MicroRNA profiles of t(14;18)–negative follicular lymphoma support a late germinal center B-cell phenotype

Abstract

IntroductionFollicular lymphoma (FL) constitutes the second most common B-cell malignancy among B-cell non-Hodgkin lymphomas (BNHLs). 1 It is considered an indolent lymphoma with a median overall survival of 8 to 10 years, but with an upward trend toward even further increased survival times because of more recent, improved treatment regimens. 2,3 FL is currently viewed as a germinal center (GC) B-cell derived lymphoma. Its origin in the GC influences the molecular characteristics but is also reflected at the morphologic level, as FL usually forms atypical follicles that in many aspects mimic their physiologic counterparts and typically express GC-associated B-cell markers, such as CD10, BCL6, and IRF-8. 1 Approximately 90% of FLs carry the translocation t(14;18)(q32;q21), leading to deregulated and aberrant expression of the antiapoptotic protein BCL2. Even with advanced, high-resolution techniques, however, a molecular rearrangement of the BCL2 gene cannot be detected in 10% of FLs, 4,5 raising the question of whether these cases belong to the biologic spectrum of "conventional" FLs. It is unclear whether they differ in their clinical behavior and whether these lymphomas display pathogenetic features equivalent to BCL2 deregulation in t(14;18)-positive FLs. Such molecular events in t(14;18)-negative FLs, however, have not been identified as of yet.We and others 4,6,7 have previously investigated the morphologic and molecular features of t(14;18)-negative FLs. Current evidence suggests that these lymphomas share many morphologic, genetic, and molecular characteristics with their t(14;18)-positive counterparts that would not justify a diagnosis other than FL (eg, marginal zone lymphoma) according to currently established WHO guidelines. In this study, we performed microRNA (miR) profiling of t(14;18)-negative FLs to further characterize this FL subgroup on the molecular level and to substantiate findings previously derived from gene expression profiling experiments. miR are transcriptional and translational inhibitors with important functions in physiologic cellular processes, but there is increasing evidence that they also play a pivotal role in the oncogenic evolution in many types of cancer. 8 In FLs, data on miR profiles are scarce, 9,10 and t(14;18)-negative FLs have not been characterized yet. We here show that t(14;18)-negative FLs have distinct miR expression profiles that are in support of a late GC B-cell phenotype and that may be associated with particular biologic properties of this Submitted June 28, 2011; accepted September 18, 2011. Prepublished online as Blood First Edition paper, September 29, 2011; DOI 10.1182 DOI 10. /blood-2011 *G.O., L.H., and A.R. contributed equally to this study as co-senior authors.The online version of this article contains a data supplement.The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked ''advertisement'' in accordance with 18 USC section 1734. 5550BLOOD, 17 N...

Role of microRNA in the pathogenesis of malignant lymphoma

“…(56) Karube et al (2007) demonstrate that CD10-negative FL cases are usually t (14;18)-negative and ⁄ or morphologically high-grade (Grade 3a or b), and, therefore, high-dose intensive chemotherapy (R-CHOP) is required. Leich et al (2011) report that these t (14;18)-negative cases, whose subtype was initially described by Karube et al, (57) have a distinct miRNA profile frequently characterized by downregulation of miR-16-1, miR-26a, miR-101, miR-29 and miR-138. (58) Because these miRNA are known to function as tumor-suppressive miRNA, their downregulation may be associated with the pathogenesis of some FL subtypes and high-grade FL.…”

“…Versus MF, Versus CD4+ MALT(gastric) Up Leich et al (58) In high stage and cases with poor reactivity to H. pylori eradication therapy miR-574-3p DLBCL(ABC) Up Malumbres et al (26) Versus GCB DLBCL (cell line) miR-574-5p DLBCL(ABC) Up Malumbres et al (26) Versus GCB DLBCL (cell line) CTCL(SzS) Up Ballabio et al…”

Genome-wide copy-number analyses reveal genomic abnormalities involved in transformation of follicular lymphoma

“…19,20 A more centromeric loss on 13q (rCNA513), occurring early in FL, affects RB1 and the miR-16-1 and miR-15a-encoding DLEU2. Additionally, 2 highly expressed miRNAs in normal GCB cells, miR-28 and miR-138, had decreased expression in lymphomas (Leich et al 21 and data not shown). A 3q27.3-q28 loss (rCNA200) in 5% of FL and 7.5% of tFL includes 3 genes, 1 of which is LPP, the miR-28 host gene.…”

Lack of expression of TUBB3 characterizes both BCL2-positive and BCL2-negative follicular lymphoma

“…20 Indeed, we found a significantly higher number of cases displaying an heterogeneous pattern in BCL2-negative follicular lymphoma, which might be a diagnostic clue, as follicular hyperplasia is usually uniformly TCL1A positive.…”