|
|
 Previous Article | Table of Contents | Next Article 
Blood, 1 August 2002, Vol. 100, No. 3, pp. 1100-1101
CORRESPONDENCE
To the editor:
CXCR4 expression is associated with survival in familial
chronic lymphocytic leukemia, but CD38 expression is not
Recent immunogenetic studies of chronic lymphocytic leukemia
(CLL) suggest a dichotomy: those developing from naive, pregerminal B
lymphocytes exhibiting germline configuration of Ig VH
status (poor outcome) and those stemming from more mature, postgerminal center memory B cells with mutated Ig VH
genes1-3 (good prognosis). Due to the cost and expertise
required for this technique, a simpler, inexpensive substitute has been
sought. CD38 antigen expression is a marker that strongly correlates
with Ig VH gene mutational status1,4 and
predicts outcome in CLL,1,4-9 although not all studies
agree.10-12 Another class of markers, chemokines, and their respective receptors, may also correlate with clinical stage and
prognosis. CXCR4, a chemokine receptor found on CLL B cells, may play a
role in the marrow infiltration observed in CLL.13 We
evaluated (1) whether CD38 or CXCR4 expression is associated with
immunoglobulin gene usage and (2) whether these markers are prognostic
for survival in familial CLL cases. Thirty-nine individuals from the NCI Familial CLL
Registry14 had cells labeled, using a 4-color staining
method, with monoclonal antibodies against the lymphoid antigens CD5
phycoerythrin, CD38 allophycocyanin, CD19 peridinin chlorophyll protein
(BD Biosciences, San Jose, CA), and CXCR4 flourescein (R&D
Systems, Minneapolis, MN). Antibody expression was measured by
FACSCaliber (Becton Dickinson, San Jose, CA) flow cytometer. CD38 and
CXCR4 expressions were scored as percent positive of the B-CLL cells
(CD5+/CD19+).6 DNA of rearranged
immunoglobulin heavy chain genes were amplified by polymerase chain
reaction and cloned and sequenced, using a previously described
method.15 Assays were conducted with laboratory personnel
blinded to VH mutation and clinical characteristics of the patients. Generalized linear models were used to estimate least-squared mean CD38
expression by heavy chain mutation status on 21 patients using SAS
Version 8.0 (SAS, Cary, NC) and to evaluate the association with CXCR4
expression data. Survival was estimated on all 39 familial CLL patients
by the Kaplan-Meier method, using SPLUS 2000 (Insightful, Seattle, WA). Median levels of CD38 and CXCR4 expression in the subset
of cases with VH data were used to group the patients into lower and higher risk; differences in survival were tested by the
Wilcoxon test. All tests of statistical significance were two-sided. In agreement with earlier reports,1,3 unmutated
VH cases displayed a higher percentage of CD38+
cells than mutated cases (23.62% versus 5.80%, P = .03).
We did not observe an association between CD38 expression and survival in the 39 patients (Wilcoxon, P = .45) (Figure
1A). Rather, expression of the CXCR4
chemokine receptor was more strongly correlated with VH
mutational status (9.53% versus 40.82%, P = .004;
adjusted for age) and a better predictor of survival (Wilcoxon,
P = .02) (Figure 1B).
View larger version (14K):
[in this window]
[in a new window]
| Figure 1.
Survival probabilities for familial CLL patients.
(A) Survival probabilities comparing CLL patients by CD38 expression
pattern. (B) Survival probabilities comparing CLL patients by CXCR4
expression pattern.
|
|
CD38 expression has been proposed as a surrogate marker for
VH mutation status to predict the clinical course in CLL
with mixed findings.4-12 Although we observed an
association between CD38 expression and VH mutation status,
CD38 expression, in contrast with VH mutation status, did
not predict survival in our familial CLL cases. The 2 assays yielded
discordant results in 8 of the 21 cases, which may account for these
findings. Furthermore, only 2 cases had advanced disease at the
time of the specimen collection, resulting in the generally lower CD38
expression observed in this series. Variability in CD38 expression may
also be lower in familial CLL than in sporadic cases, making it
difficult to observe a difference with the available number of cases.
Only 2 of 21 patients with VH mutational data had CD38
expression levels greater than 30%. The association between underexpression of the CXCR4 chemokine receptor
and survival is consistent with its involvement in the trafficking and
homing of B-CLL cells to bone marrow, and the strong down-modulation of
CXCR4 on CLL B cells that migrate into the marrow stromal cell layer
that has been reported.13 Although we were unable to
examine CXCR4 expression in relation to the extent of marrow
involvement, our data also suggest that CXCR4 down-regulation may play
a role in the marrow infiltration observed in CLL. CXCR4 may be one
factor that regulates neoplastic B cells' survival by making cells
more resistant to apoptosis and allowing for unchecked proliferation of
the malignant clone. In summary, our results suggest that CXCR4 receptor expression levels
could potentially distinguish CLL patients who will develop aggressive
disease from those who will not. In our familial CLL cases, however, no
association with prognosis with CD38 expression was observed. Future
studies in a larger study population with extensive treatment and
clinical information are clearly warranted.
Naoko Ishibe, Maher Albitar, Iman B. Jilani, Lynn
R. Goldin, Gerald E. Marti, and Neil E. Caporaso
Correspondence: Naoko Ishibe, Genetic Epidemiology Branch,
Division of Cancer Epidemiology and Genetics, National Cancer
Institute, National Institutes of Health, Rockville, MD
References
1.
Damle RN, Wasil T, Fais F, et al.
IgV gene mutation status and CD38 expression as novel prognostic indicators in chronic lymphocytic leukemia.
Blood.
1999;94:1840-1847[Abstract/Free Full Text].
2.
Hamblin TJ, Davis Z, Gardiner A, et al.
Unmutated Ig VH genes are associated with a more aggressive form of chronic lymphocytic leukemia.
Blood.
1999;94:1848[Abstract/Free Full Text].
3.
Maloum K, Davi F, Merle-Beral H, et al.
Expression of unmutated VH genes is a detrimental prognostic factor in chronic lymphocytic leukemia.
Blood.
1000;96:377-379.
4.
Matrai Z, Lin K, Dennis M, et al.
CD38 expression and Ig VH gene mutation in B-cell chronic lymphocytic leukemia.
Blood.
2001;97:1902-1903[Free Full Text].
5.
Del Poeta G, Maurill L, Venditti A, et al.
Clinical significance of CD38 expression in chronic lymphocytic leukemia.
Blood.
2001;98:2633-2639[Abstract/Free Full Text].
6.
Ibrahim S, Keating M, Do KA, et al.
CD38 expression as an important prognostic factor in B-cell chronic lymphocytic leukemia.
Blood.
2001;98:181-186[Abstract/Free Full Text].
7.
Chevallier P, Penther D, Avet-Loiseau H, et al.
CD38 expression and secondary 17p deletion are important prognostic factors in chronic lymphocytic leukemia.
Br J Haematol.
2002;116:142-150[CrossRef][Medline]
[Order article via Infotrieve].
8.
D'Arena G, Musto P, Cascavilla N, et al.
CD38 expression correlates with adverse biological features and predicts poor clinical outcome in B-cell chronic lymphocytic leukemia.
Leuk Lymphoma.
2001;42:109-114[Medline]
[Order article via Infotrieve].
9.
Hamblin TJ, Orchard JA, Ibbotson RE, et al.
CD38 expression and immunoglobulin variable region mutations are independent prognostic variables in chronic lymphocytic leukemia, but CD38 expression may vary during the course of the disease.
Blood.
2002;99:1023-1029[Abstract/Free Full Text].
10.
Thunberg U, Johnson A, Roos G, et al.
CD38 expression is a poor predictor for VH gene mutational status and prognosis in chronic lymphocytic leukemia.
Blood.
2001;97:1892-1893[Free Full Text].
11.
Hamblin TJ, Orchard JA, Gardiner A, et al.
Immunoglobulin V genes and CD38 expression in CLL [letter].
Blood.
2000;95:2455-2456[Free Full Text].
12.
Morabito F, Mangiola M, Oliva B, et al.
Peripheral blood CD38 expression predicts survival in B-cell chronic lymphocytic leukemia.
Leuk Res.
2001;25:927-932[CrossRef][Medline]
[Order article via Infotrieve].
13.
Burger JA, Burger M, Kipps TJ.
Chronic lymphocytic leukemia B cells express functional CXCR4 chemokine receptors that mediate spontaneous migration beneath bone marrow stromal cells.
Blood.
1999;94:3658-3667[Abstract/Free Full Text].
14.
Ishibe N, Sgambati MT, Fontaine L, et al.
Clinical characteristics of familial B-CLL in the National Cancer Institute Familial Registry.
Leuk Lymphoma.
2001;42:99-108[Medline]
[Order article via Infotrieve].
15.
Sakai A, Marti GE, Caporaso NE, et al.
Analysis of expressed immunoglobulin heavy chain genes in familial B-CLL.
Blood.
2000;95:1413-1419[Abstract/Free Full Text].
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
This article has been cited by other articles:
|
|
|
|
 
F. Malavasi, S. Deaglio, A. Funaro, E. Ferrero, A. L. Horenstein, E. Ortolan, T. Vaisitti, and S. Aydin
Evolution and Function of the ADP Ribosyl Cyclase/CD38 Gene Family in Physiology and Pathology
Physiol Rev,
July 1, 2008;
88(3):
841 - 886.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. S. Sellick, L. R. Goldin, R. W. Wild, S. L. Slager, L. Ressenti, S. S. Strom, M. J. S. Dyer, F. R. Mauro, G. E. Marti, S. Fuller, et al.
A high-density SNP genome-wide linkage search of 206 families identifies susceptibility loci for chronic lymphocytic leukemia
Blood,
November 1, 2007;
110(9):
3326 - 3333.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. Ocana, L. Delgado-Perez, A. Campos-Caro, J. Munoz, A. Paz, R. Franco, and J. A. Brieva
The prognostic role of CXCR3 expression by chronic lymphocytic leukemia B cells
Haematologica,
March 1, 2007;
92(3):
349 - 356.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. Tsoli, P. K Tsantoulis, A. Papalambros, B. Perunovic, D. England, D. A Rawlands, G. M Reynolds, D. Vlachodimitropoulos, S. L Morgan, C. A Spiliopoulou, et al.
Simultaneous evaluation of maspin and CXCR4 in patients with breast cancer
J. Clin. Pathol.,
March 1, 2007;
60(3):
261 - 266.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. R. Goldin and S. L. Slager
Familial CLL: Genes and Environment
Hematology,
January 1, 2007;
2007(1):
339 - 345.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J.-P. Spano, F. Andre, L. Morat, L. Sabatier, B. Besse, C. Combadiere, P. Deterre, A. Martin, J. Azorin, D. Valeyre, et al.
Chemokine receptor CXCR4 and early-stage non-small cell lung cancer: pattern of expression and correlation with outcome
Ann. Onc.,
April 1, 2004;
15(4):
613 - 617.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
I. M. Ghobrial, N. D. Bone, M. J. Stenson, A. Novak, K. E. Hedin, N. E. Kay, and S. M. Ansell
Expression of the Chemokine Receptors CXCR4 and CCR7 and Disease Progression in B-Cell Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma
Mayo Clin. Proc.,
March 1, 2004;
79(3):
318 - 325.
[Abstract]
[PDF]
|
|
|
|
|
