|Year : 2019 | Volume
| Issue : 3 | Page : 784-789
Evaluation of feline McDonough sarcoma-like tyrosine kinase 3 (CD135) expression in acute myeloblastic leukemia
Samia H Kandel1, Iman A Ahmedy1, Suzan A Al-Hassanin2, Samar S H El-Gazzar3
1 Clinical Pathology Department, Faculty of Medicine, Fever Hospital, Shebin El-Kom, Menoufia, Egypt
2 Oncology Department, Faculty of Medicine, Fever Hospital, Shebin El-Kom, Menoufia, Egypt
3 Clinical Pathology Department, Fever Hospital, Shebin El-Kom, Menoufia, Egypt
|Date of Submission||07-Oct-2017|
|Date of Acceptance||19-Nov-2017|
|Date of Web Publication||17-Oct-2019|
Samar S H El-Gazzar
Shanwan, Menoufia 32717
Source of Support: None, Conflict of Interest: None
The aim of this study was to evaluate the role of feline McDonough sarcoma (FMS)-like tyrosine kinase 3 (FLT3) in acute myeloblastic leukemia (AML).
AML is the most common acute leukemia affecting adults, and its incidence increases with age. FLT3 belongs to the class III receptor kinase family, which plays an essential role in hematopoiesis, driving differentiation of early myeloid and lymphoid lineages.
Medline databases (PubMed, Medscape, Science Direct) and all materials available in the Internet from 1996 to 2017.
The initial search yielded 107 articles, of which 20 fulfilled the inclusion criteria. The articles studied the relation between FLT3 and AML.
Midline searches with the keywords 'acute myeloblastic leukemia, Feline McDonough Sarcoma like tyrosine kinase, FLT3' in the title of the papers; extraction was performed, including assessment of the quality and validity of papers that fulfilled the previous criteria of FLT3 expression in AML.
Each study was reviewed independently; the data obtained were rebuilt in a new language according to the needs of the researcher and categorized into topics throughout the article. Comparisons were made by structured reviews, with the results tabulated.
The studies indicated that FLT3 is significantly increased in patients with AML.
FLT3 overexpression was found in patients with AML and correlated with relapsed cases, worse survival, and poor outcome. This indicated that FLT3 overexpression can be used as a poor prognostic predictor for AML.
Keywords: acute myeloblastic leukemia, class III receptor kinase family, feline McDonough sarcoma-like tyrosine kinase 3
|How to cite this article:|
Kandel SH, Ahmedy IA, Al-Hassanin SA, El-Gazzar SS. Evaluation of feline McDonough sarcoma-like tyrosine kinase 3 (CD135) expression in acute myeloblastic leukemia. Menoufia Med J 2019;32:784-9
|How to cite this URL:|
Kandel SH, Ahmedy IA, Al-Hassanin SA, El-Gazzar SS. Evaluation of feline McDonough sarcoma-like tyrosine kinase 3 (CD135) expression in acute myeloblastic leukemia. Menoufia Med J [serial online] 2019 [cited 2020 May 27];32:784-9. Available from: http://www.mmj.eg.net/text.asp?2019/32/3/784/268831
| Introduction|| |
Acute myeloblastic leukemia (AML) is a genetically heterogeneous clonal disorder characterized by the accumulation of acquired somatic genetic alterations in hematopoietic progenitor cells that alter normal mechanisms of self-renewal, proliferation, and differentiation . The incidence of AML increases with age; the median age at diagnosis is 63 years. AML accounts for about 90% of all acute leukemias in adults, but is rare in children . Feline McDonough sarcoma (FMS)-like tyrosine kinase 3 (FLT3) is also known as fetal liver kinase-2 or stem cell tyrosine kinase 1 (TK) or CD135, which belongs to the class III receptor kinase family . The class III receptor kinase family is characterized by an extracellular domain comprised of five immunoglobulin-like domains, a single transmembrane domain, a juxta-membrane domain, two intracellular kinase domains (TK1 and TK2) divided by a kinase insertion domain (K1), and a C-terminal domain [Figure 1]. The CD135 antigen/FLT3 maps to chromosome 13 (13q12) and is comprised of 24 exons extending over more than 100 kb. FLT3 exists in two forms: a 160 kDa glycosylated membrane-bound protein and a 130–143 kDa partially glycosylated protein . The FLT3 gene encodes a 1000 and 993 amino acid protein in mice and humans, respectively . The FLT3 plays an essential role in hematopoiesis, driving the differentiation of early myeloid and lymphoid lineages, but being downregulated at later stages. Its expression is usually tightly restricted to early progenitor cells and deregulation of the FLT3 receptor plays a major role in the pathogenesis of leukemia . FLT3 protein is expressed on blast cells from most AML and B-acute lymphoblastic leukemia. It is also present on other tissues such as the placenta, brain, cerebellum, and gonads, although its function in these tissues is unknown . When the FLT3 receptor binds to its ligand, a complex is formed. The formation of this complex activates signal transduction molecules that propagate the signal in the cell. Signaling through FLT3 plays a role in cell survival, proliferation, and differentiation . Mutations of FLT3 are found in 30% of AML cases, making it the most frequently mutated tyrosine kinase in the otherwise heterogeneous group . Initial studies have evaluated the FLT3 protein using the western blot method ; interestingly, few studies have evaluated FLT3 expression by Flow cytometry, whereas most studies to date have evaluated FLT3 mutations by PCR .
|Figure 1: Schematic presentation of the feline McDonough sarcoma-like tyrosine kinase 3 (FLT3) receptor monomer. Ig, immunoglobulin; JM, juxta-membrane; TK, tyrosine kinase.|
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The aim of this study was to evaluate the role of FMS FLT3 in AML [Figure 2].
| Materials and Methods|| |
This review was performed according to the guidelines developed by the center for review and dissemination. It was used to assess the outcome of the studies. The guidance published by the Centre for Reviews and Dissemination was used to assess the methodology and outcomes of the studies. This review was reported in accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analyses statement. An institutional review board and ethics committee approved this study.
We reviewed papers on the relation of FLT3 in patients with acute myeloblastic leukemia from Medline databases (PubMed, articles in Medscape, Science Direct) and also materials available on the Internet. We used FLT3 expression/CD135/acute myeloblastic leukemia, diagnosis/indicator/marker, and prognosis/survival as search terms. The search was performed in the electronic databases from 1996 to 2017.
All the studies were assessed independently for inclusion. They were included if they fulfilled the following criteria:
Inclusion criteria of the published studies were as follows:
- Published in the English language
- Published in peer-reviewed journals
- Focused on the role of FLT3 expression in AML prognosis
- If a study had several publications on certain aspects, we used the latest publication with the most relevant data.
If the studies did not fulfill the above criteria, they were excluded, report without peer-review, not within national research program, letters/comments/editorials/news.
The analyzed publications were evaluated according to evidence-based medicine (EBM) criteria using the classification of the US Preventive Services Task Force and UK National Health Service protocol for EBM in addition to the Evidence Pyramid.
US Preventive Services Task Force:
- Level I: evidence obtained from at least one properly designed randomized-controlled trial
- Level II-1: evidence obtained from well-designed controlled trials without randomization
- Level II-2: evidence obtained from well-designed cohort or case–control analytic studies, preferably from more than one center or research group
- Level II-3: evidence from multiple time series with or without the intervention. Dramatic results in uncontrolled trials might also be regarded as this type of evidence
- Level III: opinions of the respected authorities on the basis of clinical experience, descriptive studies, or reports of the expert committees.
The quality of all the studies was assessed. Important factors were included: study design, ethical approval received, evidence of a power calculation, specified eligibility criteria, appropriate controls, and adequate information and specified assessment measures. It was expected that confounding factors would be reported and controlled for and appropriate data analysis was carried out.
Each study was reviewed independently; the obtained data were rebuilt in a new language according to the needs of the researcher and categorized into topics throughout the article. Comparisons were made by a structured review. A structured systematic review was performed, with the results tabulated.
| Results|| |
Study selection and characteristics: in total, 83 potentially relevant publications were identified and 60 articles were excluded as they did not fulfill our inclusion criteria. A total of 23 studies were included in the review as they were deemed eligible on the basis of fulfillment of the inclusion criteria. The studies examined the role of FLT3 in the diagnosis and assessment of the prognosis of AML. The studies were analyzed with respect to the study design using the classification of the US Preventive Services Task Force and UK National Health Service protocol for EBM. The expression of FLT3 was discussed in five human studies [Table 1]. A higher FLT3 expression was found in AML ,,,,. Of these, there were four cohort studies with level II-2 or (level A) EBM and one case–control study with level III. The relation between FLT3 with hematological parameters and immunophenotyping in AML was discussed in six human studies [Table 2]. There was a significant association between FLT3-positive expression and low platelet count . FLT3-positive expression correlated with a high total leukocyte count (TLC). However, Mehta et al.  found no significant correlation between FLT3 overexpression and TLC, hemoglobin level, and platelet count. Four of these studies showed a positive correlation between FLT3 and blast ,,,. FLT3 was shown to be correlated with Human Leukocyte Antigen-DR isotype (HLA-DR) positivity and not with CD34 . Moreover, a positive correlation was reported between FLT3 and CD117 . Four studies discussed FLT3 expression in Fragment antigen binding (FAB) subtypes [Table 3]. Three of these found that the highest FLT3 expression was in M5 ,,. Vora et al.  found that the highest FLT3 expression was in M2, then M5, followed by M3 and M1. Six studies discussed the prognostic significance of FLT3 and its association with the survival and outcome of patients in AML [Table 4]. Two of these studies showed an association between hematological parameters and poor outcomes. High white blood cells (WBCs) count and low hemoglobin were found to be associated with poor outcomes ; in addition, high blast percentage was associated with worse survival . All six studies showed that FLT3 overexpression was associated with relapse, and predicted worse survival and poor outcomes ,,,,,.
|Table 1: Feline McDonough sarcoma-like tyrosine kinase 3 expression in acute myeloblastic leukemia|
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|Table 2: Association of feline McDonough sarcoma-like tyrosine kinase 3 with hematological and immunophenotyping|
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|Table 3: Feline McDonough sarcoma-like tyrosine kinase 3 expression among different FAB subtypes of acute myeloblastic leukemia|
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|Table 4: Prognostic significance of feline McDonough sarcoma-like tyrosine kinase 3 in acute myeloblastic leukemia|
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| Discussion|| |
The research on the FLT3 expression and its prognostic significance in AML patients is an area in which a significant number of scientific studies are ongoing both within national and international research programs, in both public and private laboratories, and as a result of the activities of standards and regulatory bodies. AML is the second most common hematological tumor and is characterized by increased proliferation and impaired maturation of early myeloid cells, leading to an accumulation of immature blood cells . The FLT3 plays an essential role in hematopoiesis, driving the differentiation of early myeloid and lymphoid lineages, but being downregulated at the later stages. Its expression is usually tightly restricted to the early progenitor cells. Deregulation of the FLT3 receptor plays a major role in the pathogenesis of leukemia . FLT3 is expressed at high levels in a spectrum of hematologic malignancies including 70–100% of AML . In AMLs, FLT3 stimulation by its ligand promotes the proliferation and survival of leukemic blasts that express the receptor . In the healthy group (control), a negative expression of FLT3 was found ,. FLT3 mutations have been described in ∼35–40% of de-novo AML . The first clue for the diagnosis of AML is an anomalous result of the total number of leukocytes. Between 5 and 20% of patients may present with a very large number of cells (>100 × 109/l). Although leukocytosis is a frequent feature, AML may also present with a normal leukocyte count and only a low number of platelets and erythrocytes, or even leukopenia . In terms of the association between FLT3 and hematological parameters, there was a significant association between FLT3-positive expression and low platelet count . Another study showed that high FLT3 (CD135) expression was correlated with high WBCs ; in addition, AML associated with the FLT3 mutation usually present as de-novo disease with a high peripheral leukocyte count . Found no significant correlation between FLT3 overexpression and TLC, hemoglobin level, and platelet count. In this systematic review, we observed a positive correlation between FLT3 and bone marrow blasts in AML patients ,,,, which leads to a poor outcome . It has been suggested that the FLT3 protein assay may be a useful biomarker to determine the prognosis of leukemia . Many immunophenotypic markers have been established in the past few decades for the diagnosis of AML. This systematic review has shown a significant positive correlation between FLT3 and HLA-DR expression  and a significant positive correlation between FLT3 and CD117 expression . The pathogenesis of AML is linked to an imbalance between proliferation and apoptosis. Among proliferative markers, receptor tyrosine kinase makes a significant contribution in leukemogenesis. The c-KIT receptor (CD117) and the FLT3 receptor (CD135) are the key proliferative receptor tyrosine kinases for AML . It was hypothesized that higher coexpression of CD135 and CD117 would imply a higher proliferative potential of myeloblasts, and that it would affect the outcome adversely . FLT3 receptor expression (CD135) is expressed selectively on bone marrow CD34-positive cells and immature hematopoietic progenitor including myeloid and B-lymphoid progenitor cells, and monocytic cells ; in addition, the FLT3 protein is expressed on blast cells from most AML and B-acute lymphoblastic leukemia . This was attributed to the fact that the FLT3 ligand selectively stimulates the proliferation, expansion, and colony formation of CD34+ progenitor cells and it may be useful in marrow recovery after cytotoxic chemotherapy and also useful in expansions of hematopoietic progenitors for various clinical applications . Therefore, a possible association between FLT3 and CD34 was evaluated; however, Vora et al.  found no significant association between FLT3 and CD34. The highest FLT3 expression was observed in FAB M5. It has been suggested that FLT3 signaling is more likely to be associated with FAB M5 and this raises the question of whether monocytic differentiation induces FLT3 expression or whether FLT3 signaling leads to monocytic differentiation , but Vora et al.  found the highest FLT3 expression in M2, followed by M5. Reviewing follow-up studies on the association of FLT3 overexpression with the outcome of the patients and assessment of the prognostic significance, we found that in AML patients, FLT3 overexpression and mutation were correlated significantly with poor outcomes, increased relapse rate, and predicted poor survival ,,,,,.
| Conclusion|| |
FLT3 (CD135) overexpression was found in patients with AML and correlated with relapsed cases and worse survival. This indicated that FLT3 overexpression could be a poor prognostic predictor for AML.
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Conflicts of interest
There are no conflicts of interest.
| References|| |
Döhner K, Döhner H. Molecular characterization of acute myeloid leukemia. Haematologica 2008; 93
Jemal A, Thomas A, Murray T, Thun M. Cancer statistics. CA Cancer J Clin 2002; 52
Grafone T, Palmisano M, Nicci C, Storti S. An overview on the role of FLT3-tyrosine kinase receptor in acute myeloid leukemia: biology and treatment. Oncol Rev 2012; 6
Takahashi S. Downstream molecular pathways of FLT3 in the pathogenesis of acute myeloid leukemia: biology and therapeutic implications. J Hematol Oncol 2011; 4
Gilliland DG, Griffin JD. The roles of FLT3 in hematopoiesis and leukemia. Blood 2002; 100
Janke H, Pastore F, Schumacher D, Herold T, Hopfner K, Schneider S, et al
. Activating FLT3 mutants show distinct gain-of-function phenotypes in vitro
and a characteristic signaling pathway profile associated with prognosis in acute myeloid leukemia. PLoS One 2014; 9
Meshinchi S, Frederick R. Structural and functional alterations of FLT3 in acute myeloid leukemia. Clin Cancer Res 2009; 15
Annesley CE, Brown P. The biology and targeting of FLT3 in pediatric leukemia. Front Oncol 2014; 4
Brown P, Levis M, Shurtleff S, Campana D, Downing J. FLT3 inhibition selectively kills childhood acute lymphoblastic leukemia cells with high levels of FLT3 expression. Blood 2005; 105
Vora HH, Shukla SN, Brahambhatt BV, Mehta SH, Patel NA, Parikh SK, et al
. Clinical relevance of FLT3 receptor protein expression in Indian patients with acute leukemia. Asia Pacific J Clin Oncol 2010; 6
Sharawat SK, Raina V, Kumar L, Sharma A, Bakhshi R, Vishnubhatla S, et al
. High fms-like tyrosine kinase-3 (FLT3): receptor surface expression predicts poor outcome in FLT3 internal tandem duplication (ITD): negative patients in adult acute myeloid leukaemia: a prospective pilot study from India. Indian J Med Res 2016; 143
Mehta SV, Shukla SN, Vora HH. Comprehensive FLT3 analysis in Indian acute myeloid leukemia. J Blood Lymph 2011; 1
Sharawat SK, Gupta R, Raina V, Kumar L, Sharma A, Iqbal S, et al
. Increased co-expression of c-KIT and FLT3 receptors on myeloblasts: Independent predictor of poor outcome in pediatric acute myeloid leukemia. Cytometry B Clin Cytom 2013; 84
Graf M, Hecht K, Reif S, Pelka-Fleischer R, Pfister K, Schmetzer H. Expression and prognostic value of hemopoietic cytokine receptors in acute myeloid leukemia (AML): implications for future therapeutical strategies. Eur J Haematol 2004; 72
Peng HL, Zhang GS, Gong FJ, Shen JK, Zhang Y. Fms-like tyrosine kinase (FLT3): and FLT3 internal tandem duplication in different types of adult leukemia: analysis of 147 patients. Croat Med J 2009; 49
Kuchenbauer F, Kern W, Schoch C, Kohlmann A, Hiddeman W. Detailed analysis of FLT3 expression levels in acute myeloid leukemia. Haematologica 2005; 90
Warren M, Luthra R, Yin CC, Ravandi F, Cortes JE, Kantarjian HM, et al
. Clinical impact of change of FLT3 mutation status in acute myeloid leukemia patients. Mod Pathol 2012; 25
Tarlock K, Alonzo TA, Loken MR, Gerbing RB, Ries RE, Aplenc R, et al
. Disease characteristics and prognostic implications of cell surface FLT3 Receptor (CD135): expression in pediatric acute myeloid leukemia: a report from the Children's Oncology Group. Clin Cancer Res 2017; 23
Ilyas AM, Ahmed S, Faheem M, Naseer MI, Kumosani TA, Al-Qahtani MH, et al
. Next generation sequencing of acute myeloid leukemia: influencing prognosis. BMC Genomics 2015; 16
Rosnet O, Buhring HJ, Marchetto S, Rappold I, Lavagna C, Sainty D, et al
. Human FLT3/FLK2 receptor tyrosine kinase is expressed at the surface of normal and malignant hematopoietic cells. Leukemia 1996; 10
Jönsson M, Engström M, Jönsson JI. FLT3 ligand regulates apoptosis through AKT-dependent inactivation of transcription factor FoxO3. Biochem Biophys Res Commun 2004; 318
Levis M, Small D. It does matter in leukemia. Leukemia 2003; 17
[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4]