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

TY - JOUR

T1 - Diffuse large B-cell lymphoma with combined TP53 mutation and MIR34A methylation

T2 - Another “double hit” lymphoma with very poor outcome?

AU - Asmar, Fazila

AU - Hother, Christoffer

AU - Kulosman, Gorjan

AU - Treppendahl, Marianne Bach

AU - Nielsen, Helene Myrtue

AU - Ralfkiaer, Ulrik

AU - Pedersen, Anja

AU - Møller, Michael Boe

AU - Ralfkiaer, Elisabeth

AU - de Nully Brown, Peter

AU - Grønbæk, Kirsten

PY - 2014/4/15

Y1 - 2014/4/15

N2 - 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.

AB - 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.

KW - Aged

KW - Antigens, CD19

KW - B-Lymphocytes

KW - Cell Line, Tumor

KW - Codon, Nonsense

KW - Female

KW - Humans

KW - Lymph Nodes

KW - Lymphoma, Large B-Cell, Diffuse

KW - Male

KW - Methylation

KW - MicroRNAs

KW - Middle Aged

KW - Mutation, Missense

KW - Prognosis

KW - Promoter Regions, Genetic

KW - Survival Rate

KW - Tumor Suppressor Protein p53

M3 - Journal article

C2 - 24722400

SN - 1949-2553

VL - 5

SP - 1912

EP - 1925

JO - Oncotarget

JF - Oncotarget

IS - 7

ER -