title: Is the c-Cbl proto-oncogene involved in chronic lymphocytic leukemia?
abstract: 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.
authors.affiliation: Research Unit Immunology and Pathology, Brest University Medical School Hospital, 5 Avenue Foch, 29609 Brest Cedex, France.
authors.forename: Amani
authors.initials: A
authors.lastname: Mankaï
authors.forename: Jean-Richard
authors.initials: JR
authors.lastname: Eveillard
authors.forename: Virginie
authors.initials: V
authors.lastname: Buhé
authors.forename: Karine
authors.initials: K
authors.lastname: Le Ster
authors.forename: Séverine
authors.initials: S
authors.lastname: Loisel
authors.forename: Ibtissem
authors.initials: I
authors.lastname: Ghedira
authors.forename: Pierre
authors.initials: P
authors.lastname: Youinou
authors.forename: Christian
authors.initials: C
authors.lastname: Berthou
authors.forename: Anne
authors.initials: A
authors.lastname: Bordron
mesh_terms: 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