PRDM1 is involved in chemoresistance of T-cell lymphoma and down-regulated by the proteasome inhibitor.
The positive regulatory domain I (PRDM1) is a master regulator of terminal B-cell differentiation. However, PRDM1 is not B-cell specific. To determine its role in T-cell lymphoma, PRDM1 expression was investigated in 60 patients. PRDM1alpha and PRDM1beta transcripts were detected in laser-microdissected T-lymphoma cells in 27 and 14 patients, respectively, mostly in cases with IRF4 expression. PRDM1beta was associated with increased c-MYC expression. PRDM1beta-positive patients displayed advanced Ann Arbor stage and high-risk International Prognostic Index and were linked to short survival times. In vitro, PRDM1beta was related to resistance to chemotherapeutic agents and could be down-regulated by the proteasome inhibitor bortezomib. Kinetic studies showed that bortezomib down-regulation of PRDM1beta preceded decreased IRF4 and c-MYC expression. An earlier retaining of cytoplasmic IkappaBalpha in bortezomib-treated cells was revealed, concomitant with blockade of NF-kappaB nuclear translocation. These results demonstrate the involvement of PRDM1beta in T-cell lymphoma, with possible therapeutic interference by the proteasome inhibitor.
Zhao
Wei-Li
WL
State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Shanghai Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, China.
Liu
Yan-Yan
YY
Zhang
Qun-Ling
QL
Wang
Li
L
Leboeuf
Christophe
C
Zhang
Yi-Wen
YW
Ma
Jie
J
Garcia
José-Francisco
JF
Song
Yong-Ping
YP
Li
Jun-Min
JM
Shen
Zhi-Xiang
ZX
Chen
Zhu
Z
Janin
Anne
A
Chen
Sai-Juan
SJ
D001897:Boronic Acids / Q000494:pharmacology* / Q000627:therapeutic use; D000069286:Bortezomib; D015536:Down-Regulation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000235:genetics; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects*; D006801:Humans; D020672:I-kappa B Proteins / Q000235:genetics / Q000378:metabolism; D050835:Interferon Regulatory Factors / Q000096:biosynthesis / Q000235:genetics; D016399:Lymphoma, T-Cell / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D042282:Microdissection; D000072000:NF-KappaB Inhibitor alpha; D009367:Neoplasm Staging; D000074462:Positive Regulatory Domain I-Binding Factor 1; D011480:Protease Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis / Q000235:genetics; D011719:Pyrazines / Q000494:pharmacology* / Q000627:therapeutic use; D012097:Repressor Proteins / Q000096:biosynthesis* / Q000235:genetics; D015996:Survival Rate; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics; D000099218:Interferon Regulatory Factor-4
D001897:Boronic Acids; D000069286:Bortezomib; D020672:I-kappa B Proteins; D050835:Interferon Regulatory Factors; D000072000:NF-KappaB Inhibitor alpha; D000074462:Positive Regulatory Domain I-Binding Factor 1; D011480:Protease Inhibitors; D046988:Proteasome Endopeptidase Complex; D061988:Proteasome Inhibitors; D016271:Proto-Oncogene Proteins c-myc; D011719:Pyrazines; D012097:Repressor Proteins; D014157:Transcription Factors; D000099218:Interferon Regulatory Factor-4; C489427:MYC protein, human; C000606204:NFKBIA protein, human; C087042:PRDM1 protein, human