Differential gene expression in B cell chronic lymphocytic leukemia patients with different clinical outcomes.

摘要

B-cell chronic lymphocytic leukemia (CLL) is the most common adult leukemia characterized by CD5+/CD23+ B cells. CLL is heterogeneous with some presenting with indolent disease, whereas others with aggressive disease. Rai stage, immunoglobulin (Ig) mutation status, ZAP-70 expression, CD38 expression, lymphocyte doubling time (LDT) and chromosome abnormalities are known prognostic markers. The molecular basis of some these markers remain unknown. This research is based on the hypothesis that CLL patients with good and poor clinical outcome are associated with unique gene expression pattern.; The clinical outcome of 94 different CLL patients was assessed using above prognostic markers, and found to have known prognostic pattern. Gene expression profiles of 40 different CLL patients were determined using oligonucleotide microarray. SAM analysis identified 21 genes including CTLA4 and MNDA to be over expressed in Ig mutated patients compared to unmutated patients. Gene expression was also compared in CLL patients with high CD38 (n = 17) and low CD38 (n = 22) expression, to determine the molecular basis of CD38 expression in CLL behavior. HEM1 was over expressed, whereas the ATM, CTLA4 and MNDA were under expressed in patients with high CD38 expression. Differential expression of ATM, HEM1, CTLA4 and MNDA was confirmed using real time PCR. Higher expression of HEM1 and lower expression of ATM, CTLA4 and MNDA correlated with shorter time to treatment in patients. Down regulation of HEM1 expression in primary CLL cells using antisense oligonucleotides, resulted in significant increase in their susceptibility to fludarabine mediated killing. In addition, under expression of ATM was associated with extensive bulky lymphadenopathy irrespective of 11q23 deletion.; Overall, these results demonstrate that poor outcome CLL patients with high CD38 expression and good outcome with low CD38 expression have unique gene expression pattern. The differential expression of some genes correlated with disease progression. This study also lays foundation for developing new therapeutic strategies, targeting key genes to increase killing of CLL cells thereby improving disease free survival in poor outcome patients.