Associations between Chromosomal Aberrations and Functional Impairment of the P53 Pathway in Chronic Lymphocytic Leukaemia.
Authors: Pettitt Andrew R. , Carter Anthony , Lin Ke , Sherrington Paul D. , Atherton Mark , Pearson Kevin , Douglas Angela , Burford Anna , Brito-Babapulle V. , Matutes Estella , Catovsky Daniel 
Published: October 2019

Adverse prognostic factors in CLL include functional impairment of the p53 pathway [Blood2002;100:1404] and the chromosomal aberrations del 17p13, del 11q23 and +12 [reviewed in Leukemia2002;16:993]. Intriguingly, TP53 is deleted at 17p13, ATM (an important positive regulator of p53) is deleted at 11q23, and MDM2 (an key negative regulator of p53) is amplified in +12. This suggests that p53 dysfunction might account for the deleterious effects of these chromosomal aberrations, and consequently that the two tests might provide similar prognostic information. To define the relationship between p53 dysfunction and karyotype, CLL clones from 178 patients were subjected to p53 functional analysis and interphase FISH for del 17p13, del 11q23, +12 and del 13q14. In order to assign cases with multiple FISH defects to single karyotypic groups, we used an hierarchical model, in which del 17p13, del 11q23, +12 and del 13q14 had a descending order of importance [N Engl J Med2000;343:1910]. The overall frequency of each hierarchical karyotype (17p−, 11q−, +12, and 13q−) was 16.3%, 16.3%, 12.4% and 33.1% respectively. p53 dysfunction, defined as impaired up-regulation of p21 (a transcriptional target of p53) in response to ionizing radiation (IR), was detected in 40.4% of cases using a validated FACS method. 5.1% of cases had the type A defect (baseline p53 increased), 35.4% the type B defect (baseline p53 not increased), and the remainder were classified as having a normal p53 functional response. The distribution of karyotype and p53 functional status is shown in Table 1.

Table 1

Karyotype Type A p53 defect Type B p53 defect No p53 dysfunction Total 17p− 7 13 9 29 11q− 1 16 12 29 12+ 1 3 18 22 13q− 0 17 42 59 Normal 0 14 25 39 Total 9 63 106 178

p53 dysfunction was positively associated with 17p− (P < 0.001) and 11q− (P = 0.029), negatively associated with +12 (P = 0.023) and 13q− (P = 0.007), and neither positively or negatively associated with normal karyotype. The frequency of p53 dysfunction in cases with 17p−, 11q−, +12, 13q−, or no FISH defects was 69.0%, 58.6%, 18.2%, 28.8% and 35.9% respectively. The frequency of 17p−, 11q−, +12, 13q−, or no FISH defects was 28.6%, 24.3%, 5.7%, 24.3% and 20.0% respectively in cases with p53 dysfunction, and 8.5%, 11.3%, 17.0%, 39.0% and 23.6% respectively in cases with no detectable p53 dysfunction. Among cases with p53 dysfunction, there was an association between the type A defect and 17p− (P < 0.001). Interestingly, among 17p− cases, the proportion of cells harbouring the 17p13 deletion negatively correlated with the amount of IR-induced p21 up-regulation (r = −0.608, P < 0.001) and positively correlated with baseline p53 levels (r = 0.398, P = 0.033). Indeed, p53 dysfunction was detected in all 15 cases with more than 50% 17p13-deleted cells but in fewer than half of the cases with less than 50% deletion. Together, these findings indicate that adverse karyotype and p53 dysfunction provide overlapping but non-identical information. The association between p53 dysfunction and 17p−/11q− supports the idea of a shared pathogenetic mechanism. On the other hand, the imperfect nature of this association justifies the continued evaluation of p53 functional analysis as a prognostic factor in CLL.