Oncotarget

Research Papers:

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

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

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Oncotarget. 2014; 5:1912-1925. https://doi.org/10.18632/oncotarget.1877

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Abstract

Fazila Asmar1,*, Christoffer Hother1,*, Gorjan Kulosman1, Marianne Bach Treppendahl1, Helene Myrtue Nielsen1, Ulrik Ralfkiaer1,2, Anja Pedersen1, Michael Boe Møller3, Elisabeth Ralfkiaer2, Peter de Nully Brown1, and Kirsten Grønbæk1

1 Department of Hematology, Rigshospitalet, Copenhagen, Denmark,

2 Department of Pathology, Rigshospitalet, Copenhagen, Denmark,

3 Department of Pathology, Odense University Hospital, Odense, Denmark.

* These authors contributed equally to the paper

Correspondence:

Kirsten Grønbæk, email:

Keywords: Epigenetic changes, DNA methylation, microRNA, Tumor suppressors, non-Hodgkin lymphoma

Received: February 9, 2014 Accepted: March 30, 2014 Published: March 31, 2014

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.


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