Is the c-Cbl Proto-Oncogene Involved in Chronic Lymphocytic Leukemia?

• Published in: Annals of the New York Academy of Sciences 2007-06, Vol.1107 (1), p.193-205
• Main Authors: MANKAÏ, AMANI, EVEILLARD, JEAN-RICHARD, BUHÉ, VIRGINIE, LE STER, KARINE, LOISEL, SÉVERINE, GHEDIRA, IBTISSEM, YOUINOU, PIERRE, BERTHOU, CHRISTIAN, BORDRON, ANNE
• Format: Article
• Language: English
• Subjects: Adult; Aged; Aged, 80 and over; c-Cbl; CD5 Antigens - metabolism; CLL; Female; Gene Expression Regulation, Neoplastic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell - enzymology; Leukemia, Lymphocytic, Chronic, B-Cell - genetics; Leukemia, Lymphocytic, Chronic, B-Cell - pathology; Male; Middle Aged; Phospholipase C gamma - metabolism; Phosphotyrosine - metabolism; PLCγ2; Proto-Oncogene Proteins c-cbl - genetics; Proto-Oncogene Proteins c-cbl - metabolism; RNA, Messenger - genetics; survival pathways; ZAP-70; ZAP-70 Protein-Tyrosine Kinase - metabolism
• ISSN: 0077-8923; 1749-6632; 1930-6547
• DOI: 10.1196/annals.1381.021

:  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 (PLCγ2) function is also influenced by c‐Cbl hypophosphorylation, the ratio of PLCγ2 to c‐Cbl.P was measured in CLL B cells and consistently found to be ≥ 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.