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Original Article

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Blood Res 2021; 56(2):

Published online June 30, 2021

https://doi.org/10.5045/br.2021.2021024

© The Korean Society of Hematology

Investigating the expression pattern of the angiopoietin-Tie system in ALL and its correlation with baseline characteristics

Saeed Zaka Khosravi1,2, Samira Molaei Ramshe3, Mehdi Allahbakhshian Farsani4, Saeed Solali2, Mohammadreza Moonesi1,2, Majid Farshdousti Hagh1,5

Author Info. +

1Immunology Research Center, 2Division of Hematology and Transfusion Medicine, Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, 3Student Research Committee, Department of Medical Genetics, School of Medicine, Shahid Beheshti University of Medical Sciences, 4HSCT Research Center, Shahid Beheshti University of Medical Sciences, Tehran, 5Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran

Correspondence to : Majid Farshdousti Hagh, Ph.D.
Immunology Research Center, Tabriz University of Medical Sciences, Golgasht Street, Tabriz 5166/15731, Iran
E-mail: m.farshdousti@gmail.com

Received: February 4, 2021; Revised: March 26, 2021; Accepted: April 6, 2021

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

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Background
Acute lymphoblastic leukemia (ALL) is the most common type of leukemia in children. Several environmental and genetic factors are known to be involved in its development and progression. The angiopoietin-Tie system is one of the most critical factors in angiogenesis, and its possible role in solid tumors and leukemia has been previously investigated. In this study, we examined the expression of these genes in ALL patients (early pre-B-ALL and pre-B-ALL) and compared them with normal samples.
Methods
Bone marrow samples were collected from 40 patients (aged 0‒19 yr) newly diagnosed with early pre-B-ALL or pre-B-ALL using molecular and flow cytometric tests and from 15 control individuals. For molecular tests, RNA extraction and cDNA synthesis were performed, and Ang1, Ang2, Ang4, Tie1, and Tie2 gene expression was examined by real-time polymerase chain reaction.
Results
Ang2, Tie1, and Tie2 gene expression were significantly increased in patients with ALL, whereas Ang1 gene expression was decreased. The Ang4 gene did not show significant expression changes between the two groups.
Conclusion
Changes in the expression of the Ang-Tie system indicate a possible role of angiogenesis in ALL prognosis. Moreover, such changes can be considered as potential diagnostic biomarkers or therapeutic targets.

Keywords Angiopoietin, Leukemia, Tie receptor, Acute lymphoblastic leukemia

Article

Original Article

Blood Res 2021; 56(2): 79-85

Published online June 30, 2021 https://doi.org/10.5045/br.2021.2021024

Copyright © The Korean Society of Hematology.

Investigating the expression pattern of the angiopoietin-Tie system in ALL and its correlation with baseline characteristics

Saeed Zaka Khosravi1,2, Samira Molaei Ramshe3, Mehdi Allahbakhshian Farsani4, Saeed Solali2, Mohammadreza Moonesi1,2, Majid Farshdousti Hagh1,5

1Immunology Research Center, 2Division of Hematology and Transfusion Medicine, Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, 3Student Research Committee, Department of Medical Genetics, School of Medicine, Shahid Beheshti University of Medical Sciences, 4HSCT Research Center, Shahid Beheshti University of Medical Sciences, Tehran, 5Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran

Correspondence to:Majid Farshdousti Hagh, Ph.D.
Immunology Research Center, Tabriz University of Medical Sciences, Golgasht Street, Tabriz 5166/15731, Iran
E-mail: m.farshdousti@gmail.com

Received: February 4, 2021; Revised: March 26, 2021; Accepted: April 6, 2021

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Background
Acute lymphoblastic leukemia (ALL) is the most common type of leukemia in children. Several environmental and genetic factors are known to be involved in its development and progression. The angiopoietin-Tie system is one of the most critical factors in angiogenesis, and its possible role in solid tumors and leukemia has been previously investigated. In this study, we examined the expression of these genes in ALL patients (early pre-B-ALL and pre-B-ALL) and compared them with normal samples.
Methods
Bone marrow samples were collected from 40 patients (aged 0‒19 yr) newly diagnosed with early pre-B-ALL or pre-B-ALL using molecular and flow cytometric tests and from 15 control individuals. For molecular tests, RNA extraction and cDNA synthesis were performed, and Ang1, Ang2, Ang4, Tie1, and Tie2 gene expression was examined by real-time polymerase chain reaction.
Results
Ang2, Tie1, and Tie2 gene expression were significantly increased in patients with ALL, whereas Ang1 gene expression was decreased. The Ang4 gene did not show significant expression changes between the two groups.
Conclusion
Changes in the expression of the Ang-Tie system indicate a possible role of angiogenesis in ALL prognosis. Moreover, such changes can be considered as potential diagnostic biomarkers or therapeutic targets.

Keywords: Angiopoietin, Leukemia, Tie receptor, Acute lymphoblastic leukemia

Fig 1.

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Figure 1.Relative expression of Ang-Tie system genes (Ang1, Ang2, Ang4, Tie1, and Tie2) in patient samples and control samples.
Blood Research 2021; 56: 79-85https://doi.org/10.5045/br.2021.2021024

Fig 2.

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Figure 2.Receiver operating characteristic curves of Ang1, Ang2, Tie1, and Tie2 genes for predicting their respective diagnostic potential in acute lymphoblastic leukemia.
Blood Research 2021; 56: 79-85https://doi.org/10.5045/br.2021.2021024

Table 1 . The forward and reverse primer sequences and polymerase chain reaction product lengths used in this study..

GeneDirectionSequenceLengthProduct
Ang1F
R		GCCAGAACCCAAAAAGGTGT
GCCTCTGACTGGTAATGGCA		20
20		188
Ang2F
R		ACTGGGAAGGGAATGAGGCTTAC
TTTGTCGTTGTCTCCATCCTTTGTG		23
25		167
Ang4F
R		ATTACAAACAGGGCTTCGGAGA
ATAGCTGGTTCTCACTGCCC		22
20		174
Tie 1F
R		GGTTCTTGCGGACAGTGGGTTC
GCTGGCGGCTCTGCTTGG		22
18		140
Tie 2F
R		ACCCTTAGTGACATTCTTCCTCCTC
TGCTGGTCTTCATTCTTGCCTTG		25
23		155
ABLF
R		ACACTTCTAAGCATAACTAAAGGTGAAAAGC
GATGTAGTTGCTTGGGACCCA		31
21		117

Abbreviations: F, forward primer; R, reverse primer..

Table 2 . General baseline characteristics and clinical data of patients and controls..

VariableValue
PatientsControls
Age (yr, mean±SD)9.3±5.410.6±6.5
First decade (N)238
Second decade (N)177
Sex (male/female)1.21.5
Male (N)229
Female (N)186
WBCs in PB (×103/mL, mean±SD)81.4±40.211.2±5.7
<50 (N)1515
>50 (N)25None
BM blasts (%, mean±SD)79±17.7<5%
25–50% (N)4None
51–75% (N)7None
76–100% (N)29None
WHO classification (pre-B-ALL/early pre-B-ALL)1.5None
Early pre-B-ALL (N)16None
Pre-B-ALL (N)24None

Abbreviations: ALL, acute lymphoblastic leukemia; BM, bone marrow; PB, peripheral blood; SD, standard deviation; WBC, white blood cell; WHO, World Health Organization..

Table 3 . Ang1, Ang2, Agn4, Tie1, and Tie2 expression levels (means of ΔCt±standard deviation) according to the demographic and clinical data of the patients..

CharacteristicsNAng1PAng2PAng4PTie1PTie2P
Age0.7900.5400.7590.4250.257
First decade236.8±1.55.1±1.19.2±3.36.3±1.14.4±1.1
Second decade176.9±1.44.9±1.29.0±3.26.2±1.14.1±1.2
Sex0.8300.2360.5560.3170.688
Male227.2±1.34.8±1.29.3±3.56.5±1.34.1±1.2
Female187.3±1.25.0±1.19.5±3.66.3±1.34.2±1.3
BM blasts0.4310.7560.4570.3450.264
25–55%47.3±1.55.5±1.29.0±3.56.6±1.44.5±1.3
56–75%77.2±1.35.3±1.28.8±3.66.3±1.54.3±1.5
76–100%297.2±1.15.4±1.18.7±3.26.4±1.24.4±1.2
PB WBCs0.3220.5870.6320.4350.475
<50157.4±1.35.4±1.29.0±3.36.1±1.24.2±1.3
>50257.1±1.25.3±1.48.9±3.56.2±1.64.4±1.4
WHO classification0.7190.3650.2350.3530.476
Early pre-B-ALL166.7±1.35.2±1.38.6±3.46.2±1.34.2±1.4
Early Pre-B-ALL246.9±1.45.3±1.48.5±3.26.4±1.44.4±1.5

Abbreviations: ALL, acute lymphoblastic leukemia; BM, bone marrow; WBC, white blood cell; WHO, World Health Organization..

Table 4 . Receiver operating characteristic curve analysis results..

GenesEstimate criterionAUCJa)SensitivitySpecificityP
Ang1≤0.0120.710.4370.073.30.01
Ang2>0.0070.890.7690.086.6<0.0001
Tie1>0.0050.770.5380.073.30.0001
Tie2>0.0150.820.5885.073.3<0.0001
Genes combination>0.0450.710.3885.053.30.01

Estimate criterion: optimal cut‐off point for gene expression. a)Youden index..

Abbreviation: AUC, area under the curve..
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