Jana Šupíková

Gene expression profiling in follicular lymphoma and its implication for clinical practice

Follicular lymphoma (FL) is characterized by an indolent and relapsing course. Recently, the clinical outcome of FL has been distinguished by immune microenvironment-associated gene signatures. In our study, gene expression profiling (GEP) was performed in 31 non-selected patients with follicular lymphoma (FL), 12 of whom were in relapse and the remaining 19 newly diagnosed. A custom oligonucleotide microarray (Agilent 8 × 15K) was used which contained probes for about 3500 genes, including those that had been previously published as demonstrating significant prognostic value. An unsupervised approach was not able to recognize clinically different FLs. As the previously published prognostically relevant gene signatures could not be properly verified, probably due to microarray platform differences, template matching was therefore used in order to define two gene sets with differential gene expression among our samples. These gene sets shared an overrepresentation of genes with similar biological functions and were termed ‘T-CELL’ and ‘PROLIFERATION’ profiles. The ‘poor profile’ was then defined by a high PROLIFERATION score (upper tertile) and/or low T-CELL score (lower tertile). The ‘poor profile’ cohort contained a significantly higher proportion of relapsed cases (p < 0.05, Fishers exact test). Additionally, a comparison of samples from initial diagnosis and from relapse showed significant differences mainly in the T-CELL profile (p = 0.036; χ2). This supports the hypothesis that the number of T-cells and their expression pattern play a major role in FL development.

Molecular evidence for antigen drive in the natural history of mantle cell lymphoma

To further our understanding about antigen involvement in mantle cell lymphoma (MCL), we analyzed the expression levels of activation-induced cytidine deaminase (AID), a key player in B-cell responses to antigen triggering, in 133 MCL cases; assessed the functionality of AID by evaluating in vivo class switch recombination in 52 MCL cases; and sought for indications of ongoing antigen interactions by exploring intraclonal diversification within 14 MCL cases. The AID full-length transcript and the most frequent splice variants (AID-ΔE4a, AID-ΔE) were detected in 128 (96.2%), 96 (72.2%), and 130 cases (97.7%), respectively. Higher AID full-length transcript levels were significantly associated (P < 0.001) with lack of somatic hypermutation within the clonotypic immunoglobulin heavy variable (IGHV) genes. Median AID transcript levels were higher in lymph node material compared to cases in which peripheral blood was analyzed, implying that clonal behavior is influenced by the microenvironment. Switched tumor-derived IGHV-IGHD-IGHJ transcripts were identified in 5 of 52 cases (9.6%), all of which displayed somatic hypermutation and AID-mRNA expression. Finally, although most cases exhibited low levels of intraclonal diversification, analysis of the mutational activity revealed a precise targeting of somatic hypermutation indicative of an active, ongoing interaction with antigen(s). Collectively, these findings strongly allude to antigen involvement in the natural history of MCL, further challenging the notion of antigen naivety.

Transmission of t(11;14)-positive cells by allogeneic stem cell transplant: 10-year journey to mantle cell lymphoma

Mantle cell lymphoma (MCL) is considered, with some exceptions, to be one of the most aggressive lymphomas, with relatively short median survival [1]. Th e biological hallmark of MCL is t(11;14)(q13;q32) resulting in cyclin D1 overexpression, which is not usually expressed in normal B cells [2]. Although the initial oncogenic translocation is acquired at the pre-B stage during the V(D)J recombination in the bone marrow [3], MCL is composed of mature B cells that grow in the mantle zone of lymphatic follicles and express the corresponding phenotype. To date, the oncogenic steps from the early event to the development of MCL have not been well documented. Rare cases of donor-derived malignancies can provide better insights into the biology and growth of different tumors under real conditions.