MUTATION IN HISTOLOGICALLY PROVEN, DIFFUSE LARGE B-CELL VITREORETINAL LYMPHOMA

Abstract Background: Recently, copy number alteration (CNA) of 9p24.1 were demonstrated in 10% of diffuse large b-cell lymphoma (DLBCL), with gene expression and mutation profiles that were similar to those of primary mediastinal large B-cell lymphoma(PMBCL). However, their CNA-based profile and clinical impact still remain unclear. Methods: Multiplex ligation-dependent probe amplification were employed to investigate the prevalence of JAK2/PD-L2 amplification in DLBCL and their CNA-based pattern of driver genes. The clinical outcome and characteristics were also analyzed. Results: Using unsupervised hierarchical clustering, a small group of DLBCL (10.5%, 8/76) was clustered together with PMBCL as Cluster_2, demonstrating amplification of JAK2 (100%,8/8) and PD-L2 (75.0%,6/8). This subgroups of DLBCL demonstrated significant higher expression of PD-L1 than those with MYD88 L265P mutation(p=0.024). And they exhibited dismal OS and PFS as compared with DLBCL_others(p=0.003 and 0.001, respectively), which is similar to DLBCL with MYD88 L265P mutation. Conclusions: DLBCL with amplification of JAK2/PD-L2 exhibits CNA pattern that is similar to PMBCL, and demonstrates unfavorable clinical outcome that resembles those with MYD88 L265P mutation. It is essential to identify this subgroup of DLBCL who may acquire more benefits from the JAK2 and PD-L1 signaling inhibition.

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Primary vitreoretinal lymphomas display a remarkably restricted immunoglobulin gene repertoire

Blood Advances ◽

10.1182/bloodadvances.2019000980 ◽

2020 ◽

Vol 4 (7) ◽

pp. 1357-1366

Author(s):

Nabila Belhouachi ◽

Aliki Xochelli ◽

Myriam Boudjoghra ◽

Claude Lesty ◽

Nathalie Cassoux ◽

...

Keyword(s):

B Cell ◽

Central Nervous System Lymphoma ◽

B Cell Lymphoma ◽

Gene Repertoire ◽

Immunoglobulin Gene ◽

Heavy Chains ◽

Vitreoretinal Lymphoma ◽

Myd88 L265p Mutation ◽

Myd88 L265p ◽

Antigen Selection

Abstract Primary vitreoretinal lymphoma (PVRL) is a high-grade lymphoma affecting the vitreous and/or the retina. The vast majority of cases are histopathologically classified as diffuse large B-cell lymphoma (DLBCL) and considered a subtype of primary central nervous system lymphoma (PCNSL). To obtain more insight into the ontogenetic relationship between PVRL and PCNSL, we adopted an immunogenetic perspective and explored the respective immunoglobulin gene repertoire profiles from 55 PVRL cases and 48 PCNSL cases. In addition, considering that both entities are predominantly related to activated B-cell (ABC) DLBCL, we compared their repertoire with that of publicly available 262 immunoglobulin heavy variable domain gene rearrangement sequences from systemic ABC-type DLBCLs. PVRL displayed a strikingly biased repertoire, with the IGHV4-34 gene being used in 63.6% of cases, which was significantly higher than in PCNSL (34.7%) or in DLBCL (30.2%). Further repertoire bias was evident by (1) restricted associations of IGHV4-34 expressing heavy chains, with κ light chains utilizing the IGKV3-20/IGKJ1 gene pair, including 5 cases with quasi-identical sequences, and (2) the presence of a subset of stereotyped IGHV3-7 rearrangements. All PVRL IGHV sequences were highly mutated, with evidence of antigen selection and ongoing mutations. Finally, half of PVRL and PCNSL cases carried the MYD88 L265P mutation, which was present in all 4 PVRL cases with stereotyped IGHV3-7 rearrangements. In conclusion, the massive bias in the immunoglobulin gene repertoire of PVRL delineates it from PCNSL and points to antigen selection as a major driving force in their development.

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