Mutations in the ATM gene lead to impaired overall and treatment-free survival that is independent of IGVH mutation status in patients with B-CLL

Austen, Belinda; Powell, Judith E.; Alvi, Azra J.; Edwards, Ian; Hooper, Laura C.; Starczynski, Jane; Taylor, Alexander M.; Fegan, Christopher; Moss, Paul; Stankovic, Tatjana

doi:10.1182/blood-2004-11-4516

Cited by 212 publications

(173 citation statements)

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“…This supports previous reports where only a proportion of cases with 11q deletion show a complete inactivation of ATM (by mutation), and the status of the second allele may be crucial in this respect. 7,10,12 Our analysis supports these findings by showing that 11q deletion may be associated with normal response to DNA damage (p53/p21 induction) as well as normal levels of miR-34a with an intact up-regulation upon IR. The detailed study of miR-34a may thus help dissect the heterogeneity of 11q cases and its differential prognostic impact.…”

Section: Discussionsupporting

confidence: 77%

“…[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.…”

Section: Introductionmentioning

confidence: 99%

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miR-34a as part of the resistance network in chronic lymphocytic leukemia

Zenz

Mohr

Eldering³

et al. 2009

Blood

247

188

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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 ...

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Section: Discussionsupporting

confidence: 77%

Section: Introductionmentioning

confidence: 99%

miR-34a as part of the resistance network in chronic lymphocytic leukemia

Zenz

Mohr

Eldering³

et al. 2009

Blood

247

188

View full text Add to dashboard Cite

show abstract

“…3 A follow-up study identified ATM mutations with deletion of the ATM gene in only 38% of patients, contrasting with the high concordance found between TP53 loss and mutation. Preliminary data suggest that the outcome of patients with an ATM mutation is poorer than for those with ATM loss without mutation.…”

mentioning

confidence: 80%

A novel functional assay using etoposide plus nutlin-3a detects and distinguishes between ATM and TP53 mutations in CLL

et al. 2008

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“…1,[9][10][11][12][13][14][15][16][17][18][19][20] p53 Mutations and CLL Mutations of TP53 are found in 4% to 37% of patients with CLL and unselected cohorts of untreated patients can be expected to show TP53 mutations in the order of 10%. 1,[9][10][11][12][13][14][15][16][17][18][19][20] On the other hand, the highest incidence of TP53 mutation is seen in patients with Fludarabine-refractory CLL and much of the heterogeneity in mutation prevalence is explained by different patient cohorts. 21 The presence of mutations in TP53 has been associated with poor prognosis in a number of retrospective studies but the association of 17p deletion and TP53 mutation has led to the pooling of mutations with 17p deletion (usually the majority) and cases without 17p deletion.…”

confidence: 99%