17p (TP53) deletion identifies patients with chronic lymphocytic leukemia (CLL) who are resistant to chemotherapy. The members of the miR-34 family have been discovered to be direct p53 targets and mediate some of the p53-dependent effects. We studied miR-34a and miR-34b/c expression in a large cohort to define their potential role in refractory CLL. While no expression of miR-34b/c could be detected, we found variable expression levels of miR-34a. miR-34a levels were upregulated after DNA damage in the presence of functional p53, but not in cases with 17p deletion (P < .001). We found a strong correlation of low miR-34a levels with impaired DNA damage response, TP53 mutations (without 17p deletion), and fludarabine-refractory disease (also in the absence of 17p deletion). Up-regulation of miR-34a after irradiation was associated with induction of Bax and p21, but not Puma. CLL cells with reduced miR-34a expression showed increased viability after DNA damage independently of 17p status. Therefore, low expression of miR-34a in CLL is associated with p53 inactivation but also chemotherapy-refractory disease, impaired DNA damage response, and apoptosis resistance irrespective of 17p deletion/TP53 mutation. The elucidation of mechanisms underlying miR-34a regulation and overcoming its role in chemotherapy resistance warrant further study. IntroductionChronic lymphocytic leukemia (CLL) is the most frequent type of leukemia in the Western world and is characterized by a highly variable clinical course. 1-3 Traditionally, therapy has been used for advanced stage or symptomatic disease and consists of chemotherapy with alkylating agents, purine analogs, and more recently antibody-chemotherapy combinations. Different molecular prognostic factors have been used to predict time to treatment, likelihood of responding to chemotherapy and survival time. [4][5][6] A central role of the DNA damage-response pathway and particularly p53 has been suggested by the prognostic role of 17p and 11q deletions in CLL. In the critical regions, 2 prominent genes are located that are involved in the cells' response to DNA damage (eg, induced by chemotherapy). ATM and TP53 have been shown to be deleted in virtually all cases with deletion 11q and 17p, respectively. In contrast, TP53 and ATM are mutated in different proportions. [7][8][9][10][11] There is growing evidence that mutations of TP53 or ATM also in the absence of deletion of 17p or 11q are associated with poor prognosis as a result of impaired response to chemotherapy. 12 Particularly loss of 17p has been associated with failure to respond to chemotherapy and short event-free and overall survival. 8,13,14 However, in chemotherapy-refractory CLL, only 30% to 40% percent of cases will have a deletion or mutation of TP53, whereas approximately one-third of the remaining cases have a deletion of 11q. 15 This suggests that almost half of the refractory cases cannot be explained by a direct defect of p53 or loss of 11q. A hypothesis explaining resistance in these cases might be defects ...

We recently reported that Swedish V H 3-21-using chronic lymphocytic leukemia (CLL) patients showed restricted immunoglobulin gene features and poor prognosis despite V H mutation status. To investigate this further, we analyzed the V H and V L gene rearrangements in 90 V H 3-21 ؉ patients from Sweden, Germany, Italy, United States, Finland, and Australia and correlated these data with survival and other prognostic markers. Sixty-three percent exhibited mutated V H genes and 37% unmutated V H genes. Fifty (56%) patients displayed a short and homologous heavy-

Telomere length is associated with mutation status of the immunoglobulin heavy chain variable (IGHV) gene and clinical course in B-cell chronic lymphocytic leukemia (B-CLL). In a B-CLL cohort of 152 patients, we analyzed telomere length, genomic aberrations, IGHV mutation status, CD38 and ZAP-70 expression to study the prognostic impact and associations among these factors. An inverse correlation existed between telomere length and IGHV homology (P < .001), CD38 (P < .001), and ZAP-70 expression (P ‫؍‬ .01). Patients with telomere lengths below median (ie, "short telomeres") and above median (ie, "long telomeres") had similar incidences of genomic aberrations (74% vs 68%), 13q؊ (57% vs 49%), and ؉12q (5% vs 12%). In contrast, 13q؊ as a single aberration was more frequent in patients with long telomeres (51% vs 21%; P ‫؍‬ .006), whereas 11q؊ (27% vs 9%; P ‫؍‬ .014), 17p؊ (17% vs 0%; P < .001), and 2 or more genomic aberrations (39% vs 8%; P < .001) were more frequent in patients with short telomeres.Compared with patients with long telomeres, treatment-free survival (TFS) and overall survival (OS) was significantly shorter (P < .001 and P ‫؍‬ .015, respectively) in the group with short telomeres, and telomere length was an independent prognostic indicator for TFS. IntroductionB-cell chronic lymphocytic leukemia (B-CLL), the most common leukemia in adults in the Western world, is characterized by a monoclonal expansion of mature B lymphocytes expressing CD19, CD5, and CD23 on the cell surface. 1 B-CLL is a clinically heterogeneous disease with survival times ranging from months to normal lifespan. 2 As a consequence of the variable clinical course, it has become very crucial to identify reliable prognostic factors useful in planning therapeutic strategies and predicting the outcome. A number of biological features of B-CLL have been described, and several of them can be used to discern different groups of patients with significant differences in clinical course and outcome. The immunoglobulin heavy chain variable (IGHV) gene mutation status analysis reveals 2 subgroups of B-CLL, [3][4][5] with a more favorable clinical course for patients with mutated IGHV genes. [6][7][8][9] The surface marker CD38 has been proposed as a surrogate marker for IGHV gene mutation status in B-CLL, 3 but the association between these markers was shown to be rather weak. 7-11 Furthermore, CD38 has been shown to be an independent prognostic marker, although no consensus has been reached concerning cut-off levels. 7,8,[11][12][13] Expression of the protein tyrosine kinase ZAP-70 is strongly associated with IGHV gene mutation status and can be used as an independent prognostic factor. 14-16 Although discordant results have been reported lately, certain IGHV gene usage (eg, and presence of high-risk genomic aberrations (eg, 11qϪ and 17pϪ) can explain these findings at least in part. 17,18 In mature B-cell neoplasms, telomere length correlates with histopathogenesis according to the germinal center. 19 This feature includes B-CLL showing a...

There were characteristic modes of discordance between ZAP-70 and VH mutation status depending on the presence or absence of additional genetic high-risk features such as 11q and 17p deletion or V3-21 usage. Although the biologic background for these findings is yet to be determined, these data have biologic and clinical implications regarding ZAP-70 as a pathogenic factor and outcome predictor, respectively.