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Tetraspanin CD37 is predominantly expressed on the cell surface of mature B lymphocytes and is currently being studied as novel therapeutic target for B-cell lymphoma. Recently, we demonstrated that loss of CD37 induces spontaneous B-cell lymphoma in Cd37-knockout mice and correlates with inferior survival in patients with diffuse large B-cell lymphoma (DLBCL). Here, CD37mutation analysis was performed in a cohort of 137 primary DLBCL samples, including 44 primary immune-privileged site-associated DLBCL (IP-DLBCL) samples originating in the testis or central nervous system. CD37mutations were exclusively identified in IP-DLBCL cases (10/44, 23%) but absent in non-IP-DLBCL cases. The aberrations included 10 missense mutations, 1 deletion, and 3 splice-site CD37mutations. Modeling and functional analysis of CD37missense mutations revealed loss of function by impaired CD37 protein expression at the plasma membrane of human lymphoma B cells. This study provides novel insight into the molecular pathogenesis of IP-DLBCL and indicates that anti-CD37 therapies will be more beneficial for DLBCL patients without CD37mutations.

The proteins of the Fanconi anemia/BRCA pathway are thought to function in specific DNA repair processes. Disruption of these genes results in genomic instability and hypersensitivity to DNA cross-linking agents. As illustrated by patients with Fanconi anemia (FA) [OMIM#227650] this cellular phenotype confers an increased risk for the development of malignancies, in particular acute myeloid leukemia (AML). In the past years several studies have shown that inherited and somatic abnormalities in individual FA genes play a role in the development of sporadic cancers. To study the involvement of the FA genes in sporadic cases of leukemia we analyzed the presence of aberrant promoter methylation of the 11 known FA genes by Methylation Specific-Multiplex Ligation dependent Probe Amplification (MS-MLPA).

In acute myeloid leukemia (AML) promoter methylation has been observed for the estrogen receptor (ESR1) as well as for a number of Tumor Suppressor Genes (TSGs). These individual aberrancies were suggested to be part of a general methylation defect in subsets of AML patients, rather than random events. The objective of this study was to assess whether aberrant promoter methylation of multiple genes, as observed in AML samples, are associated and whether such associations render impact on clinical outcome. By Methylation-Specific Multiplex Ligation Probe Amplification (MS-MLPA) the methylation status of 26 TSGs was determined in bone marrow samples of 119 primary AML patients and 5 control individuals. No promoter methylation was detected in any of the controls, while at least one TSG was methylated in 59/119 patients. Methylation was observed in 12 out of 26 assessed sites, most frequently for ER, CDKN2B/p15,and IGSF4(28–36% of all patients). A substantial intra-class correlation of 0.38 existed between methylation of different TGSs. ESR1methylation (34/119) strongly predicted concurrent methylation of TSGs, OR 7.33 (95%CI 4.13–12.99). A regression model that included both the ESR1methylation status and the number of methylated TSGs (methylation index), showed both parameters to be independent oppositely directed predictors for overall survival (OS), HR 0.06 (95%CI 0.01–0.33; p=.001) and HR 1.92 (95%CI 1.19–3.10; p=.007), respectively. In line with this observation, a higher methylation index was found to yield a significant negative effect on patient OS in both the ESR1methylated (ESR1+) and ESR1unmethylated (ESR1−) subgroups.