PRDM1 is required for mantle cell lymphoma response to bortezomib.
Mantle cell lymphoma (MCL) is an aggressive form of B-cell lymphoma with a poor disease-free survival rate. The proteasome inhibitor bortezomib is approved for the treatment of relapsed and refractory MCL and has efficacy in about 30% of patients. However, the precise mechanism of action of bortezomib is not well understood. This report establishes a requirement for the transcription repressor PR domain zinc finger protein 1 (PRDM1, Blimp1) in the response to bortezomib. Bortezomib rapidly induces transcription of PRDM1 as part of the apoptotic response in both cell lines and primary MCL tumor cells. Knockdown of PRDM1 blocks activation of NOXA and inhibits apoptosis, whereas ectopic expression of PRDM1 alone leads to apoptosis in MCL. Two novel direct targets of PRDM1 were identified in MCL cells: MKI67 (Ki67) and proliferating cell nuclear antigen (PCNA). Both MKI67 and PCNA are required for proliferation and survival. Chromatin immunoprecipitation and knockdown studies reveal that specific repression of MKI67 and PCNA is mediated by PRDM1 in response to bortezomib. Furthermore, promoter studies and mutation/deletion analysis show that PRDM1 functions through specific sites in the PCNA proximal promoter and an MKI67 distal upstream repression domain. Together, these findings establish PRDM1 as a key mediator of bortezomib activity in MCL.
H. Lee Moffitt Cancer Center, 12902 Magnolia Drive, MRC-4East, Tampa, FL 33612, USA.
Shruti
S
Desai
Michelle
M
Maurin
Matthew A
MA
Smith
Sophia C E
SC
Bolick
Sophie
S
Dessureault
Jianguo
J
Tao
Eduardo
E
Sotomayor
Kenneth L
KL
Wright
D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D014408:Biomarkers, Tumor / Q000235:genetics / Q000502:physiology*; D001897:Boronic Acids / Q000378:metabolism / Q000627:therapeutic use*; D000069286:Bortezomib; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors; D020522:Lymphoma, Mantle-Cell / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors; D000074462:Positive Regulatory Domain I-Binding Factor 1; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D017434:Protein Structure, Tertiary / Q000187:drug effects / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors; D011719:Pyrazines / Q000378:metabolism / Q000627:therapeutic use*; D012097:Repressor Proteins / Q000235:genetics / Q000502:physiology*
D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D001897:Boronic Acids; D047908:Intracellular Signaling Peptides and Proteins; C492406:NIFK protein, human; D009687:Nuclear Proteins; C498702:PMAIP1 protein, human; D018809:Proliferating Cell Nuclear Antigen; D019253:Proto-Oncogene Proteins c-bcl-2; D011719:Pyrazines; D012097:Repressor Proteins; C087042:PRDM1 protein, human; D000069286:Bortezomib; D000074462:Positive Regulatory Domain I-Binding Factor 1