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(P<0.03). Published data regarding the association between CD25 and +12 report conflicting findings.72-74
Stereotyped B-cell receptor prevalence in patients with +12 CLL
Recurrent 'stereotyped' patterns,75,76 known as subsets, have been reported in +12 CLL patients, including a high- er prevalence of the IGHV 4-39 gene, particularly in patients who developed Richter Syndrome.77-79 Falisi et al. highlighted the fact that 44% of +12 CLL patients carried stereotyped B-cell receptor33 and found a significantly higher prevalence of stereotyped IGHV configurations in +12 CLL patients than in controls (27%; P=0.01). The most prevalent stereotyped subset was subset #1, fol- lowed by subsets #8, #10, #28 and #59. The most fre- quently observed IGHV gene was V4-39*01, followed by V1-3*01. IGHV 4-39*01 was the most common gene in +12 CLL patients in the literature, confirming the strong association between +12, IGHV 4-39*01 stereotype, and Richter syndrome.77-80
Immunoglobulin heavy chain mutational status in patients with +12 CLL
Chronic lymphocytic leukemia subgroups with del11q/del17p and +12 showed greater percentages of unmutated IGHV cases (80.0% and 53.8%, respectively) than those with del13q or with normal karyotype (37.5% and 31.5%, respectively).38 Cytogenetic subgroups also showed differences in the IGHV repertoire: IGHV1 genes were observed more frequently in the +12 subgroup (26.9%) than in other subgroups (20.0% in del11q/del17p and in del13q subgroups and 12.3% in the normal kary- otype). IGHV4 genes were noted at similar frequencies in the +12 subgroup and in the normal group (34.6% and 30.1%, respectively), and they were not identified in any cases in the del11q/del17p subgroup.38
Molecular abnormalities in patients with +12 CLL
Chronic lymphocytic leukemia patients with +12 or normal karyotype at diagnosis have an approximately 2- fold higher probability of developing poor-risk genetic lesions and entering the intermediate- or high-risk sub- groups associated with shorter survival, compared with low-risk CLL patients harboring del13q only.12
Chronic lymphocytic leukemia patients with +12 rarely show TP53 mutations or acquire them over time.12,81,82 On the contrary, NOTCH1 mutations can be identified in 30- 40% of CLL patients carrying +12.83-86 NOTCH1 is a human gene encoding a single-pass transmembrane pro- tein, whose signaling network regulates interactions between physically adjacent cells. Following the pivotal study that identified NOTCH1 mutations in CLL and pro- vided initial evidence on the unfavorable clinical outcome associated with NOTCH1 alterations,87 two additional independent studies of the CLL coding genome have identified activating mutations of NOTCH1 gene in approximately 10% of CLL at diagnosis.88,89 The biological contribution of NOTCH1 mutations in determining the aggressive behavior of CLL could be due to the over-rep- resentation of genes involved in the cell cycle and prolif- eration. In at least four series, NOTCH1 mutations had an adverse impact on outcome independently of other clini- co-biological features.87-90 In an analysis by Del Giudice et al.,91 NOTCH1 mutations clustered within 104 untreated +12 CLL patients accounted for 24% of those cases, and
were frequently detected in cases with unfavorable bio- logical markers, associated with a particular gene expres- sion profile predicting a poor outcome. NOTCH1 muta- tions are not associated with TP53 disruption or del11q; this mutual exclusivity could be useful in a genetic hierar- chical prognostic model.91 NOTCH1 mutations were rep- resented in all cases included by frameshift deletions, in particular c.7544_7545delCT in 88% of cases, and were preferentially associated with unmutated IGHV (84% of cases; P=0.003).91 NOTCH1 mutations were not associat- ed with sex or ZAP-70 positivity (mutated NOTCH1 cases were 62.5% ZAP-70+, and wild-type NOTCH1 cases were 44.2% ZAP-70+; P=0.116). NOTCH1 muta- tions have been reported at CLL diagnosis in approxi- mately 20% of chemoresistant cases.33 NOTCH1 muta- tions conferred a higher cumulative probability of Richter syndrome.88,92,93 The impact of NOTCH1 mutations on prognosis is less relevant in the presence of concurrent chromosomal aberrations, as worse outcomes are observed among patients with +12 associated with addi- tional chromosomal abnormalities irrespective of NOTCH1 mutation status.30
Landau et al. have published the results of a large retro- spective cohort study using whole-exome sequencing to analyze the frequency of somatic mutation and copy number abnormalities in 160 patients with CLL. They found that favorable alterations, such as MYD88 muta- tion, del13q and +12, represented early clonal drivers of disease; instead, more unfavorable alterations, such as ATM, TP53 and SF3B1 mutations, were subclonal during the early stages of disease, and became clonal at time of first treatment or treatment failure. The same group has more recently published prospective genetic data collect- ed from 278 patients with CLL; while confirming previ- ously published retrospective data, this study found also an association between +12 and mutations in BIRC3 and BCOR. Interestingly, neither BIRC3 nor BCOR mutation was associated with worse survival, in contrast to what had previously been published in smaller studies.34,35
Maura et al. studied the association of CLL with IGF1R expression.94,95 IGF1R-IGF1/2 interaction is involved in intracellular cell signaling pathways such as RAS/RAF/MEK/ERK kinases and PI3K-Akt. IGF1R, which is implicated in the activation of the PI3K/Akt and MAPK pathways, was generally over-expressed in CLL cells compared with healthy B cells.96 IGF1R expression was strongly associated with unfavorable/intermediate-risk cytogenetic features, in particular +12, independently from unmutated IGHV, NOTCH1 mutation, or clinical monoclonal B-cell lymphocytosis status. Thus, IGF1R represents a potential novel candidate for specific target- ed therapy in +12 CLL patients. In a prospective series, a group of +12 patients, showing low IGF1R expression, mutated IGHV, and wild-type NOTCH1 status had an indolent clinical course, whereas the others, characterized by unmutated IGHV and/or high CD38, mutated NOTCH1, and high IGF1R, had a more aggressive evolu- tion and shorter TTFT. Thus, IGF1R may have a role in discriminating aggressive CLL from intermediate-risk or favorable CLL in the presence of +12.95
The overexpression of ATF5 in CLL was significantly (P<0.001) associated with chromosomal abnormalities including del11q and +12.97 ATF5 is known for its role in the regulation of cell cycle progression and of differentia- tion and apoptosis. ATF5 overexpression was most com-
haematologica | 2018; 103(6)