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

doi:10.1196/annals.1381.021

Chronic lymphocytic leukemia (CLL) is characterized by survivaladvantage and accumulation of CD5+ mature B lymphocytes. Expressionof zeta-chain-associated protein-70 (ZAP-70), normally presentin T lymphocytes or immature B cells, is associated with diseaseaggressiveness, as IgVH mutational status, and some proteinsimplicated in survival signal pathways are found to be constitutivelyactivated in CLL cells. ZAP-70 signaling is regulated throughmolecular adaptors, such as the proto-oncogene product c-CasitasB lineage lymphoma (c-Cbl). The aim of this study was to determinethe implication of this proto-oncogene product in CLL in survivalsignals. It appeared that expression of c-Cbl was increasedin CLL and not correlated to that of B cell linker protein orZAP-70. Furthermore, c-Cbl was significantly hypophosphorylatedin progressive disease, so that hypophosphorylated form of c-Cbl(c-Cbl.P) along with ZAP-70, set a cutoff ratio distributingpatients with stable situation below 1, and those with progressivedisease equal or above 1. Given that phospholipase gamma 2 (PLC ${gamma}$ 2)function is also influenced by c-Cbl hypophosphorylation, theratio of PLC ${gamma}$ 2 to c-Cbl.P was measured in CLL B cells and consistentlyfound to be $≥$ 1 in Binet stage B CLL patients, as opposed tostage A CLL patients. These findings invite analysis of therole of c-Cbl in CLL.

Part III. Autoimmunity and Cancer