Expression profile of 11 proteins and their prognostic significance in patients with chronic lymphocytic leukemia (CLL)

Abstract

It has been suggested that the expansion of the leukemic cells in chronic lymphocytic leukemia (CLL) is due to dysregulation of pathways of programmed cell death (apoptosis) rather than cell proliferation, although differences may exist in early vs late and treated vs untreated patients. In the present study, we analyzed the expression of 11 proteins in CLL cells that are implicated in the control of apoptosis, proliferation, and differentiation, and correlated this expression profile with survival. Using a quantitative solid-phase radioimmunoassay (RIA), we measured the cellular protein levels of Bcl-2, cyclin D1, PCNA, ATM, Fas, Bax, retinoic acid receptor alpha (RAR␣), retinoic acid receptor beta (RXR␤), Flt1, VEGF, and cellular ␤ 2 -microglobulin in 230 samples of CLL. Univariate analysis using the Cox proportional hazard model showed a correlation with survival of only the following proteins: Bcl-2 (P Ͻ 0.001), cyclin D1 (P = 0.027), Fas (P = 0.055), PCNA (P Ͻ 0.001), and ATM (P = 0.028). In a multivariate analysis using classification and regression tree analysis (CART), five groups of patients (nodes) could be generated with significant differences of survival expectation (P Ͻ 0.0001) based on levels of expression of the above proteins. Based on CART analysis, Bcl-2 levels emerge as the most important protein in predicting survival between all 11 proteins studied. Patients with marked elevation in Bcl-2 levels had the worst outcome while patients with intermediate levels, but with high levels of PCNA and cyclin D1 or abnormal ATM expression had intermediate survival. These data indicate that intracellular levels of proteins such as Bcl-2, ATM, cyclin D1, and PCNA can be used as markers to predict clinical behavior and survival in patients with CLL. The pathways in which these proteins are involved may also represent possible targets for future therapeutic trials in CLL.

Chronic Lymphocytic Leukemia: Recent Advances in Diagnosis and Treatment

“…Montserrat et al reported a median survival time of over 118 months for patients with slow lymphocyte doubling times, while patients with rapid doubling times had a median survival time of only 61 months [7], which is independent of Rai stage [8]. Bcell CLL/lymphoma 2 (BCL2) expression is associated with a shorter survival time in CLL [9]. Conflicting data exist regarding whether an elevated serum B2M level is an independent adverse prognostic feature [10,11].…”

The role of microRNAs in normal hematopoiesis and hematopoietic malignancies

“…24 These 13q14 deletions result in lowered miR-15a and miR-16-1 levels which in turn would result in high BCL-2 levels, an indicator of bad prognosis. 36 These results are obviously conflicting and need careful further investigation.…”

Deguelin inhibits expression of IκBα protein and induces apoptosis of B-CLL cells in vitro

“…35 The gradual accumulation of leukemic cells in B-CLL is thought to be due to a dysregulation of apoptotic pathways and abrogation of programmed cell death. 18,36,37 We investigated whether deguelin, a natural compound recently described to have potential as a cancer chemopreventive or inhibitor of carcinogenesis, 3,38 was able to enhance apoptosis of B-CLL cells in vitro.…”