Leukemia
J Clin Oncol. 2006 Feb 20;24(6):969-75. Epub 2006 Jan
17. J Immunol. 2006 Jan 15;176(2):931-8.
Additional genetic high-risk features
such as 11q deletion, 17p deletion, and V3-21 usage characterize
discordance of ZAP-70 and VH mutation status in chronic lymphocytic
leukemia.
Krober
A, Bloehdorn
J, Hafner
S, Buhler A, Seiler T, Kienle
D, Winkler D,
Bangerter
M, Schlenk
RF, Benner A, Lichter
P, Dohner
H, Stilgenbauer
S.
Department of Internal Medicine,
PURPOSE: Immunoglobulin heavy chain variable-region (VH) gene mutation
status and zeta-associated protein 70 (ZAP-70) expression
are correlated in chronic lymphocytic leukemia
(CLL), but their concordance is variable. The goal of this study was to
elucidate additional factors potentially characterizing their discordance.
PATIENTS AND METHODS: We evaluated ZAP-70 expression by flow cytometry, VH status by DNA sequencing, and genomic
aberrations by fluorescence in situ hybridization in 148 CLL patients. The
parameters were analyzed for their associations and their individual
prognostic impact. RESULTS: ZAP-70 expression and VH mutation status were
strongly associated in CLL without additional genetic high-risk-features as
defined by the absence of 11q or 17p deletion and V3-21 usage (concordance
84%). In contrast, the proportion of discordant cases was significantly
higher (39%), if such additional genetic high-risk features were present.
Discordant cases with V3-21 usage were almost exclusively ZAP-70 positive
and VH mutated (89%), whereas all but one of the discordant cases with
high-risk aberrations were ZAP-70 negative and VH unmutated (92%). By multivariate regression analysis,
two models were developed, which both include high-risk genomic aberrations
and, alternatively, VH mutation status and V3-21 usage or ZAP-70 expression
as independent outcome predictors. CONCLUSION: There were characteristic
modes of discordance between ZAP-70 and VH mutation status depending on the
presence or absence of additional genetic high-risk features such as 11q
and 17p deletion or V3-21 usage. Although the biologic background for these
findings is yet to be determined, these data have biologic and clinical
implications regarding ZAP-70 as a pathogenic factor and outcome predictor,
respectively.
PMID: 16418492 [PubMed - indexed for MEDLINE]
The 77C->G mutation in the human CD45
(PTPRC) gene leads to increased intensity of TCR signaling in T cell lines
from healthy individuals and patients with multiple sclerosis.
Do HT, Baars
W, Borns
K, Windhagen
A, Schwinzer
R.
Transplantationslabor, Klinik
fur Viszeral-und Transplantationschirurgie,
Hannover, Germany.
The 77C-->G mutation in exon A of the human
CD45 gene occurs with low frequency in healthy individuals. An enhanced
frequency of 77C-->G individuals has been reported in cohorts of
patients suffering from multiple sclerosis, systemic sclerosis, autoimmune
hepatitis, and HIV-1. To investigate the mechanisms by which the variant
allele may contribute to disease susceptibility, we compared T cell
reactivity in heterozygous carriers of the mutation (healthy individuals
and multiple sclerosis patients) and wild-type controls. In vitro-generated
T cell lines and freshly isolated CD4+CD45R0+ primed/memory T cells from
77C-->G individuals aberrantly expressed CD45RA isoforms
and showed enhanced proliferation and IL-2 production when stimulated with
anti-TCR/CD3 mAb or Ag. Mutant T cell lines
contained a more active pool of p56lck tyrosine kinase
and responded with increased phosphorylation of
Zap70 and TCR-zeta and an enhanced Ca2+ flux to TCR/CD3 stimulation. These
data suggest that 77C-->G may act as a risk factor for certain diseases
by increasing the intensity of TCR signaling.
PMID: 16393978 [PubMed - indexed for MEDLINE]