Strikingly homologous immunoglobulin gene rearrangements and poor outcome in VH3-21-using chronic lymphocytic leukemia patients independent of geographic origin and mutational status.
We recently reported that Swedish VH3-21-using chronic lymphocytic leukemia (CLL) patients showed restricted immunoglobulin gene features and poor prognosis despite VH mutation status. To investigate this further, we analyzed the VH and VL gene rearrangements in 90 VH3-21+ patients from Sweden, Germany, Italy, United States, Finland, and Australia and correlated these data with survival and other prognostic markers. Sixty-three percent exhibited mutated VH genes and 37% unmutated VH genes. Fifty (56%) patients displayed a short and homologous heavy-chain CDR3, many of these with the amino acid motif DANGMDV. Also, a highly biased Vlambda2-14 use was evident in 72% of patients with a restricted light-chain CDR3, QVWDS(S/G)SDHPWV. Combined restricted heavy- and light-chain CDR3s were found in patients from all included countries. Although VH3-21+ CLLs have a remarkably predominant lambda expression, analyses of kappa deleting element indicated a conserved light-chain rearrangement order. The overall survival was poor in the VH3-21+ cohort (median survival, 88 months), with no significant difference in relation to mutation status or CDR3 homology. High ZAP-70 and CD38 expression was found in both mutated and unmutated VH3-21+ cases as well as a slight increase of 11q-aberrations. In summary, highly restricted B-cell receptors and worse outcome characterize VH3-21+ CLLs independent of geographic origin and mutation status.
Thorsélius
Mia
M
Department of Genetic and Pathology, Rudbeck Laboratory, Uppsala University, SE-751 85 Uppsala, Sweden.
Kröber
Alexander
A
Murray
Fiona
F
Thunberg
Ulf
U
Tobin
Gerard
G
Bühler
Andreas
A
Kienle
Dirk
D
Albesiano
Emilia
E
Maffei
Rossana
R
Dao-Ung
Lan-Phuong
LP
Wiley
James
J
Vilpo
Juhani
J
Laurell
Anna
A
Merup
Mats
M
Roos
Göran
G
Karlsson
Karin
K
Chiorazzi
Nicholas
N
Marasca
Roberto
R
Döhner
Hartmut
H
Stilgenbauer
Stephan
S
Rosenquist
Richard
R
D000595:Amino Acid Sequence; D001315:Australia; D002869:Chromosome Aberrations; D005060:Europe; D005843:Geography; D006801:Humans; D007128:Immunoglobulin Fragments / Q000737:chemistry / Q000235:genetics; D007143:Immunoglobulin Heavy Chains / Q000235:genetics*; D007147:Immunoglobulin Light Chains / Q000235:genetics*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics* / Q000276:immunology* / Q000401:mortality; D008969:Molecular Sequence Data; D009154:Mutation; D016019:Survival Analysis; D016896:Treatment Outcome; D014481:United States
D007128:Immunoglobulin Fragments; D007143:Immunoglobulin Heavy Chains; D007147:Immunoglobulin Light Chains