Effects of rapamycin in combination with fludarabine on primary chronic lymphocytic leukemia cells

Abstract

Chronic lymphocytic leukemia (CLL) is the most commontype of leukemia in adults, characterized by the expansionof a population of monoclonal CD5þB-lymphocytesthat accumulate in the blood, bone marrow, and secondarylymphoid tissues [1]. CLL continues to be an incurabledisease and can arise in two forms, aggressive and indolent,both characterized by a typical defect in apoptosis.Unfavorable prognosis is associated with the absence ofmutations in the immunoglobulin heavy chain variable(UM-IGHV) genes and by the expression of CD38 andhigh level of 70 kD zeta-associated protein (ZAP-70),among other markers [2,3]. Chromosomal alterations aredetected in >80% of cases and can discriminate patientswith different outcomes [4]. Deletions at chromosome13q14 are the most frequent genomic aberrationdetected by interphase fluorescence in situ hybridization(FISH) analysis. Interestingly, the microRNA miR-15a andmiR-16-1, which target the antiapoptotic molecule Bcl-2,are located in this chromosomal region. [4]. Accordingly,the majority of CLL patients are characterized by aconstitutively elevated expression of Bcl-2, suggestingthat resistance to apoptosis plays an important role inthe disease