Is the c-Cbl proto-oncogene involved in chronic lymphocytic leukemia?
Chronic lymphocytic leukemia (CLL) is characterized by survival advantage and accumulation of CD5+ mature B lymphocytes. Expression of zeta-chain-associated protein-70 (ZAP-70), normally present in T lymphocytes or immature B cells, is associated with disease aggressiveness, as IgVH mutational status, and some proteins implicated in survival signal pathways are found to be constitutively activated in CLL cells. ZAP-70 signaling is regulated through molecular adaptors, such as the proto-oncogene product c-Casitas B lineage lymphoma (c-Cbl). The aim of this study was to determine the implication of this proto-oncogene product in CLL in survival signals. It appeared that expression of c-Cbl was increased in CLL and not correlated to that of B cell linker protein or ZAP-70. Furthermore, c-Cbl was significantly hypophosphorylated in progressive disease, so that hypophosphorylated form of c-Cbl (c-Cbl.P) along with ZAP-70, set a cutoff ratio distributing patients with stable situation below 1, and those with progressive disease equal or above 1. Given that phospholipase gamma 2 (PLC gamma 2) function is also influenced by c-Cbl hypophosphorylation, the ratio of PLC gamma 2 to c-Cbl.P was measured in CLL B cells and consistently found to be >or= 1 in Binet stage B CLL patients, as opposed to stage A CLL patients. These findings invite analysis of the role of c-Cbl in CLL.
Mankaï
Amani
A
Research Unit Immunology and Pathology, Brest University Medical School Hospital, 5 Avenue Foch, 29609 Brest Cedex, France.
Eveillard
Jean-Richard
JR
Buhé
Virginie
V
Le Ster
Karine
K
Loisel
Séverine
S
Ghedira
Ibtissem
I
Youinou
Pierre
P
Berthou
Christian
C
Bordron
Anne
A
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018956:CD5 Antigens / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D008297:Male; D008875:Middle Aged; D051966:Phospholipase C gamma / Q000378:metabolism; D019000:Phosphotyrosine / Q000378:metabolism; D000090063:Proto-Oncogene Mas; D050721:Proto-Oncogene Proteins c-cbl / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D051746:ZAP-70 Protein-Tyrosine Kinase / Q000378:metabolism