Immunogenetics of hairy cell leukemia
with poor overall survival, BCR proliferation signals, and unfavorable genetic abnormalities [24,42,50], including TP53 dysfunction by mutation and/or deletion [45,46]. In a separate study by Kreitman et al., the clinical
significance of IGHV usage and status was also investigated in relapsed/refractory patients with classical and variant HCL, and thus representing a poor-prognosis population per se [51]. The analysis confirmed that U-IGH status had the prognostic power to identify a short progression-free survival after treatment with cladribine. Most remarkably it was found that HCL cases with IGHV4-34 rearran- gements were more frequently unmutated, had higher white blood cell counts at diagnosis, lower response rates, shorter progression-free survival after initial cladribine therapy, and shorter overall survival from the time of diagnosis [51]. However, use of IGHV4-34 was closely linked to diagnostic features of the variant type of HCL, which is now included in a new disease chapter of the 2008 WHO [World Health Organization] classification of tumours of haematopoietic and lymphoid tissues [4]. It would be interesting to review IGHV4-34-positive variant HCL according to the new diagnostic criteria using ANXA-1 as a discriminator between HCL and the other splenic B cell lymphomas/leukemias unclassi- fied, which include variant HCL [4].
Conclusions and perspectives
Overall, IG analysis has provided several opportu- nities to gain molecular insight into the biology and clinical course of HCL. First, it confirms that HCL derives from a mature B cell type. Second, it suggests that the HCL cell is under selective pressures and continues CSR and other peripheral BCR selection events similar to those of any B cell interacting with antigen. Third, the data strongly suggest that BCR status plays a role in HCL outcome. The observation that HCL with U-IGH is resistant to single-agent cladribine may provide a new means of identifying a minor group of refractory patients within ‘classical’ HCL, while the observation that IGHV4-34 recog- nizes a variant form of HCL with a poor outcome suggests that IG analysis may have both diagnostic and prognostic relevance. As a matter of fact, variant HCL is now included in the chapter regarding splenic B cell lymphomas/leukemias unclassified, and is no longer part of the HCL category [4]. Clearly, the prognostic role of IG mutational status and IG use will need validation in independent studies. In an expansion of our prospective clinical analysis in classical HCL, comparing HCL carrying U-IGH/IG light chain and HCL carrying M-IGH/IG light chain pairs, U-HCL has been confirmed to have
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a shorter progression-free surivival after initial treat- ment with cladribine [Figure 1(A)]. The evidence that a proportion of patients with U-HCL have defects of the TP53 gene provides an explanation for the mechanisms of resistance and rapid progression in this group of patients [Figure 1(B)]. In our hypothetical model (Figure 2), HCL with U-IGH may resemble U-CLL that has a BCR
Figure 1. (A) Molecular parameters predicting progression-free survival in HCL. Unmutated immunoglobulin gene status predicts progression-free survival shorter than mutated immunoglobulin
gene. This figure represents HCL with 98% homology to germline of tumor IGV heavy and light chain pairs (U-IGH/light HCL, continuous line) versus HCL with598% homology to germline of tumor IGV heavy and light chain pairs (M-IGH/light HCL, dotted line). For each category, median progression-free survival time after first treatment with cladribine single-agent is indicated in months. (B) Molecular parameters predicting progression-free survival after first treatment with cladribine in HCL. TP53 disruption predicts shorter progression-free survival. This figure represents HCL with TP53 genetic disruption (TP53mut/del, continuous line) versus HCL with no documenta- tion of TP53 disruption (no TP53mut/del, dotted line), identified by TP53 point mutation or 17p deletion. For each category, median progression-free survival time after first treatment with cladribine single-agent is indicated in months.
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