|Year : 2014 | Volume
| Issue : 3 | Page : 122-127
The usefulness of immunoglobulin-like transcript-3 receptor expression in the diagnosis of acute myeloid leukemia with monocytic differentiation
Maha Atfy MD 1, Hoda F Ebian1, Ashraf M Elhefni2, Hebatallah H Atteia3
1 Department of Clinical Pathology, Hospitals of Zagazig University, Zagazig University, Zagazig, Egypt
2 Department of Hematology and Medical Oncology, Faculty of Medicine, Zagazig University, Zagazig, Egypt
3 Department of Biochemistry, Faculty of Pharmacy, Zagazig University, Zagazig, Egypt
|Date of Submission||23-Mar-2014|
|Date of Acceptance||08-Jul-2014|
|Date of Web Publication||31-Dec-2014|
Department of Clinical Pathology, Hospitals of Zagazig University, Faculty of Medicine, Zagazig University, Zagazig 44519
Source of Support: None, Conflict of Interest: None
Background Immunoglobulin like transcript (ILT3) is an immunohibitory transmembrane receptor expressed by plasmacytoid dendritic cells (PDCs), monocytoid dendritic cells (MDCs), and monocytes/macrophages. ILT3 has been previously utilized as a highly sensitive and specific marker for the identification of aggressive chronic lymphocytic leukemia (CLL) and to distinguish AML with monocytic differentiation from other types of AML.
Aim and Methods0 Therefore, in the current study, we investigated the diagnostic impact of ILT3 receptor expression in 72 Egyptian patients having AML with monocytic differentiation and 20 healthy volunteer using flow cytometry technique.
Results Our results demonstrated significant overexpression of ILT3 receptor (P < 0.001) in all AML cases displaying monocytic differentiation patients. ILT3 receptor expression was positively correlated with CD4, CD14, CD64, CD11c, MPO and NSE.
Conclusion These data present a significant role for ILT3 receptor expression in combination with CD14, CD64, MPO and NSE in diagnosis of AML with monocytic differentiation. Further clinical studies should be directed towards ILT3 receptor blockade as a future target for AML immunotherapy.
Keywords: acute myeloid leukemia, diagnosis, flow cytometry, immunoglobulin-like transcript-3, monocytic
|How to cite this article:|
Atfy M, Ebian HF, Elhefni AM, Atteia HH. The usefulness of immunoglobulin-like transcript-3 receptor expression in the diagnosis of acute myeloid leukemia with monocytic differentiation. Egypt J Haematol 2014;39:122-7
|How to cite this URL:|
Atfy M, Ebian HF, Elhefni AM, Atteia HH. The usefulness of immunoglobulin-like transcript-3 receptor expression in the diagnosis of acute myeloid leukemia with monocytic differentiation. Egypt J Haematol [serial online] 2014 [cited 2017 Jun 25];39:122-7. Available from: http://www.ehj.eg.net/text.asp?2014/39/3/122/148235
| Introduction|| |
Acute myeloid leukemia (AML) is a malignancy that arises from self-renewing hematopoietic stem cells/progenitors with multiple genetic and/or epigenetic changes and mostly affects adults. Clinically, it is a heterogeneous disease marked with clonal proliferation of abnormal blast cells in the bone marrow (BM) interfering with the production of normal cells  . The rate of survival after intensive chemotherapy varies depending on the patient's age, blast cell morphology, and molecular and cytogenetic alterations , .
AMLs with a monocytic component can be classified by the French-American-British and WHO according to the degree of monocytic differentiation into acute myelomonocytic leukemia having more than 20% monocytic cells (MCs) and acute monocytic leukemia (AMoL) having more than 80% MCs (the majority of which are immature)  . AML with monocytic differentiation is associated with recurring cytogenetic abnormalities with important prognostic significance. Meanwhile, about 40% of AML patients are free from cytogenetic abnormalities. Monocytic differentiation can be detected by the morphological characteristics and confirmed by cytochemical stains or flow cytometry  . Although monocytic lineage cells preferentially express several immunophenotypic markers such as lysozyme, elastase, urokinase receptor (UPA-R), and granulocyte macrophage colony-stimulating factor receptor (GM-CSF-R), none of them can be used for the proper identification of the pure AMoL subtype of AML  . Consequently, the major problem in the diagnosis of AML with monocytic differentiation is the absence of highly sensitive and specific monocytic markers  .
Immunoglobulin-like transcript-3 (ILT-3), a member of the immunoglobulin superfamily, is a transmembrane inhibitory receptor expressed on antigen-presenting cells (APCs) such as monocytes and dendritic cells (DCs) as well as on endothelial cells  . It is essential for the generation of regulatory T cells in humans. Upregulation of this inhibitory receptor (ILT-3) plays a crucial role in graft adaptation and protection against the recipient's immune response  . Structurally, ILT-3 contains immunoreceptor tyrosine-based inhibitory motifs in the cytoplasmic region such as killer cell inhibitory receptors. The inhibitory function of ILT-3 could be attributed to immunoreceptor tyrosine-based inhibitory motifs  . ILT-3 not only captures and presents antigens (Ags) but can also cross-link and deliver these Ags to an intracellular compartment where it is processed and presented to T cells. Moreover, ILT-3 can negatively regulate the activation of APC  .
ILT-3 is expressed by normal and leukemia myeloid precursors as a reliable marker that distinguishes AML with monocytic differentiation from other types of AML  . Its expression identifies normal hematopoietic precursors committed to the monocytic lineage  . The expression of ILT-3 in AML patients has been analyzed by flow cytometry and proven to be a new phenotypic marker expressed by myelomonocytic cells or by MCs and DCs. Therefore, the current study was designed to investigate the usefulness of ILT-3 receptor expression to distinguish AMoL from other types of AML for the proper monitoring of these patients.
| Materials and methods|| |
This study was carried out on 72 patients with AML at initial diagnosis between September 2012 and August 2013. Diagnosis and classification of the AML cases were based on the morphology and the cytochemistry according to FAB classifications and the presence of maturation and differentiation Ags that were determined by routine immunophenotyping criteria of WHO 2008  . Informed consent was obtained from each patient.
Regarding the FAB classification, 72 AML patients were categorized to have undifferentiated leukemia (M0 and M1, n = 2, 7), 18 patients with immature granulocytic leukemia (M2, n = 12; M3, n = 6), 45 patients with monocytoid leukemia (M4, n = 27; M5, n = 18), and only one patient was diagnosed with M6. The median age was 58 years (range 25-67 years). The male/female ratio was 1.8: 1. All patients were previously untreated and entered this study at the time of initial diagnosis.
The assessment of monocytic differentiation and the designation of M4/M5 subtypes were based on the cytomorphology and the cytochemistry [as nonspecific esterase (NSE)] , . The differential count of mature monocytes, promonocytes, and monoblasts was performed on air-dried, Leishman-stained film from peripheral blood (PB) and/or BM samples.
Twenty samples used as the control group were obtained from patients with no evidence of BM involvement, as established by clinical evaluation and morphology. Eight of the noninvolved samples were obtained from patients with hypersplenism, two samples from patients with idiopathic thrombocytopenic purpura (ITP), five from patients with aplastic anemia, and five from acute lymphoblastic leukemia (ALL) patients in remission.
The following investigations were carried out for all participants: complete blood count was determined using Sysmex KX21 (Roche Diagnostics, Meylan, France) to assess white blood cell and PB monocyte counts, the hemoglobin level, and the platelet count. Examination of BM and PB was performed to determine the percent of blast and monocytic element using a blood film after staining with Leishman stain. Cytogenetic analysis to determine any abnormalities was performed. Cytochemistry staining of PB and BM using myeloperoxidase (MPO) and NSE stains (Sigma, St Louis, Missouri, USA) was used to differentiate blast and monocytic elements from other types of cells. Routine immunophenotyping was performed for every AML case for diagnosis and subclassification using a panel of monoclonal antibodies labeled with fluorescene isothiocyanate (FITC), phycoerythrin (PE), and perCp. The panel consisted of CD13 PE, CD33 PE, CD34 FITC, CD64 PE, CD14 FITC, CD45 FITC, HLA-DR FITC, MPO PE, CD3 FITC, and CD79a perCp.
Flow cytometric analysis
EDTA-BM samples were used to establish the blast phenotype in every single AML case; a panel of monoclonal antibodies directed against the monocyte lineage (e.g. CD14, CD11c, CD4, CD64, MPO).
ILT-3 analysis was performed by flow cytometry; ILT-3 antibody was obtained from CliniLab (Cairo, Egypt) (imported from R&D Systems, Minneapolis, Minnesota, USA), and labeled with FITC. All the other antibodies were obtained from BD Bioscience (Roche Diagnostics, Meylan, France). Calibration of FACScan flow cytometry using the mean equivalent soluble fluorescence method was performed weekly and no major change in the setting was made during the analysis in this study.
PB and BM samples on lithium heparin were studied by G-banding analysis with trypsin-Giemsa staining. BM karyotype analysis was carried out for all cases as a routine laboratory work.
Data were statistically described in terms of mean ± SD. Comparison of quantitative parametric variables between the two studied groups was performed by the Student 't'-test. The χ2 -test and correlation coefficient study were performed. A probability value (P-value) less than 0.05 was considered statistically significant. All statistical calculations were performed using SPSS version 15 for Microsoft Windows (Statistical Package for the Social Science; SPSS Inc., Chicago, Illinois, USA).
| Results|| |
To characterize the expression of inhibitory receptor ILT-3 on neoplastic hematopoietic precursors in our study, we analyzed 72 patients including 33 male and 39 female patients, with a ratio of 1.8 : 1.
The cutoff level of ILT-3 was 10%. This level was determined using the log curve in comparison with the normal control group (data not shown).
Patients were classified according to the positivity of ILT-3 into the ILT-3-positive group, which included 41 patients (59.6%), and the ILT-3-negative group, which included 31 patients (43.05%) ([Table 1]).
|Table 1 Demographic and laboratory data of 72 patients according to ILT-3 positivity|
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Hence, it was revealed that ILT-3 positivity was found in 41 patients (59.6%) (20 male and 21 female patients) and ILT-3 negativity was found in 31 patients (43.05%) (18 male and 13 female patients). Thus, in this study, patients were divided into two groups: group 1 was the ILT-3-positive group and group 2 the ILT-3-negative group.
The age of the ILT-3-positive group ranged from 42 to 69 years (mean ± SD 54 ± 12 years) and the age of the negative group ranged from 34 to 55 years (mean ± SD 44 ± 10 years). In this study, it was found that the frequency of ILT-3 positivity in AML M4/M5 patients was significantly elevated as compared with patients with other types of AML (χ2 = 3.6; P < 0.001).
There was no significant differences regarding total leucocytic count (TLC), hemoglobin, and platelets between ILT-3-negative cases in comparison with TLC in ILT-3-positive cases (P < 0.307, P < 0.101, and P < 0.057, respectively).
Flow cytometric analysis of the BM obtained from AML patients showed variable expression of inhibitory receptors ILT-3 on neoplastic hematopoietic precursors.
It was found that there was a statistically significant association between the positive expression of ILT-3 presented in different types of leukemic blast cells and other positive monocytic markers such as CD64, CD14, CD11c, and MPO (P < 0.0001 for all). Positive CD4 had no significant association with positive ILT-3 in AML cases (χ2 = 1.03; P < 0.310) ([Table 2]; [Figure 1]).
|Figure 1 Flow cytometric analysis of two AMoL cases. Case 1: positive ILT-3 showed coexpression with CD64, MPO, and CD14, whereas CD11c and CD4 were negative. Case 2: positive ILT-3 showed coexpression with CD64, CD11c, and CD14, whereas MPO and CD4 were negative. AMoL, acute monocytic leukemia; ILT-3, immunoglobulin-like transcript -3.|
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|Table 2 The coexpression CD14, CD11c, CD4, CD64, and MPO on ILT-3-positive and ILT-3-negative leukemic AML cells|
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[Table 3] shows the performance of ILT-3 for the diagnosis of AMoL. Using the NSE cytochemical diagnostic test as the gold standard test, ILT-3 was more specific (100%) than other monocytic markers such as CD64, MPO, CD14, CD11c, and CD4 (11.2, 18.5, 88.9, and 81.5%, respectively); these markers lack specificity in their expression in a significant fraction of other AML types, but ILT-3 had moderate sensitivity (88.9%) among these markers.
|Table 3 Sensitivity, specifi city, PPV, NPV, and accuracy of markers in AML|
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CD14-positive and CD14-negative cells are consistent with the maturation pattern in which ILT-3 expressed by BM MCs is acquired before the expression of CD14, which was expressed in 86.6% of AML monocytic differentiation, indicating that ILT-3 is a highly sensitive and specific marker that can be reliable to distinguish AML M4/M5 from other types.
Coexpression of interleukin-3 and the early marker CD34 suggests that ILT-3 is acquired at an early step of hematopoietic differentiation.
| Discussion|| |
The ILT-3 molecule, an immunoglobulin superfamily, is a transmembrane protein immune inhibitory receptor selectively expressed by myeloid APCs as monocytes and at high levels by tolerogenic DCs, where it plays a crucial role in the generation of regulatory T cells  .
The major finding of the present study is that the inhibitory receptor ILT-3 is a highly sensitive and specific marker for the identification, diagnosis, and monitoring of AML patients with monocytic differentiation by flow cytometry, making it important to be incorporated not only into the diagnostic workup usefulness, but also in monitoring AML patients. This is in agreement with the previous findings of Sakaguchi and Sakaguchi  .
Our study also determined that ILT-3 was expressed by 40/45 cases of monocytic AML and in 1/27 cases of AML including M0, M1, M2, and M3 cases. We also determined the presence and the importance of ILT-3 as a diagnostic marker for monocytic forms of AML compared with other cell markers CD64, MPO, CD11c, and CD4. However, the frequency of ILT-3-positive cells in patients with AML displaying monocytic differentiation (M4/M5) was much more than that observed in patients with other forms of AML. Our results are in agreement with the previous findings of Dobrowolska et al.  .
AML with monocytic differentiation must be distinguished from other types of AML, especially microgranular acute promyelocytic leukemia (APL), as the treatment strategies are completely different , . In this study, there were six cases of APL: two cases were the microgranular type, but all of them were negative for ILT-3. Thus, ILT-3 can be used as a dependent marker to differentiate monocytic AML from other types.
The prognosis of all acute leukemia depends on the morphology, cytochemistry, flow cytometry, and other molecular parameters such as cytogenetics, on which the definition of risk categories is largely based  . In our study, we found that monocytic AML patients with cytogenetic abnormalities, especially deletion-5 and trisomy 8, most frequently presented with ILT-3-positive leukemic blast cells as these observed abnormalities in cytogenetics are categorized as intermediate prognosis. However, ILT-3 has a potential value as a diagnostic and prognostic marker in patients having monocytic differentiated AML with or without cytogenetic abnormalities , . Hence, ILT-3 can be used as a dependent marker for the determination and the differentiation of monocytic AML  . The most powerful diagnostic indicators in AML have been recognized for the detection of minimal residual disease as delayed detection is always associated with poor prognosis. Therefore, earlier therapeutic interventions have a very important clinical benefit in monitoring these patients  . Hence, our study suggests that ILT-3 can be used as a candidate marker for minimal residual disease (MRD) detection in AML patients displaying monocytic differentiation due to its high sensitivity and specificity. Besides, our study determined the most important value of ILT-3 in the diagnosis, the prognosis, and the monitoring of monocytic AML, but there was a limitation in other prognostic molecular investigations, such as cytogenetic, especially those normally presented, and hence, this aspect remains to be determined , .
Precursor cells rarely carry the ILT-3-positive, CD34-positive, and CD117-positive phenotyping in the noninvolved BM, and so the normal feature of early precursors are committed to the monocytic lineage. Therefore, coexpression of ILT-3 and early immature markers such as CD34 by myeloid leukemic blasts may be interpreted as a synchronism of abnormal cells and mature monocytes as characterized by positive CD64, ILT-3, CD11c, CD33, and CD13. Monocytes, macrophages, and myeloid DCs originate from hematopoietic progenitor stem cells  .
ILT-3 is expressed by monocytes, but is not presented by granulocytes as shown in our study, indicating that its expression is acquired by early progenitors toward the commitment to a monocytic lineage, and this occurs at an early step of hematopoietic differentiation  .
Vlad et al.  and Chang et al.  found that ILT-3 on MCs and DCs was upregulated by allogenic T8 + suppressor cells, rendering these APCs more tolerogenic, and thus expressing ILT-3 at high levels. Also, ILT-3 in its soluble form can directly suppress T-lymphocyte function.
Tolerogenic APC-induced unresponsiveness in CD4 + T-helper cells makes it feasible to be incorporated into the initial diagnostic workup and in the monitoring of AML patients with monocytic differentiation. This is in agreement with Lanza  and is in line with our results, suggesting that ILT-3 has a potential value for therapy in addition to its diagnostic usefulness as a phenotypic marker for the recognition of monocytic variants of AML, and so using specific antagonists or antibodies to prevent or block ILT-3 signals, AML cells that are ILT-3 positive will be more susceptible to differentiation agents and to antitumor T-cell responses  .
ILT-3-positive cells including CD14-positive and CD14-negative cells are consistent with the maturation pattern in which ILT-3 expression by BM MCs is acquired before CD14 expression. Coexpression of ILT-3 and the early marker CD34 suggests that ILT-3 is acquired at an early stage of maturation and the degree of expression of CD14 usually depends on the maturation stage  .
Also, we found that CD64 was a positive marker expressed on leukemic blasts and it determined monocytic differentiation. It has been reported that CD64 can be utilized to differentiate between acute myelomonocytic leukemia and other subtypes of AML as it is normally brightly expressed on promonocytes of all acute myelomonocytic leukemia AMoLs with intensity 3+ greater than in other subtypes of AML M1, M3, and M2 that were 1+ to 2+ intensity, respectively  . Thus, on the basis of our findings, the addition of ILT-3 analysis to CD64, MPO, and CD14 enhances flow cytometric analysis and the recognition of AML with monocytic compartment significantly.
Also, we found that the expression for monocytes is positive for ILT-3, but not for granulocytes. ILT-3 is, therefore, a biomarker used to identify the normal hematopoietic precursor committed to the monocytic lineage and to distinguish AML M4/M5 from other types of AML by this phenotypic marker, and the recognition of the monocytic variants of AML needs to be validated in a large population of patients  . Also, detection of ILT-3 expression is the basis for new methods of diagnosis and treatment of AML cancer-expressing ILT-3  .
| Conclusion|| |
ILT-3 is a highly specific and sensitive biomarker that is used as a diagnostic tool to distinguish AML with monocytic differentiation from other types of AML. This is the basis for new methods for the diagnosis, the monitoring, and the treatment of AML cancer-expressing ILT-3.
| Acknowledgements|| |
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3]