Diffuse large B-cell lymphoma with combined TP53 mutation and MIR34A methylation: Another "double hit" lymphoma with very poor outcome?
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.
Department of Hematology, Rigshospitalet, Copenhagen, Denmark.
Fazila
F
Asmar
Christoffer
C
Hother
Gorjan
G
Kulosman
Marianne Bach
MB
Treppendahl
Helene Myrtue
HM
Nielsen
Ulrik
U
Ralfkiaer
Anja
A
Pedersen
Michael Boe
MB
Møller
Elisabeth
E
Ralfkiaer
Peter
P
de Nully Brown
Kirsten
K
Grønbæk
D000368:Aged; D018941:Antigens, CD19 / Q000032:analysis; D001402:B-Lymphocytes / Q000737:chemistry / Q000378:metabolism; D045744:Cell Line, Tumor; D018389:Codon, Nonsense; D005260:Female; D006801:Humans; D008198:Lymph Nodes / Q000378:metabolism; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008745:Methylation; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism*; D008875:Middle Aged; D020125:Mutation, Missense; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000235:genetics*; D015996:Survival Rate; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
D018941:Antigens, CD19; D018389:Codon, Nonsense; C522425:MIRN34 microRNA, human; D035683:MicroRNAs; D016159:Tumor Suppressor Protein p53