Peripheral blood lymphocyte phenotype of ZAP-70⁺ and ZAP-70⁻ patients with B-cell chronic lymphocytic leukaemia
Background: Up to now, the immune status of chronic lymphocytic leukemia (CLL) patients in association with the expression of zeta-chain-associated protein kinase 70 (ZAP-70) in leukemic cells has not been evaluated. Aim: The aim of this work was the study of the peripheral blood (PB) T-lymphocyte p...
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| Опубліковано в: : | Experimental Oncology |
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| Дата: | 2015 |
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Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України
2015
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| Цитувати: | Peripheral blood lymphocyte phenotype of ZAP-70⁺ and ZAP-70⁻ patients with B-cell chronic lymphocytic leukaemia / A. Rivkina, Kholodyuk I. Holodnuka, M. Murovska, M. Soloveichika, S. Lejniece // Experimental Oncology. — 2015. — Т. 37, № 1. — С. 73-76. — Бібліогр.: 31 назв. — англ. |
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Digital Library of Periodicals of National Academy of Sciences of Ukraine| _version_ | 1859813962055417856 |
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| author | Rivkina, A. Kholodyuk I. Holodnuka Murovska, M. Soloveichika, M. Lejniece, S. |
| author_facet | Rivkina, A. Kholodyuk I. Holodnuka Murovska, M. Soloveichika, M. Lejniece, S. |
| citation_txt | Peripheral blood lymphocyte phenotype of ZAP-70⁺ and ZAP-70⁻ patients with B-cell chronic lymphocytic leukaemia / A. Rivkina, Kholodyuk I. Holodnuka, M. Murovska, M. Soloveichika, S. Lejniece // Experimental Oncology. — 2015. — Т. 37, № 1. — С. 73-76. — Бібліогр.: 31 назв. — англ. |
| collection | DSpace DC |
| container_title | Experimental Oncology |
| description | Background: Up to now, the immune status of chronic lymphocytic leukemia (CLL) patients in association with the expression of zeta-chain-associated protein kinase 70 (ZAP-70) in leukemic cells has not been evaluated. Aim: The aim of this work was the study of the peripheral blood (PB) T-lymphocyte phenotypes in ZAP-70-positive (ZAP-70⁺) and ZAP-70-negative (ZAP-70⁻) untreated patients with CLL. Materials and Methods: ZAP-70⁻, CD25-, CD3-, CD4-, and CD8-positive lymphocytes were enumerated by flow cytometry in PB of 120 untreated CLL patients. CD8+, CD3+CD4+ and CD3+CD25+ cells were counted for the non-leukemic lymphocytes. Results: The patients were distributed into two groups: the ZAP-70⁺ group of high CLL progression (n = 61), and the ZAP-70− group of low CLL progression (n = 59). In the ZAP-70⁺ group, the ratio CD4/CD8 (0.33 ± 0.62; p = 0.001) and the numbers of the CD3+ (34.8 ± 8.1%; p = 0.01), CD3+CD4+ (24.4% ± 4.8; p = 0.001), and CD3+CD25+ (6.2 ± 0.91%; p = 0.001) lymphocytes were reduced and the percentage of the CD8+ cells (73.1 ± 4.6%; p = 0.0001) was above the norm. In the ZAP-70− group, the number of the CD3+CD4+ cells (36.9 ± 6.1%; p = 0.001) was within the norm, but the numbers of the CD8+ (11.3 ± 1.1%; p = 0.0001) and CD3+ (41.2 ± 5.3%; p = 0.05) lymphocytes were reduced; the ratio CD4/CD8 (3.26 ± 0.88; p = 0.001) and the percentage of the CD3+CD25+ cells (27.1 ± 3.4%; p = 0.0001) were above the norm. Conclusions: Our data show that the increased CD4/CD8 ratio, caused by the reduced number of the CD8+ lymphocytes, and the increased number of CD3+CD25+ cells are characteristic for the ZAP-70− group (slow progressing) of untreated CLL patients. In ZAP-70⁺ patients, the CD4/CD8 ratio was significantly below the norm indicating an active disease process. Results of our study contribute to identification of CLL patients with different prognosis in routine diagnostic/prognostic procedures. Key Words: chronic lymphocytic leukemia, ZAP-70, immune status, CD4/CD8 ratio, regulatory T cell.
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Experimental Oncology 37, 73–76, 2015 (March) 73
PERIPHERAL BLOOD LYMPHOCYTE PHENOTYPE OF ZAP-70+
AND ZAP-70− PATIENTS WITH B-CELL CHRONIC LYMPHOCYTIC
LEUKAEMIA
A. Rivkina1–4, *, I. Holodnuka Kholodnyuk4, M. Murovska4, M. Soloveichika3, S. Lejniece1–3
1Riga Stradins University, Internal Diseases Department, Riga LV1007, Latvia
2Riga Eastern Clinical University Hospital, Chemotherapeutic and Hematological Clinic,
Riga LV1038, Latvia
3Riga Hematology Centre, Riga LV1006, Latvia
4Riga Stradins University, A. Kirchenstein Institute of Microbiology and Virology, Riga LV1067, Latvia
Background: Up to now, the immune status of chronic lymphocytic leukemia (CLL) patients in association with the expression
of zeta-chain-associated protein kinase 70 (ZAP-70) in leukemic cells has not been evaluated. Aim: The aim of this work was
the study of the peripheral blood (PB) T-lymphocyte phenotypes in ZAP-70-positive (ZAP-70+) and ZAP-70-negative (ZAP-70−)
untreated patients with CLL. Materials and Methods: ZAP-70-, CD25-, CD3-, CD4-, and CD8-positive lymphocytes were
enumerated by flow cytometry in PB of 120 untreated CLL patients. CD8+, CD3+CD4+ and CD3+CD25+ cells were counted
for the non-leukemic lymphocytes. Results: The patients were distributed into two groups: the ZAP-70+ group of high CLL progres-
sion (n = 61), and the ZAP-70− group of low CLL progression (n = 59). In the ZAP-70+ group, the ratio CD4/CD8 (0.33 ± 0.62;
p = 0.001) and the numbers of the CD3+ (34.8 ± 8.1%; p = 0.01), CD3+CD4+ (24.4% ± 4.8; p = 0.001), and CD3+CD25+
(6.2 ± 0.91%; p = 0.001) lymphocytes were reduced and the percentage of the CD8+ cells (73.1 ± 4.6%; p = 0.0001) was above
the norm. In the ZAP-70− group, the number of the CD3+CD4+ cells (36.9 ± 6.1%; p = 0.001) was within the norm, but the num-
bers of the CD8+ (11.3 ± 1.1%; p = 0.0001) and CD3+ (41.2 ± 5.3%; p = 0.05) lymphocytes were reduced; the ratio CD4/
CD8 (3.26 ± 0.88; p = 0.001) and the percentage of the CD3+CD25+ cells (27.1 ± 3.4%; p = 0.0001) were above the norm.
Conclusions: Our data show that the increased CD4/CD8 ratio, caused by the reduced number of the CD8+ lymphocytes, and
the increased number of CD3+CD25+ cells are characteristic for the ZAP-70− group (slow progressing) of untreated CLL patients.
In ZAP-70+ patients, the CD4/CD8 ratio was significantly below the norm indicating an active disease process. Results of our
study contribute to identification of CLL patients with different prognosis in routine diagnostic/prognostic procedures.
Key Words: chronic lymphocytic leukemia, ZAP-70, immune status, CD4/CD8 ratio, regulatory T cell.
Chronic lymphocytic leukemia (CLL) is the most
common type of leukemia among all neoplastic di-
seases of the hematopoietic and lymphoid tissues.
CLL is heterogeneous in its course and is characterized
not only by rates of progression but also by survival
of CLL patients. Currently, morphological structure
and clinical manifestations of CLL are described fully
and detailed, whereas the pathophysiological features
of this form of leukemia are not completely investigated
and are the subject of many research studies [1–4].
A significant role in CLL is assigned to the inter-
action of leukemic cells with the microenvironment,
which ensures their survival, proliferation, and re-
sistance to the action of pro-apoptotic stimuli [5, 6].
Clarification of the relationship between the immune
system and the development of the tumor in the body
is of current importance in modern oncoimmunology,
as it plays a significant role in the delay of growth and
regression of tumors [7]. CLL immune deficiency
caused by the both the tumor lesions of lymphoid
tissue and the influence of chemotherapy on hema-
topoiesis, results in the inhibition of the cellular and
humoral responses [8, 9].
T cells in CLL have been poorly studied despite
researchers’ growing interest in the peculiarities
of the functional activity of T-cell subpopulations and
their participation in the anti-tumor immune respon-
ses. It has been shown that in CLL, there is a decrease
in CD3+ T-lymphocytes [9]. The ratio of lymphocytes
with the CD4 and CD8 receptors or the helper/suppres-
sor (CD4/CD8) ratio (norm 1.5–2.5) in the PB is an as-
sessment of the immune status [10]. The increase
in lymphocytes with the CD8 receptor (the reduced
CD4/CD8 ratio, < 1.5) is characteristic for tumor devel-
opment [11, 12]. In CLL, an absolute CD8+ lymphocy-
tosis correlates with clinical stage of the disease [13].
A number of recent studies have shown that CLL
patients usually have abnormalities in the phenotype
of CD4 and CD8 T cells, including inversion of the nor-
mal CD4/CD8 ratio [14–16].
CD25 is the alpha chain of the IL-2 receptor (critical
for maintenance and expansion of the T-cell response
to antigen presentation) present on activated T and
B cells. When the immune system is hyperactive,
the count of the CD25+ lymphocytes in PB is increased.
Normally, the percentage of cells with the CD25 recep-
tor in the blood of a health adult is 13–24% [17]. In CLL
patients, the frequency of CD25+ regulatory T cells
is higher, when compared with healthy donors, and
Submitted: August 04, 2014.
*Correspondence: E-mail: alla.rivkina@aslimnica.lv
Abbreviations used: CLL — chronic lymphocytic leukemia;
FC — flow cytometry; PB — peripheral blood; ZAP-70 — zeta-
chain-associated protein kinase 70; ZAP-70+ — ZAP-70-positive;
ZAP-70− — ZAP-70-negative.
Exp Oncol 2015
37, 1, 73–76
74 Experimental Oncology 37, 73–76, 2015 (March)
is further increased in patients with advanced stage
disease [16, 18, 19].
One of the most differentially expressed lym-
phocytes genes is the gene encoding the Zeta-
chain-associated protein kinase of 70 kDa (ZAP-70),
which is normally expressed in T cells and NK cells.
Crespo et al. [20] were the first who confirmed
the value of ZAP-70 as a surrogate marker for
the immunoglobulin variable region heavy chain
(IgVH) mutation status in CLL. In a number of studies
of recent years, it has been shown that, in CLL, high
expression of ZAP-70 is significantly associated with
an unmutated IgVH gene [21, 22] and high expres-
sion of CD38 (> 30% of leukemic cells) and is cor-
related with shorter treatment-free survival indicating
an adverse clinical prognosis [23, 24]. Expression
of the ZAP-70 protein above a certain threshold of cells
(> 20%) has proven to be an independent marker
of clinical outcome [25].
Up to now, the association between the levels
of the T-lymphocyte subpopulations in the subgroups
of CLL patients, positive for the ZAP-70 (ZAP-70+, rap-
idly progressive) and negative for the ZAP-70 ( ZAP-70−,
slowly progressive), has not been evaluated. The aim
of our study was to analyze the immune status (the CD4/
CD8 ratio) and the proportion of the CD8+, CD3+CD4+,
and CD3+CD25+ lymphocytes in PB of ZAP-70+ and
ZAP-70− groups of untreated CLL patients.
MATERIALS AND METHODS
Selection of patients and clinical assessments.
The study group consisted of 120 patients who were
diagnosed with CLL for the first time. The patients en-
rolled in this study (60 males, 60 females) had an age
range of 34–86 years (median age was 67 years).
The median age of males and females was 65.6 and
69.3 years, respectively. The Rai classification for
the estimation of clinical stages was used. The selec-
tion of patients was carried out at the Chemotherapeu-
tic and Hematological Clinic (Riga, Latvia) in the period
from July 2007 to July 2008. The study design, pa-
tients’ information, and consent forms were approved
by the Central Ethics Commission at the Latvian Medi-
cal Association, Riga, Latvia (22.03.2007. N. A-9).
Flow cy tometr y analyses. The indices
of CD19, CD5, CD23, CD3, CD4, CD8, CD25, and
ZAP-70 in PB were determined by flow cytometry (FC)
for all new CLL patients. After establishing the pre-
sence of the CD19+CD5+ population and diagnosis
of CLL, analysis of ZAP-70 expressing cells was per-
formed using the PN 772587 kit (Beckman Coulter Inc.,
USA). The pairs of fluorochrome-labeled reagents from
Beckman Coulter, CD3-FITC and CD4-PE, CD4-FITC
and CD8-PE, and CD3-FITC and CD25-PE were used
and the FC analyses were carried out according
to the standard protocol from Beckman Coulter using
the flow cytometer EPICS XL (Beckman Coulter).
The number of the CD3+ cells and the CD4/CD8 ratio
were counted for the total number of gated lympho-
cytes. The percentages of the CD8+, CD3+CD4+,
and CD3+CD25+ cells were calculated for the non-
leukemic lymphocytes. Statistical analysis of the data
was performed using the D’Agostino-Pearson test and
the Mann — Whitney U test [26].
Statistical analysis. All data were statistically
processed, using the statistic programs GraphPad-
Prism version 5 (San Diego, California, USA). The data
were presented as M ± SE, p < 0.05 was considered
significant.
RESULTS AND DISCUSSION
All 120 CLL patients in the study were classified
by Rai stages (Table 1). The largest numbers of pa-
tients were in Rai stage I (n = 38) and Rai stage II
(n = 40).
Table 1. Number of patients in the study with low and high levels
of ZAP-70 in CLL stages of Rai classification
Rai classification ZAP-70+ subgroup (rapid
rate of CLL progression)
ZAP-70− subgroup (slow
rate of CLL progression)
Stage Number of pa-
tients, n (%)
Number of patients with
the ZAP-70 level > 20%
Number of patients with
the ZAP-70 level 0–20%
0 7 (6.0) 1 6
I 38 (32.0) 14 24
II 40 (33.0) 26 14
III 19 (16.0) 12 7
IV 16 (13.0) 8 8
In practice, flow cytometry turned out to be the pre-
ferred technique for assaying ZAP-70 expression
in CLL cells. Crespo et al. [20] were the first, who had
described such a flow cytometric method and who
confirmed the value of ZAP-70 as a marker for the IgVH
mutation status. In our study, we had defined two levels
of ZAP-70 expression: low (within the interval of 0–20%
of positive cells), corresponding to a slowly pro-
gressing CLL, and high (with more than 20% of posi-
tive cells), corresponding to the rapidly progressing
disease [3, 4, 21, 22]. The CLL patients were distribu-
ted into two groups: the ZAP-70+ subgroup, with high
level of ZAP-70 (61 patients), and the ZAP-70− or slowly
progressing CLL subgroup (59 patients), with the low
ZAP-70 level (see Table 1).
Table 2 presents the data of the levels of CD3+,
CD8+, CD3+CD4+, and CD3+CD25+ lymphocytes
in the ZAP-70+ and ZAP-70− subgroups of patients.
In the ZAP-70+ subgroup, the CD4/CD8 ratio below
the norm was due to the decrease in the number
of CD4+ lymphocytes and the increase in the number
of CD8+ cells (cytotoxic T-lymphocytes and NK cells).
In the ZAP-70− subgroup, the CD4/CD8 ratio was above
the norm. In this case, the amount of CD8+ cells was
below the norm and the amount of CD4+ lymphocytes
corresponded to the norm. In the ZAP-70+ subgroup,
the amount of CD3+CD4+, and CD3+CD25+ cells
were below the norm with the statistical significance
p = 0.001, but the level of CD8+ lymphocytes was
increased. On contrary, in the ZAP-70− subgroup,
the count of CD8+ lymphocytes was below the norm,
the count of the CD3+CD25+ cells was above the norm,
whereas the count of CD3+CD4+ cells corresponded
to the norm, indicating the activity of the immune cells.
There was a significant correlation between the pa-
rameters of CD25, CD8, CD4 and the ratio of CD4/
Experimental Oncology 37, 73–76, 2015 (March) 75
CD8 in both subgroups. The correlation for the para-
meter CD3 was not identified in the above-mentioned
subgroups.
Table 2. Parameters of PB T-lymphocytes in the ZAP-70+ and ZAP-70−
subgroups of CLL patients
Parameters (the nor-
mal reference range,
norm)
ZAP-70+ subgroup ZAP-70− subgroup
> 20%
of positive
cells
(n = 61)
values 0–20%
of positive
cells
(n = 59)
values
p r p r
CD3+ cells*, %
(norm: 58–76%) 34.8 ± 8.1 0.01 0.33 41.2 ± 5.3 0.05 0.15
CD4/CD8 ratio*
(norm: 1.5–2.5) 0.33 ± 0.62 0.001 0.33 3.26 ± 0.88 0.001 0.37
CD8+ cells**, %
(norm: 17–37%) 73.1 ± 4.6 0.0001 0.41 11.3 ± 1.1 0.0001 0.48
CD3+CD4+ cells**, %
(norm: 35 — 65%) 24.4 ± 4.8 0.001 0.44 36.9 ± 6.1 0.001 0.34
CD3+CD25+ cells**, %
(norm: 13–24%) 6.2 ± 0.91 0.001 0.32 27.1 ± 3.4 0.0001 0.49
CD marker(s) positive cells were detected within the lymphocyte analysis gate
defined on the basis of light scatter (FSC vs SSC). *The number of the CD3+
cells and the CD4/CD8 ratio were counted for the total number of lympho-
cytes; **the percentages of the CD8+, CD3+CD4+, and CD3+CD25+ cells
were calculated for the non-leukemic lymphocytes; norm — the normal re-
ference ranges for percentages of CD marker(s) positive cells in lympho-
cytes of health adults [17, 31].
To our knowledge, no research has been con ducted
on the immune status of the ZAP-70+ vs ZAP-70− CLL
patients. In the study of Zhang et al. [27] of 67 patients
with B-cell CLL, the number of CD3+, CD4+, CD8+,
and NK cells was reduced significantly and the CD4/
CD8 ratio was not severely changed. However, the group
of CLL patients was not divided into rapidly progressive
(ZAP-70+) and slowly progressive ( ZAP-70−) subgroups
and the CD25 immunophenotype was not analyzed.
In a number of studies of recent years, it has been
shown that T cells with the phenotype CD3+CD4+CD25+
suppress the activity of the effector T-lymphocytes and
thus may contribute to tumorogenesis [11]. Indeed,
Hus et al. [28] showed that stimulation of the tumor
immunity reduce lymphocytosis in CLL patients and
a decrease in the number of CD4+CD25+FOXP3+
(forkhead box P3) regulatory T cells was detected.
Another study has demonstrated that, in patients
at later CLL stages, the levels of CD4+FOXP3+ T cells
were significantly increased and the immune response
was reduced [29]. However, in the study by Gowda
et al. [30], it was shown that the high levels of cells
with CD4 and CD25 receptors contributed to better
survival of patients with CLL. Recently, it was reported
that inverted CD4/CD8 ratios (< 1) are associated with
shorter lymphocyte doubling time, shorter time to first
treatment, and reduced progression-free survival
in CLL disease, suggesting that T-cell dysfunction
contributes toward disease progression [16].
Our study also revealed that in the slowly prog-
ressing ZAP-70− subgroup of CLL patients, the number
of CD3+CD25+ cells and the CD4/CD8 ratio were
significantly higher than in the rapidly progressing
ZAP-70+ subgroup. In ZAP-70+ patients, the CD4/
CD8 ratio was substantially below the norm, indicating
a cell cytotoxic activity and an active disease process.
The increased number of the CD3+CD25+ cells,
the level of the CD3+CD4+ cells within the normal refe-
rence range and the CD4/CD8 ratio above the norm
in the ZAP-70− subgroup of CLL patients, evidence
the better functional immune activity and the low rate
of the disease progression.
ACKNOWLEDGMENTS
This work was supported by the Latvian Council
of Science projects Nr. 09.1392 and Nr. 651/2014.
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| id | nasplib_isofts_kiev_ua-123456789-145459 |
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| language | English |
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| publisher | Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України |
| record_format | dspace |
| spelling | Rivkina, A. Kholodyuk I. Holodnuka Murovska, M. Soloveichika, M. Lejniece, S. 2019-01-22T10:53:32Z 2019-01-22T10:53:32Z 2015 Peripheral blood lymphocyte phenotype of ZAP-70⁺ and ZAP-70⁻ patients with B-cell chronic lymphocytic leukaemia / A. Rivkina, Kholodyuk I. Holodnuka, M. Murovska, M. Soloveichika, S. Lejniece // Experimental Oncology. — 2015. — Т. 37, № 1. — С. 73-76. — Бібліогр.: 31 назв. — англ. 1812-9269 https://nasplib.isofts.kiev.ua/handle/123456789/145459 Background: Up to now, the immune status of chronic lymphocytic leukemia (CLL) patients in association with the expression of zeta-chain-associated protein kinase 70 (ZAP-70) in leukemic cells has not been evaluated. Aim: The aim of this work was the study of the peripheral blood (PB) T-lymphocyte phenotypes in ZAP-70-positive (ZAP-70⁺) and ZAP-70-negative (ZAP-70⁻) untreated patients with CLL. Materials and Methods: ZAP-70⁻, CD25-, CD3-, CD4-, and CD8-positive lymphocytes were enumerated by flow cytometry in PB of 120 untreated CLL patients. CD8+, CD3+CD4+ and CD3+CD25+ cells were counted for the non-leukemic lymphocytes. Results: The patients were distributed into two groups: the ZAP-70⁺ group of high CLL progression (n = 61), and the ZAP-70− group of low CLL progression (n = 59). In the ZAP-70⁺ group, the ratio CD4/CD8 (0.33 ± 0.62; p = 0.001) and the numbers of the CD3+ (34.8 ± 8.1%; p = 0.01), CD3+CD4+ (24.4% ± 4.8; p = 0.001), and CD3+CD25+ (6.2 ± 0.91%; p = 0.001) lymphocytes were reduced and the percentage of the CD8+ cells (73.1 ± 4.6%; p = 0.0001) was above the norm. In the ZAP-70− group, the number of the CD3+CD4+ cells (36.9 ± 6.1%; p = 0.001) was within the norm, but the numbers of the CD8+ (11.3 ± 1.1%; p = 0.0001) and CD3+ (41.2 ± 5.3%; p = 0.05) lymphocytes were reduced; the ratio CD4/CD8 (3.26 ± 0.88; p = 0.001) and the percentage of the CD3+CD25+ cells (27.1 ± 3.4%; p = 0.0001) were above the norm. Conclusions: Our data show that the increased CD4/CD8 ratio, caused by the reduced number of the CD8+ lymphocytes, and the increased number of CD3+CD25+ cells are characteristic for the ZAP-70− group (slow progressing) of untreated CLL patients. In ZAP-70⁺ patients, the CD4/CD8 ratio was significantly below the norm indicating an active disease process. Results of our study contribute to identification of CLL patients with different prognosis in routine diagnostic/prognostic procedures. Key Words: chronic lymphocytic leukemia, ZAP-70, immune status, CD4/CD8 ratio, regulatory T cell. This work was supported by the Latvian Council of Science projects Nr. 09.1392 and Nr. 651/2014. en Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України Experimental Oncology Original contributions Peripheral blood lymphocyte phenotype of ZAP-70⁺ and ZAP-70⁻ patients with B-cell chronic lymphocytic leukaemia Article published earlier |
| spellingShingle | Peripheral blood lymphocyte phenotype of ZAP-70⁺ and ZAP-70⁻ patients with B-cell chronic lymphocytic leukaemia Rivkina, A. Kholodyuk I. Holodnuka Murovska, M. Soloveichika, M. Lejniece, S. Original contributions |
| title | Peripheral blood lymphocyte phenotype of ZAP-70⁺ and ZAP-70⁻ patients with B-cell chronic lymphocytic leukaemia |
| title_full | Peripheral blood lymphocyte phenotype of ZAP-70⁺ and ZAP-70⁻ patients with B-cell chronic lymphocytic leukaemia |
| title_fullStr | Peripheral blood lymphocyte phenotype of ZAP-70⁺ and ZAP-70⁻ patients with B-cell chronic lymphocytic leukaemia |
| title_full_unstemmed | Peripheral blood lymphocyte phenotype of ZAP-70⁺ and ZAP-70⁻ patients with B-cell chronic lymphocytic leukaemia |
| title_short | Peripheral blood lymphocyte phenotype of ZAP-70⁺ and ZAP-70⁻ patients with B-cell chronic lymphocytic leukaemia |
| title_sort | peripheral blood lymphocyte phenotype of zap-70⁺ and zap-70⁻ patients with b-cell chronic lymphocytic leukaemia |
| topic | Original contributions |
| topic_facet | Original contributions |
| url | https://nasplib.isofts.kiev.ua/handle/123456789/145459 |
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