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Chronic lymphocytic leukemia with trisomy 12
surrogate marker of unmutated IGHV genes.46 When the threshold for CD38 positivity was set at the standard 30%, higher expression of CD38 was not associated with a significantly impaired TTFT, but a threshold of 40% for CD38 expression retained its prognostic value for TTFT (P=0.008); so the threshold of CD38 positivity may be raised to 40% in +12 CLL cases to preserve its prognostic value.46 CD38 inhibitors may have particular efficacy in this cytogenetic subtype.47 CD3848-50 also showed higher expression among CLL cases with both +12 and del11q,19 which could explain the adverse prognosis of this sub- group compared to CLL patients with +12.50-52
ZAP-70
The negative prognostic impact of ZAP-70 expression and the association of ZAP-70 with unmutated IGHV are maintained in patients with +12 CLL.46,53,54
CD20
CLL patients with +12 have higher expression of CD20 than CLL patients with del17p, del11q, del13q, or nega- tive FISH results; this expression of CD20 may predict a better response to rituximab-based regimens.55
FMC7
FMC7, an epitope on the CD20 molecule itself, is sig- nificantly (P=0.035) more frequent in the +12 subgroup of CLL (32.0%) than in the del13q CLL subgroup, normal patients, and the del11q/del17p CLL subgroup (in which 20.0%, 11.1%, and 10.0% were FMC7 positive, respec- tively).38
CD49
CD49d is expressed in a vast majority of +12 CLL cases and emerged as a negative prognostic factor.56-58 Using a 30% cut off, an analysis was performed on 1200 CLL patients:59 735 cases (61.2%) were CD49d-, whereas 465 cases (38.8%) were CD49d+. A significantly (P<0.001) higher percentage of cases were CD49d+ (89.4%) in the +12 subgroup than in the other cytogenetic subgroups. Among the CD49d+ CLL patients, those with +12 expressed CD49d at higher mean fluorescence intensity (MFI) levels [median MFI 2200; 95% confidence interval (CI) 1810-2546] compared with patients without +12 (median MFI 1386; 95%CI: 1050-1673; P<0.001). CD49d overexpression in +12 CLL is associated with ITGA4 hypomethylation, as shown by quantitative real-time polymerase chain reaction analysis in 74 CLL patients (31 patients who were CD49d- and lacked +12, and 43 patients who were CD49d+ and had +12). Patients with +12 who were CD49d+ showed a shorter TTFT than that of patients with +12 who were CD49d- (P<0.001).56 A specific tropism of +12 CLL cells toward lymph nodes has been confirmed by the higher proportion of +12 CLL cells in lymph nodes than in peripheral blood or bone marrow.60 CD49d overexpression may provide a molecu- lar basis for the peculiar biological behavior of +12 CLL and may predict the development of additional cytoge- netic lesions.61
CD23
CD23, a low-affinity receptor for IgE, is expressed on B cells and on monocytes and eosinophils.62 CD23 expres- sion varies in CLL:63 low CD23 expression, which was correlated with the presence of a prolymphocyte infiltrate
in the bone marrow, a higher white blood cell count, and an advanced stage of disease, was reported to be a nega- tive prognostic factor for CLL.64 There are two isotypes of CD23: CD23a, whose expression is higher than that of CD23b, has a role in survival, while CD23b enhances proliferation.65 CLL patients can be divided into two groups: one group expressing both isotypes of CD23 at a high level and CD20, CD22, and CD38 at low levels, and one group expressing both CD23 isotypes at a low level, most of them carrying +12.66 Therefore, a high CD23a/CD23b ratio and low CD23 expression combined with high CD20 and CD38 expression may be a useful tool in predicting +12 in CLL and could serve as a marker for a high likelihood of +12.
Integrins
Circulating +12 CLL cells show increased expression of the integrins CD11b, CD18, CD29, and ITGB7, and of the adhesion molecule CD323 compared with other CLL cytogenetic groups. These changes are modulated by NOTCH1 mutation status; NOTCH1-mutated +12 cases have lower expression of CD11a, CD11b, and CD18 than wild-type cases. +12 CLL cells also have upregulation of signaling pathways that increase ligand binding and enhance VLA-4–directed adhesion and motility.46 Also, increased expression of the α-integrins CD11a and CD11b was associated with a shortened TTFT (P=0.002 for CD11a; P=0.027 for CD11b). The presence of NOTCH1 mutations in the context of +12 was associated with decreased CLL cell expression of CD11a, CD11b, and CD18 to levels similar to those of CLL cells without +12. Notably, the presence of a NOTCH1 mutation had no impact on CD29, CD49d, or ITGB7 expression on CLL cells. The observed heterogeneity of expression of β2- integrins in +12 CLL cases can be explained largely by the presence of NOTCH1 mutations.46 The expression of the β2-integrins CD11a/CD18 (LFA-1) and CD11b/CD18 (Mac-1) is down-regulated by the co-existence of NOTCH1 mutations, indicating a novel interaction that may be of importance in aggressive, high-risk CLL.46
Adhesion molecules
Other cell surface markers with a possible prognostic role in +12 CLL are CD25 (also called activation-associat- ed interleukin-2 receptor), which has a role in B-cell pro- liferation; CD54 (i.e. intercellular adhesion molecule-1), which has a role in cell adhesion and in the homing process; and CD95 (i.e. FasR), which has a role in regula- tion of apoptosis in lymphoid tissues. Patients with levels of 30% or higher of CD25+ B-CLL cells had a shorter median TTFT (P=0.01).67 Low CD54 expression was asso- ciated with a prolonged median TTFT (P=0.004), low leukocyte count (P<0.05), and low serum lactate dehydro- genase level (P=0.03). CD54 could be a prognostic marker for CLL68,69 and might be a determiner of whether patients present with localized or widespread lym- phadenopathies.70 High CD95 expression has been corre- lated with elevated serum lactate dehydrogenase level (P=0.02) and lymphadenopathy (P=0.02). Hjalmar et al. correlated these markers on CD19+ cells with the occur- rence of +12 and atypical lymphocyte morphology.71 They found that the mean percentage of CD25+ B cells in CLL with atypical morphology and in patients with +12 was lower than that in CLL with typical morphology (P<0.02) and in patients with disomic tumor cells
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