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consistent with a possible ongoing influence of antigen on the tumor clone [9,11,12,14]. Third, the majority of HCLs are characterized by the very unusual and unique feature of expressing multipleIGHisotypes on the tumor cell surface while class switch recombina- tion (CSR) events are still ongoing [9,15]. Phenotypic and transcript analyses from primary samples of HCL expressing multiple IGH isotypes have revealed no evidence for subpopulations. Consistent with the ongoing SM and CSR events, HCL tumor cells express activation-induced cytidine deaminase (AID), a molecule essential for SM and CSR [16– 19]. We have also recently found multiple (double) tumor-related IG kappa (K) and/or L light chain expression in a relatively high proportion of HCL, as compared to normal B cells [20]. Most interestingly, these double IG light chain expressers re-induce the recombination activating gene (RAG). The evidence of double light chain expression in single hairy cells and the observation of RAG re-induction have provided additional indications that ongoing selective influences on the BCR may be relevant requirements to promote or maintain the tumor clone in a relatively large number of HCL cases [20]. Overall, the immunogenetic data suggest selective
events of theBCRand are consistent with the origin of HCL from a mature B cell with features of activation [12,14,21]. In these terms, the tumorIGevents appear to be induced by some sort of external pressure on the BCR of the transformed B cells and to continue after transformation, likely outside the canonical germinal center (GC) structures of the follicle [22,23]. If these suggestions are valid, it would be logic to expect that HCL would behave differently according to distin- guishing immunogenetic features of HCL subsets, such as, for example, subsets expressing mutated (M-) IGH or U-IGH [24].
Rationale and clinical significance of immunoglobulin gene analysis in hairy cell leukemia
Despite the relevant progress made in managing patients with HCL over the past 50 years, additional work is required in order to achieve the optimal outcome for these patients. HCL is generally respon- sive to purine analogs, including cladribine, and only a minority of patients are refractory [25,26]. Patients with HCL who obtain either complete or partial responses are expected to have a normal lifespan and/ or will have a high chance of benefiting from second treatments if they relapse, and not die ofHCL[27,28]. Conversely, the minority of patients refractory to cladribine often do not respond to subsequent treat- ments and have a poorer prognosis [25]. With the advent of new treatment compounds and modalities
[29–31], it seems important to characterize the unresponsive group more accurately in order to define the most effective treatment strategies, possi- bly at disease onset [32]. In HCL, several studies have investigated clinical parameters that predict relapse, progression, or overall survival in patients after that they have received purine analogs [33]. Single-institution analyses identified the presence of lymphadenopathy [34,35], hemoglobin levels [28,34, 36], splenomegaly [36,37], leukopenia [34], or leukocytosis [34,38] as possible factors predicting response, although no consensus has been achieved as yet [28]. Additionally, the molecular features associated with the clinical behavior of HCL have rarely been a matter of investigation [33,39]. In chronic lymphocytic leukemia (CLL), muta-
tional status of the tumorIGHVhas a major impact on prognosis and is recommended for treatment stratifi- cation in clinical trials [24,40]. In fact, CLL with U- IGHV is associated with poor overall survival, BCR proliferation signals, and unfavorable genetic abnorm- alities, which may cause resistance to purine analogs [24,41,42]. Among these abnormalities, deletion or mutations of TP53, a gene located at the 17p13 locus crucial in the mechanisms of cell proliferation and apoptosis, DNA repair, and sensitivity to purine analogs [43,44], emerge as a major prognostic para- meter of poor outcome [45,46]. Similarly, U-IGHV also indicates a poor prognosis in other lymphomas [47,48]. The above factors raise the question whether the situation in HCL may be similar, i.e. whether IG status has any clinical significance on HCL outcome. In an Italian multicenter clinical trial using single-
agent cladribine in newly diagnosed cases of classical HCL, clinical and molecular parameters predicting response and the immunogenetic and molecular profile of the refractory patients were investigated prospectively [10]. From molecular analysis, it emerged that U-IGHV status was an almost absolute discriminator of response failure to cladribine and rapid clinical progression after therapy. This novel U-HCL subset identified a group of patients asso- ciated with leukocytosis, splenomegaly, and frequent TP53 dysfunction. The observation that U-HCL is associated with high tumor burden, leukocytosis, and impressive splenomegaly at presentation suggests that patients with U-HCL may accumulate tumor cells more rapidly than those with M-HCL, in a manner similar to patients with U-CLL who are frequently diagnosed at advanced stages of disease [49]. Patients with U-HCL resistant to cladribine frequently harbor genetic damage leading to TP53 dysfunction, which is a known cause of resistance to purine analogs [43,44]. These data mirror the model of CLL, the most common type of leukemia in the Western world, where U-IGHV status is associated
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