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 Table of Contents  
ORIGINAL ARTICLE
Year : 2017  |  Volume : 42  |  Issue : 4  |  Page : 155-160

Can CD34/CD123 distinguish between normal and leukemic B-cell precursors?


1 Department of Clinical Pathology, Faculty of Medicine, Zagazig University, Zagazig, Egypt
2 Department of Pediatrics, Faculty of Medicine, Zagazig University, Zagazig, Egypt

Date of Submission20-Mar-2017
Date of Acceptance20-Mar-2017
Date of Web Publication9-Feb-2018

Correspondence Address:
Nashwa M Al Azizi
Mafarek Almansura, Mostafa Aref Street, Zagazig, 44159
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ejh.ejh_10_17

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  Abstract 


Background/objective B-cell acute lymphoblastic leukemia (B-ALL) is the most common acute leukemia in children. There are many overlaps between leukemic lymphoblast and hematogones regarding their morphologic and immunophenotypic characteristics. CD123 is one of the markers that can be used to distinguish between leukemic lymphoblast and hematogones. In this study, we aimed to demonstrate the pattern of CD34/CD123 expression in hematogones and leukemic lymphoblast to monitor therapy response and detect minimal residual disease.
Patients and methods This case–control study was conducted on 40 newly diagnosed patients with B-lineage ALL. They were 14 boys and 26 girls with a mean age of 4.29±2.31 and a range from 2 to 10 years. Expression of CD34/CD123 by flow cytometry was carried out at diagnosis and at the end of induction. In addition, 20 patients with reactive bone marrow were included to asses hematogones.
Results In the patient group, cells with dim CD45 were found in 24 cases, 75% of them expressed CD34 and 83.3% expressed CD123. In addition, cells with moderate CD45 were 16, all expressed CD34 and 87.5% of them expressed CD123. Thirty-two (80%) leukemic blasts expressed both CD34 and CD123; in contrast, in four (10%) patients neither antigen was expressed. In hematogones, immature hematogones (dim CD45, CD34+) did not express CD123, whereas 75% of mature hematogones (moderate CD45, CD34) expressed CD123. On the other hand, at the end of induction, 18 (45%) leukemic blasts expressed both CD34 and CD123 and four (10%) showed no expression of both antigens.
Conclusion This distinct pattern of CD34 and CD123 expression on B-ALL blasts (concordant) and hematogones (discordant) can help differentiate residual leukemic blasts from hematogones in patients with B-ALL.

Keywords: Bcellbrecursor, CD123, CD34, leukemic lymphoblast


How to cite this article:
Esh SS, Al Azizi NM, Elsafy UR, Sherief LM, Zakaria M, Abdalah MM. Can CD34/CD123 distinguish between normal and leukemic B-cell precursors?. Egypt J Haematol 2017;42:155-60

How to cite this URL:
Esh SS, Al Azizi NM, Elsafy UR, Sherief LM, Zakaria M, Abdalah MM. Can CD34/CD123 distinguish between normal and leukemic B-cell precursors?. Egypt J Haematol [serial online] 2017 [cited 2018 Apr 23];42:155-60. Available from: http://www.ehj.eg.net/text.asp?2017/42/4/155/225085




  Introduction Top


Acute lymphoblastic leukemia (ALL) is a clonal hematologic disorder. It involves excessive proliferation and impaired differentiation of leukemic blasts that lead to inadequate normal hematopoiesis. It comprises ∼80% of pediatric acute leukemia [1]. It is an aggressive but potentially curable disease in which monitoring the immediate and early response to therapy is of critical importance for optimal management. Current management protocols require assessment of residual leukemic cells at defined intervals after initiation of chemotherapy. The non-neoplastic counterparts of leukemic B lymphoblasts, normal bone marrow B-cell precursors, are commonly referred to as hematogones. They are more commonly found and are generally present in higher numbers in children [2].

Hematogones are often increased (45%) in regenerating marrow and in some clinical conditions, particularly various types of cytopenias and neoplastic diseases [3]. Hematogones may morphologically resemble the neoplastic lymphoblasts of precursor B-cell acute lymphoblastic leukemia (B-ALL), and their immunophenotyping also has features in common with neoplastic lymphoblasts that can be mistaken for minimal residual disease [4].

CD123 is the α-chain of interleukin-3 receptor, a member of the cytokine receptor super family that is involved in proliferation and many stages of maturation of B lymphocytes including pre-B and pro-B cells [5]. In addition, many studies have shown the important role of interleukin-3 in leukemogenesis of lymphoid and myeloid cells [6].

CD34 is a human stage-specific hematopoietic differentiation antigen in leukemia cells; it remains expressed over several stages of lymphoid and myeloid maturation [7]. With four-color flow cytometry using CD34/CD123 combinations, the distinction between hematogones and leukemic B-cell precursors can nearly be made.

In this study, we aimed to demonstrate the pattern of CD34/CD123 expression in hematogones and leukemic lymphoblast to monitor therapy response and detect minimal residual disease.


  Patients and methods Top


This case–control study was carried out at Clinical Pathology and Pediatric Oncology Unit of Zagazig University Hospital during the period from April 2014 to July 2016. This study was approved by the ethical committee of Zagazig University, Egypt and written informed consent from parents was provided. It included 40 newly diagnosed patients with B-lineage ALL treated with CCG-1961 protocol. They were 14 boys and 26 girls with a mean age of 4.29±2.31 years and a range from 2 to 10 years. Twenty children who were subjected to bone marrow examination for a reason other than malignancy with reactive bone marrow were included as a control group.

Complete general and clinical examination was done with special emphasis on pallor, bleeding tendency, fever, and evidence of organ and central nervous system infiltration. Laboratory data including complete blood count, liver and kidney function, cerebrospinal fluid examination in addition to bone marrow examination and immunophenotyping for all participants (for cases it was done at diagnosis and the end of induction), and immunophenotyping of bone marrow samples were performed on Becton Dickinson FACScalibur flow cytometer (Becton Dickinson, San Diego, California, USA) using acute leukemia panel CD3, CD5, CD7, CD10, CD13, CD14, CD19, CD20, CD22, CD33, CD34, CD64, CD79a, TdT, HLA-DR, and MPO. Cells were considered to be positive for malignancy when more than 20% of cells express these markers, except for TdT and CD34 for which the cutoff value is 10%. In addition, the association of CD34/CD123 was assessed in leukemic and nonleukemic specimens. Diagnosis of ALL was based on morphological, cytochemical, and immunophenotypic characteristics of the leukemic blasts.

Sampling

For blood sample, 4 ml of venous blood was obtained from each patient and healthy control by sterile syringe under complete aseptic conditions, and it was divided as follows: 1 ml of peripheral blood was aseptically collected on K-EDTA for complete blood count and Leishman-stained peripheral blood smears were prepared, and 3 ml of blood was left in a tube to clot to obtain serum for liver and kidney functions and lactate dehydrogenase. For bone marrow sample, 1 ml of bone marrow sample was added on EDTA for immunophenotyping to establish diagnosis. Fluorochrome-conjugated antibodies to the following antigens were used to profile hematogones and B-ALL cells at indicated quantities per test: fluorescein isothiocyanate-conjugated isotype control antibodies for IgG1 and CD34. Phycoerythrin-conjugated isotype control antibodies for IgG2a, CD10, and CD123 were used at 10 µl per test. CD45 and CD19 were labeled with peridinin chlorophyll protein–cyanine and used at 10 µl per test. All monoclonal antibodies were purchased from Becton Dickinson. Additional combinations were used for analysis of B-ALL cases to classify them immunophenotypically and examine the aberrant expression of myeloid antigen.

Staining and acquisition

Staining was performed using the two or three color combinations of the conjugated antibodies listed in the preceding section by adding 10 μl of monoclonal antibody on 100 μl of bone marrow sample and incubating tubes for 20 min in the dark at room temperature. RBCs were lysed using FACSLyse solution (Becton Dickinson) for 10 min and centrifuged at 1200 rpm for 5 min. The supernatant was aspirated and the pellet was resuspended and washed with 2.0 ml of PBS twice before being resuspended in 0.5 ml of PBS and examined. An isotype-matched negative control sample (BD Biosciences, San Jose, California, USA) was used in all cases to assess background fluorescence intensity. Stained cells were acquired on FACSCalibur flow cytometer (BD Biosciences) that was set up using validated quality assurance procedures. At least 10 000 events were acquired for patients and control at diagnosis and 50 000 events were acquired for cases at day 28.

Data analysis

The data were analyzed using the CellQuest software program (BD Biosciences). For hematogones, besides being positive for CD10 and CD19, they were identified by their low side scatter and variable CD45 (dim to moderate) and divided into two groups. The first group comprised less mature hematogones that expressed CD34 and had dim CD45. The second group was composed of more mature hematogones lacking CD34 but with moderate CD45 expression. CD123 was examined in relation to CD34 in both groups of hematogones. Mature B lymphocytes, besides being positive for CD19 and CD20, were identified by their specific side scatter and bright CD45 and examined for CD123 in relation to CD34. Therefore, CD123 expression in relation to CD34 was assessed in dim, moderate, and high CD45 to assess the pattern of expression. In leukemic blast cells at diagnosis, an inclusion gate (G1) was first set on viable blast cells based on forward light scatter and side light scatter. An isotype control was used for quadrant adjustment to subtract autofluorescence and nonspecific binding. Then the dominant population of leukemic blasts was identified in the CD45 versus side scatter histogram (G2), and the expression of CD34 and CD123 on this population was then assessed (CD34 vs. CD45, CD123 vs. CD45, and CD34 vs. CD123) according to this gate. The double positive population for CD34 and CD123 (CD34+/CD123+) was then gated (G3). At the end of induction treatment, the cell population with dim to moderate expression of CD45 was identified in the CD45 vs. side scatter histogram (G2), and the expression of CD34 and CD123 on this population was then assessed (CD34 vs. CD45, CD123 vs. CD45, and CD34 vs. CD123) according to this gate. The double positive population for CD34 and CD123 was identified by applying G3 gated at diagnosis on the CD34 versus CD123 histogram at day 28 of induction treatment.
  1. Cutoff value of CD34: cutoff value used for CD34 was 10% [8].
  2. Cutoff value of CD123: cutoff value used for CD123 was 20% [9].


Statistical analysis

All data were collected, tabulated, and statistically analyzed using SPSS 15.0 for windows (SPSS Inc., Chicago, Illinois, USA) and MedCalc 13 for windows (MedCalc Software bvba). Continuous quantitative variables (e.g. age) were expressed as the mean±SD and median (range), and categorical qualitative variables were expressed as absolute frequencies (N) and relative frequencies (%). Continuous data were checked for normality by using Shapiro–Wilk test. Independent Student’s t-test was used to compare two groups of normally distributed data, and Mann–Whitney U-test was used for two groups of non-normally distributed data. Kruskall–Wallis H-test was used to compare non-normally distributed variables between more than two groups. Paired data were analyzed using the paired t-test for normally distributed data and Wilcoxon signed-rank test for non-normally distributed data. Categorized data were compared using the χ2-test for unpaired data, whereas McNemar test for paired data with Yates correction was done by adding 0.5 to all cells, and as the count in some cell was less than 20 we used Fisher’s exact correction. P values less than 0.05 was considered statistically significant, less than 0.01 was considered highly statistically significant, and more than 0.05 was considered nonstatistically significant.


  Results Top


In our study, the mean age of the patient group was 4.29±2.31, with a male-to-female ratio of 1 : 1.86, whereas in the control group it was 3.80±1.22, with a male-to-female ratio of 1 : 0.43. The mean±SD of red blood cell count, hemoglobin level, white blood cell count, and platelet count was 3.17±1.47, 7.2±2.39, 38.97±124.52, and 52.94±53.89 in the patient group, whereas it was 3.65±0.57, 9.7±1.16, 11.93±3.60, and 185±66.37 in the control group, respectively ([Table 1]).
Table 1 Demographic and hematological parameters of the patient and control groups

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Regarding clinical presentation of our patients, 75% of them presented with fever, 50% presented with pallor, 37.5% presented with purpura, 15% presented with bone ache, 50% presented with lymphadenopathy, 22.5% presented with hepatomegaly, and 50% presented with splenomegaly ([Table 2]).
Table 2 Clinical data of the studied acute lymphoblastic leukemia patients at diagnosis

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In addition, mean lymphoblast cell percentage in peripheral blood was 68.42±17.76% and in bone marrow it was 88.63±7.82% at diagnosis, whereas at the end of induction it was 0 and 0.4±0.5%, respectively, with a P value less than 0.001 ([Table 3]). Regarding immunophenotyping results, in the patient group (at diagnosis), 24 (60%) B lymphocytes had dim CD45 and showed expression of CD10 (100%), CD19 (100%), CD34 (75%), and CD123 (83.3%), whereas 16 (40%) B lymphocytes had moderate CD45 and showed expression of CD10 (100%), CD19 (100%), CD34 (100%), and CD123 (87.5%) in the control group; CD10 was expressed in all B lymphocytes with dim, moderate, and bright CD45. CD19 was also expressed in 100% of B lymphocytes with dim and moderate CD45), whereas it was not expressed in 90% of B lymphocytes with bright CD45, with a P value less than 0.001. CD34 was expressed in 100 and 76% of B lymphocytes with dim and moderate CD45, respectively. Although it was not expressed in B lymphocytes with bright CD45, with a P value of 0.001, CD123 was found to be asynchronous in relation to CD34 where 100% of B lymphocytes with dim CD45 show no expression of CD123 and 70% of B lymphocytes with bright CD45 express CD123, with a P value of 0.001 ([Table 4]). At the end of induction, the following results were observed: there was a significant change in CD10, CD19, and CD34 expression, as there was loss of CD10, CD19, and CD34 expression in 10 patients (P=0.031). In addition, there was a significant change in TdT expression after treatment (loss of expression in 12 patients; P=0.015). However, there were no significant changes regarding CD123, CD33, and CD7 (P=0.315, 0.656, and 0.102, respectively) ([Table 5]).
Table 3 Comparison between pretreatment and post-treatment blast cells of B-cell acute lymphoblastic leukemia patients

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Table 4 Comparison of pretreatment flow cytometry of B-cell acute lymphoblastic leukemia between patient and control groups

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Table 5 Comparison of flow cytometry between pretreatment and post-treatment acute lymphoblastic leukemia patients

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Regarding expression pattern of CD34 and CD123 in blast cells at initial diagnosis, 32 (80%) blast cells were positive for CD34 and CD123 and four (10%) were negative for both CD34 and CD123. The expression pattern of these two antigens remains constant, as after chemotherapy 18 (45%) blast cells were positive for CD34 and CD123 and four (10%) were negative for both CD34 and CD123 (concordant expression); on the other hand, four (10%) and 18 (45%) blast cells at diagnosis and after chemotherapy, respectively, showed discordant expression ([Table 6] and [Table 7]).
Table 6 CD34 and CD123 expression pattern in B-cell acute lymphoblastic leukemia patients before treatment

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Table 7 CD34 and CD123 expression pattern in B-cell acute lymphoblastic leukemia patient after treatment

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  Discussion Top


Although significant progress has been made in the treatment of B-ALL, the prognosis following relapse is still poor. High-risk patients have been offered more intensive treatment at the time of diagnosis to improve leukemia-free survival [10].

Indeed, the overall majority of patients experiencing disease relapse cannot be adequately assessed for their chance of experiencing relapse at diagnosis. Additional immunophenotypic and cytogenetic prognostic markers for these patients offer the possibility to reassign them to a lower or higher risk grouping [11].

Our study was carried out on 40 patients diagnosed with B-ALL where peripheral blood and bone marrow samples were taken at presentation and at the end of induction therapy. In addition, 20 age-matched and sex-matched nonmalignant persons were subjected to bone marrow aspiration for a reason other than malignancy as a control group.

Distinguishing hematogones from neoplastic lymphoblast may be problematic in postchemotherapy and postbone-marrow transplant regenerating marrow. With four-color flow cytometry using optimal antibody combinations, the distinction can nearly always be made. Hematogones populations always exhibit a continuous and complete maturation spectrum of antigen expression typical of the normal evolution of B-lineage precursors; they lack aberrant or asynchronous antigen expression. The neoplastic lymphoblast in precursor B-ALL deviate from the normal B-lineage maturation spectrum and exhibit maturation arrest and oversynchronous, undersynchronous, and asynchronous expression of antigens observed on normal B-cell precursors [12].

In our study, we used four-color flow cytometry to define the pattern of antigen expression on hematogones and lymphoblast cells in bone marrow using CD34 and CD123.

The present study revealed that there was a statistically high significant difference between the patient group and the control group as regards CD10, CD45 (%), CD19, CD34, and CD123 (P<0.001).

In addition, our results showed that 80% of leukemic blast at diagnosis expressed both CD34 and CD123, whereas in 10% of cases neither antigen was expressed. This concordant expression of both antigens remains constant even after the start of chemotherapy, as we found that 45% of blast cells were positive for CD34 and CD123 and 10% were negative for both at the end of the induction. Unlike in hematogones, we found that less mature hematogones with dim CD45 expressed CD34 in 100% of cases and lack CD123 expression, whereas in mature hematogones with bright CD45 CD123 was expressed in 70% of cases and CD34 expression was absent in 100% of cases. This discordant pattern is in contrast with the invariable concordant expression of these two antigens in B-ALL. This was in agreement with Shallan and Musa [13], who reported in their study that the less mature hematogones (dim CD45+) that expressed CD34 lacked CD123 expression, whereas the more mature hematogones (moderate CD45+) lacked CD34 but always expressed CD123. These results also agreed with Hassanein et al. [14], who examined the expression of CD123 on bone marrow hematogones, mature B lymphocytes, and B lymphoblast from ALL in 75 specimens and on leukemic blasts in 45 newly diagnosed B-ALL cases. They found that the less mature hematogones (dim CD45+) that express CD34 lack CD123 expression, whereas the more mature hematogones (moderate CD45+) lack CD34 but always express CD123. In contrast with this discordant pattern of CD34 and CD123 expression in hematogones, blasts in 41 (91%) of 45 cases of B-ALL showed concordant expression of the two antigens: 80% (36 of 45) of cases expressed both antigens, whereas 11% (5 of 45) expressed neither. They found that these distinct patterns of CD34/CD123 expression on hematogones (discordant) and B-ALL blasts (concordant) remain stable after chemotherapy and are useful in differentiating small populations of residual blasts from hematogones that may be simultaneously present. In addition, these finding were in agreement with those of Muñoz et al. [6], who found that CD123 was negative in normal lymphoid progenitors that were CD34+, CD33, CD19+, and CD10+. In addition, this was in agreement with Djokic et al. [15], who reported in his study that the early B-cell precursors were CD123, whereas intermediate precursors and mature B cells showed weak CD123 expression. Farahat et al. [16] have reported methods for discriminating between normal B-cell precursors and neoplastic lymphoblasts. They used quantitative double-labeling flow cytometry and found B-lineage ALL lymphoblasts to express fewer TdT and CD19 and more CD10 molecules than did hematogones. Weir et al. [17] demonstrated quantitative differences in light scatter and intensity of antigen expression between these two populations. Rimsza et al. [18] found a predominance of more mature B-cell precursors in hematogone-rich specimens relative to the least mature (CD34+/TdT+) cells that predominated in cases of ALL. However, these methods depend on evaluating subtle differences in the degree of antigen expression pattern that are subject to daily variation in staining and instrument set up. In contrast, the expression patterns of CD34 and CD123 provide a useful clue to discriminate between immature B cells as residual leukemic blasts and hematogones in bone marrow of patients treated for ALL. Although all our patients achieved hematological remission based on bone marrow blast percentage at the end of the induction, the concordant pattern of CD34 and CD123 expression in immature B cells can help in minimal residual disease detection.


  Conclusion Top


Pattern of CD34 and CD123 expression can be used to overcome the great potential for mistaking the least mature hematogones for neoplastic lymphoblasts. In addition, this combination may be used for minimal residual disease detection, which needs further research.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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Dworzak MN, Fritsch G, Fleischer C, Printz D, Fröschl G, Buchinger P et al. Multiparameter phenotype mapping of normal and post-chemotherapy B lymphopoiesis in pediatric bone marrow. Leukemia 1997; 11:1266–1273.  Back to cited text no. 3
    
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Xia X, Li L, Choi YS. Human recombinant IL-3 is a growth factor for normal B cells. J Immunol 1992; 148:491–497.  Back to cited text no. 5
    
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Muñoz L, Nomdédeu JF, Lopez O, Carnicer MJ, Bellido M, Aventin A et al. Interleukin-3 receptor alpha chain (CD123) is widely expressed in hematologic malignancies. Haematologica 2001; 86:1261–1269.  Back to cited text no. 6
    
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Supriyadi E, Veerman A, Purwanto I et al. Detection of CD10, CD34 and their combined expression on childhood acute lymphoblastic leukemia and the association with clinical outcome in Indonesia. J Cancer Res Ther 2012; 1:10–20.  Back to cited text no. 7
    
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Wang YZ, Qin YZ, Jiang B, Zhu HH, Chang Y, Hao L et al. Relationship of immunophenotypic features with minimal residual disease detection and gene types in 221 cases of acute promyelocytic leukemia. Zhongguo Shi Yan Xue Ye Xue Za Zhi 2009; 17:271.  Back to cited text no. 8
    
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Almohsen F. Al-Mudallal S. Relationship between the expression of CD34, CD123 and myeloperoxidase markers by flow cytometry and response to induction therapy in acute myeloid leukemia. Iraqi J Med Sci 2014; 12:161.  Back to cited text no. 9
    
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Khan NI, Cisterne A, Devidas MC, Shuster J, Hunger SP et al. Expression of CD44, but not CD44v6, predicts relapse in children with B cell progenitor acute lymphoblastic leukemia lacking adverse or favorable genetics. Leuk Lymphoma 2008; 49:710.  Back to cited text no. 11
    
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McKenna RW, Washington LT, Aquino DB, Picker LJ, Kroft SH. Immunophenotypic analysis of hematogones (B-lymphocyte precursors) in 662 consecutive bone marrow specimens by 4-color flow cytometry. Blood 2001; 98:2498–2507.  Back to cited text no. 12
    
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Shallan YA, Musa RJ. Immunophenotypic comparison between reactive bone marrow B-lymphocyte precursor (hematogones) and B-neoplastic lymphoblast leukaemia using Cd 34, Cd 123 by Flowcytometry. Iraqi J Med Sci 2015; 13:23.  Back to cited text no. 13
    
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Hassanein NM, Alcancia F, Perkinson KR, Buckley PJ, Lagoo AS. Distinct expression patterns of CD123 and C34 on normal bone marrow B-cell precursors (‘hematogones’) and B lymphoblastic leukemia blasts. Am J Clin Pathol 2009; 132:573–580.  Back to cited text no. 14
    
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Djokic M, Bjorklund E, Blennow E et al. Overexpression of CD123 correlates with hyperdiploid genotype in acute lymphoblastic leukemia. Haematologica 2009; 94:1016–1019.  Back to cited text no. 15
    
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Farahat N, Lens D, Zomas A et al. Quantitative flow cytometry can distinguish between normal and leukaemic B-cell precursors. Br J Haematol 1995; 91:640–646.  Back to cited text no. 16
    
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Rimsza LM, Larson RS, Winter SS, Foucar K, Chong YY, Garner KW et al. Benign hematogone-rich lymphoid proliferations can be distinguished from B-lineage acute lymphoblastic leukemia by integration of morphology, immunophenotype, adhesion molecule expression, and architectural features. Am J Clin Pathol 2000; 114:66–75.  Back to cited text no. 18
    



 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7]



 

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