Diffuse large B-cell lymphoma with combined TP53 mutation and MIR34A methylation: Another "double hit" lymphoma with very poor outcome?

Fazila Asmar,Kirsten Grønbæk,Michael Boe Møller,Peter De Nully Brown,Elisabeth Ralfkiaer,Anja Pedersen,Christoffer Hother,Marianne Bach Treppendahl,Helene Myrtue Nielsen,Ulrik Ralfkiaer,Gorjan Kulosman

doi:10.18632/oncotarget.1877

Fazila Asmar, Kirsten Grønbæk + Show 9 more

Open Access

https://doi.org/10.18632/oncotarget.1877

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Journal: Oncotarget	Publication Date: Mar 31, 2014
Citations: 57	License type: cc-by

Affiliation: Rigshospitalet, Odense University Hospital

Abstract

MiR34A, B and C have been implicated in lymphomagenesis, but information on their role in normal CD19+ B-cells (PBL-B) and de novo diffuse large B-cell lymphoma (DLBCL) is limited. We show that in normal and activated B-cells miR34A-5p plays a dominant role compared to other miR34 family members. Only miR34A-5p is expressed in PBL-B, and significantly induced in activated B-cells and reactive lymph nodes. In PBL-B, the MIR34A and MIR34B/C promoters are unmethylated, but the latter shows enrichment for the H3K4me3/H3K27me3 silencing mark. Nine de novo DLBCL cases (n=150) carry both TP53 mutation and MIR34A methylation ("double hit") and these patients have an exceedingly poor prognosis with a median survival of 9.4 months (P<0.0001), while neither TP53 mutation, MIR34A or MIR34B/C promoter methylation alone ("single hit") influence on survival. The TP53/MIR34A "double-hit" is an independent negative prognostic factor for survival (P=0.0002). In 2 DLBCL-cell lines with both TP53 mutation and promoter methylation of MIR34A, miR34A-5p is upregulated by 5-aza-2'deoxycytidine. Thus, the TP53/MIR34A "double hit" characterizes a very aggressive subgroup of DLBCL, which may be treatable with epigenetic therapy prior to or in combination with conventional immunochemotherapy.

Highlights

Diffuse large B-cell lymphoma (DLBCL) comprise a variety of morphological and clinical phenotypes, resulting from miscellaneous, underlying molecular defects
P53 has been shown to directly bind to and regulate the transcription of both miR34A and miR34B/C [16], and we speculated whether these molecules were involved in diffuse large B-cell lymphoma (DLBCL) lymphomagenesis in a mutually exclusive manner, as it was previously suggested in CLL [20]
We examined the components of the p53-miR34 axis including TP53 mutational status and hypermethylation of the MIR34A and MIR34B/C promoters in a panel of 150 newly diagnosed DLBCL and in 6 DLBCL cell lines, and compared these data to those obtained from peripheral blood B-lymphocytes (PBL-B) and reactive lymph nodes

Summary

Introduction

Diffuse large B-cell lymphoma (DLBCL) comprise a variety of morphological and clinical phenotypes, resulting from miscellaneous, underlying molecular defects. Gene expression profiles and their immunohistochemical surrogate markers have been used to classify DLBCL into prognostic subgroups [1, 2], still, diversity in biology and clinical outcome exists within the individual categories. Few genetic or epigenetic defects have been identified as prognostic markers. Most previous studies of tumor suppressor pathways in DLBCL have focused on the disruption of the coding sequences of genes. Epigenetic alterations and aberrant expression of microRNAs (miRs) may be important for growth control. As for protein encoding genes, the transcription of miR genes may be inactivated by promoter hypermethylation [9, 10]

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