Leukemia & Lymphoma, June 2011; 52(S2): 103–107
Insight into the behavior of hairy cell leukemia by immunogenetic analysis
FRANCESCO FORCONI, EMANUELE CENCINI, ELISA SOZZI, ANNA SICURANZA, DONATELLA RASPADORI, & FRANCESCO LAURIA
Ematologia e Trapianti, Universita ` di Siena & AOUS, Siena, Italy
Abstract The B cell receptor (BCR) is the functional distinguishing unit that defines any B cell. Immunoglobulin gene (IG) status is preserved in the neoplastic B cell clone and can provide an indicator of the maturation stage reached by the B cell prior to transformation. In hairy cell leukemia (HCL), several data from IG analysis provide clear hints regarding the cell of origin and the ongoing selective interactions of the tumor BCR with environmental stimuli: HCLs (i) have variable levels of IG somatic mutations, (ii) continue somatic mutations at low levels, (iii) have active processes of IG class switching after transformation, and (iv) have a relatively high frequency of selective events in the light chain of the BCR. It has recently emerged that an unmutated status of the HCL-derived IG can be associated with failure to respond to cladribine, genetic abnormalities indicative of poor outcome, and aggressive disease. These observations suggest that IG gene analysis may have biological and prognostic relevance in HCL and merits further characterization.
Keywords: Hairy cell leukemia, cladribine, IGH, immunogenetics, prognosis
Hairy cell leukemia: clinical and diagnostic features
Hairy cell leukemia (HCL) is a rare neoplasm of peripheral B cells with typical cytoplasmic projec- tions [1]. The most frequent clinical features include weakness and fatigue and enlarged but rarely symptomatic splenomegaly [1]. Hepatomegaly is observed in about half of the patients while lymph nodes are very rarely enlarged [1]. Pancytopenia with absolute monocytopenia, dry aspiration tap due to reticulin fibrosis of the bone marrow, demonstration of hairy cells with a typical ‘activated’ phenotype, and annexin 1 (ANXA-1) expression at bone marrow immunohistochemistry complete the diagnostic fea- tures of this disease [2–4].
Pathogenetic significance of immunoglobulin gene analysis in hairy cell leukemia
The B cell receptor (BCR) is the functional distin- guishing unit of any B cell [5]. Immunoglobulin gene
(IG) status is preserved in the neoplastic B cell clone and can be an indicator of the maturation stage of theB cell prior to transformation [5,6]. InHCL,several data from IG analysis provide hints regarding HCL origin, and suggest selection of the tumor BCR and ongoing interactions of the tumor BCR with yet undefined environmental stimuli. First, HCL preferentially selects IG heavy (H) variable (V) domains IGHV3- 21, IGHV3-30, and IGHV3-33 [7–9] and IG lambda (L) light chain with universal selection of IGLJ3 [9]. Complementarity-determining regions 3 of the L chain (LCDR3s) have highly homologous motifs in 40% of IGL, and selective pairing of IGHV3-21/30/ 33 segments to specific LCDR3-J3 subsets has been observed [9]. Second, HCL carries variable levels of somatic mutations (SMs) in the tumor IGH and IG light chains, and only aminority have unmutated (U) IGHV and IGK/LV [9,10], indicating that the cell of origin has encountered a site where mutation is activated [7–9,11–14]. The documentation of intra- clonal variations also indicated that mutation continued at a low level after transformation,
Correspondence: Francesco Forconi, MD, DM, PhD, Sezione di Ematologia e Trapianti, Dipartimento di Medicina Clinica e Scienze Immunologiche, Universita
` di Siena, AOUS, Viale Bracci, 53100 Siena, Italy. Tel: þ39-0577-586798. Fax: þ39-0577-586185. E-mail:
forconif@unisi.it
ISSN 1042-8194 print/ISSN 1029-2403 online 2011 Informa UK, Ltd. DOI: 10.3109/10428194.2011.569620
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