Hairy cell leukemia: at the crossroad of somatic mutation and isotype switch.
Hairy cell leukemia (HCL) commonly expresses multiple immunoglobulin isotypes, a feature rare in other B-cell malignancies or in normal B cells. In HCL, there is no phenotypic evidence for subpopulations, and single cells from one previous case contained transcripts for several isotypes. This raises the questions of the differentiation status of the cell of origin and of posttransformation events. We have investigated 9 cases, all expressing multiple immunoglobulin isotypes. Multiple tumor-derived variable-(diversity)-joining-constant mu delta, gamma, alpha (V(D)J-Cmu, delta, gamma, alpha) transcripts were confirmed in single cells of a further case. All cases were negative for germinal center (GC)-associated markers CD27 and CD38. Seven of 9 cases had mutated V(H) genes, with low levels of intraclonal heterogeneity, but 2 of 9 were unmutated, indicative of pre-GC origin. Eight of 9 cases expressed activation-induced cytidine deaminase (AID), a molecule essential for somatic mutation and isotype switch. All cases expressed germ line heavy-chain I exon (I(H))-C(H) transcripts which paralleled surface immunoglobulin (sIg) isotype. Significantly, no circle transcripts indicative of deletional recombination of switched isotypes were detectable in 9 of 9 cases. These data indicate heterogeneity in the cell of origin in terms of mutational status, but reveal common features of AID expression and isotype-switching events occurring prior to deletional recombination. Both mutational and switching events may be influenced by environmental factors at extrafollicular sites.
Forconi
Francesco
F
Unità Operativa Complessa Ematologia e Trapianti, Dipartimento di Medicina Clinica e Scienze Immunologiche, Università di Siena, Italy. forconif@unisi.it.
Sahota
Surinder S
SS
Raspadori
Donatella
D
Ippoliti
Micaela
M
Babbage
Gavin
G
Lauria
Francesco
F
Stevenson
Freda K
FK
D036541:ADP-ribosyl Cyclase / Q000378:metabolism; D051997:ADP-ribosyl Cyclase 1; D015703:Antigens, CD / Q000378:metabolism; D014408:Biomarkers, Tumor; D003564:Cytidine Deaminase; D043525:Cytosine Deaminase / Q000235:genetics; D017353:Gene Deletion; D015973:Gene Expression Regulation, Leukemic / Q000276:immunology; D018858:Germinal Center / Q000378:metabolism; D006801:Humans; D007070:Immunoglobulin A / Q000235:genetics; D017578:Immunoglobulin Class Switching / Q000276:immunology*; D007072:Immunoglobulin D / Q000235:genetics; D007074:Immunoglobulin G / Q000235:genetics; D007075:Immunoglobulin M / Q000235:genetics; D007943:Leukemia, Hairy Cell / Q000235:genetics* / Q000276:immunology*; D008562:Membrane Glycoproteins; D009154:Mutation / Q000276:immunology; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7 / Q000378:metabolism; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
D015703:Antigens, CD; D014408:Biomarkers, Tumor; D007070:Immunoglobulin A; D007072:Immunoglobulin D; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D008562:Membrane Glycoproteins; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7; D036541:ADP-ribosyl Cyclase; C498154:CD38 protein, human; D051997:ADP-ribosyl Cyclase 1; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D043525:Cytosine Deaminase; D003564:Cytidine Deaminase