Purine-rich box-1-mediated reduced expression of CD20 alters rituximab-induced lysis of chronic lymphocytic leukemia B cells.
The anti-CD20 monoclonal antibody rituximab has been less successful in treating chronic lymphocytic leukemia (CLL) than lymphoma, possibly due to the lower density of CD20 on B lymphocytes from CLL patients than on those from lymphoma patients. This lowering may result from insufficiency of one of the transcription factors of cd20. Of these, purine-rich box-1 (PU.1) is poorly expressed in CLL. To estimate its weight in CD20 expression, pu.1 cDNA was transfected into CLL B cells and shown to raise the membrane expression of CD20 and to improve the rituximab-induced lysis of transfected cells. Granulocyte macrophage colony-stimulating factor and all-trans-retinoic acids were not involved in the defective expression of PU.1 or the excessive methylation of the pu.1 gene, because 6 of 14 CLL samples tested were normally methylated. This was confirmed by the failure of DNA methyltransferase inhibitors to restore pu.1 transcription in hypermethylated CLL, and, in fact, the expression of PU.1 was down-regulated by excessive expression of the FMS proto-oncogene-like tyrosine kinase 3 (Flt3) receptor. This abnormality is consistent with our finding of elevated levels of Flt3 ligand (FL) in 20 of 23 CLL sera tested. We propose that FL-dependent increased Flt3 signaling prevents the expression of PU.1, which down-regulates that of CD20, and accounts for resistance of leukemic B cells to rituximab-induced lysis.
Mankaï
Amani
A
Immunologie et Pathologie Research Unit, Medical School, Brest, France.
Bordron
Anne
A
Renaudineau
Yves
Y
Martins-Carvalho
Christine
C
Takahashi
Shinichiro
S
Ghedira
Ibtissem
I
Berthou
Christian
C
Youinou
Pierre
P
D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D058846:Antibodies, Monoclonal, Murine-Derived; D018951:Antigens, CD20 / Q000096:biosynthesis* / Q000235:genetics; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001402:B-Lymphocytes / Q000276:immunology; D019175:DNA Methylation; D005260:Female; D015316:Genetic Therapy / Q000379:methods; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000097:blood / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D008297:Male; D008875:Middle Aged; D027701:Organic Cation Transport Proteins / Q000096:biosynthesis; D000075102:Organic Cation Transporter 2; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D000069283:Rituximab; D015534:Trans-Activators / Q000096:biosynthesis / Q000235:genetics*; D014162:Transfection; D051941:fms-Like Tyrosine Kinase 3 / Q000096:biosynthesis / Q000378:metabolism; D000099232:Proto-Oncogene Protein Spi-1
D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D018951:Antigens, CD20; D000970:Antineoplastic Agents; D027701:Organic Cation Transport Proteins; D000075102:Organic Cation Transporter 2; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D000069283:Rituximab; D015534:Trans-Activators; D051941:fms-Like Tyrosine Kinase 3; D000099232:Proto-Oncogene Protein Spi-1; C000715470:MAS1 protein, human; C491013:SLC22A2 protein, human; C497970:FLT3 protein, human