What Is Adult T-Cell Leukemia Pathogenesis? System Virology as a Solution of This Puzzle

AUTHORS

Mohsen Karbalaei 1 , Masoud Keikha ORCID 2 , 3 , *

1 Department of Microbiology and Virology, School of Medicine, Jiroft University of Medical Sciences, Jiroft, Iran

2 Antimicrobial Resistance Research Center, Mashhad University of Medical Sciences, Mashhad, Iran

3 Department of Microbiology and Virology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran

How to Cite: Karbalaei M, Keikha M. What Is Adult T-Cell Leukemia Pathogenesis? System Virology as a Solution of This Puzzle, Jundishapur J Chronic Dis Care. Online ahead of Print ; 8(3):e93351. doi: 10.5812/jjcdc.93351.

ARTICLE INFORMATION

Jundishapur Journal of Chronic Disease Care: 8 (3); e93351
Published Online: June 16, 2019
Article Type: Letter
Received: May 11, 2019
Revised: May 26, 2019
Accepted: May 30, 2019
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Keywords

Adult T-Cell Leukemia/Lymphoma HTLV-1 Cancer Microbial Pathogenesis System Biology

Copyright © 2019, Jundishapur Journal of Chronic Disease Care. This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/) which permits copy and redistribute the material just in noncommercial usages, provided the original work is properly cited.

Dear Editor,

Human T-cell leukemia virus type 1 (HTLV-1) is a causative agent of HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and the adult T-cell leukemia/lymphoma (ATLL) (1). There are 20 million HTLV-1 infected individuals worldwide. Of which, approximately 2% to 4% of HTLV-1 infected cases were developed to ATL; although, 90% of HTLV-1 infected individuals remain as an asymptomatic carrier (ACs) during their lives (2, 3).

ATLL is a progressive lymphoid malignancy, which characterized with an uncontrollable proliferation of CD4+ T cells after a long-lasting period of infection with HTLV-1 in ACs cases (3). The main mechanism of ATL remains unknown; however, it is suggested that cytokines and the immune system play a key role in the development of ATL (3, 4). Due to the existence of several inquiries regarding the ATL pathogenesis; this study was done for the analysis of the main changes in ATL patients compared to ACs via transcriptomic information during a system biology report.

In this study, the differentially expressed genes (DEGs) were retrieved from gene expression omnibus (GEO) datasets (accession number: GSE19080). DEGs were limited to immune-system, apoptosis, cell cycle, and cell growth was analyzed using Benjamini-Hochberg FDR-adjusted P < 0.05 in two different groups of ATLs and ACs individuals. Then, the protein-protein interaction network (PPIN) for significant genes was constructed via STRING online server. Finally, the signaling network for ATLs was proposed for completion of ATL pathogenesis model.

According to our analysis, there are over-expression of different genes including NF-kB, mTOR, PI3K/Akt, transactivation factor, T cell surface molecule as well as anti-apoptotic genes in ATLs; whereas downregulation of IFNG, Caspase, Foxp3, JAK-STAT, or cytokine such as TGF-β in this group. Several of these changes are predictable, for example, downregulation of IFN-γ production followed the destruction of functionality T cells; or decline of TGF-β in ATLs, which inhibits by HTLV-1 (HTLV-1 is inducing production of T cells whereas suppresser effects of TGF-β on T cells proliferation). In addition, our analysis showed that Foxp3 was downregulated in ATLs; given that T regulatory cells are limited T cell proliferation. Therefore, the expression levels of Foxp3 should be down-regulated in ATLs, which was confirmed in this study. Moreover, Janus tyrosine kinases (JAKs) is cause to proliferation or NF-kB and IL-2 was essential for T cell activation and proliferation. Therefore, JAK-STAT, NF-kB signaling pathway, and IL-2 production should be over-expressed in ATLs for T cells proliferation and develop to ATL, which is confirmed in our data analysis (Table 1) (2-5). According to the review of the literatures, Tax is induction of the transcription factors such as CREB, SRF, and AP-1, which is confirmed in our analysis (4, 5).

Table 1. The Expression Profiles of ATLs and ACs Compared with Healthy Individuals
Gene SymbolDescriptionFunctionATLsACs
BIRC5Baculoviral IAP repeat containing 5Apoptosis inhibitor-0.38-0.59
CDC2Cell division cycle 2Cell proliferation-0.460.21
CDKN2ACyclin dependent kinase inhibitor 2ACell proliferation0.26-0.13
KCNAB1Potassium voltage-gated channel subfamily a member regulatory beta subunit 1Potassium channel0.310.16
CREB1CAMP responsive element binding protein 1Transactivation-0.540.001
CD25Interleukin 2 receptor subunit alphaIL-2 receptor-0.53-1.07
NFKBIENuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, epsilonPro- inflammatory response0.240.25
mTORMechanistic target of rapamycin kinaseCell survive1.150.37
Jak1Janus kinase 1Inflammation0.110.04
TP53Tumor protein P53Tumor suppressor0.74-0.26
PI3KPhosphatidylinositol-4,5-bisphosphate 3-kinaseCell proliferation0.08-0.02
C-mycC-myc myelocytomatosis viral oncogeneCell proliferation-0.78-0.72
CCR5C-C motif chemokine receptor 5Fusion co-receptor0.061.09
CDK6Cyclin dependent kinase 6Cell cycle regulators0.310.41
JunJun proto-oncogeneTranscription-0.250.08
CDKN1ACyclin dependent kinase inhibitor 1ACell cycle regulators0.07-0.004
IRF-1Interferon regulatory factor 1Transactivation0.480.63
SYKSpleen associated tyrosine kinaseInflammation0.09-0.85
NFKB1Nuclear factor kappa B subunit 1Inflammation0.701.27
TGFBTransforming growth factor-betaSuppression of immune-system-0.060.23
Foxp3Forkhead box P3Transcription-0.49-0.07
TRAFTNF receptor associated factorInflammatory response0.11-0.024
ATF3Activating transcription factor 3Transcription0.070.3
CREBcAMP response element binding protein Transcription0.570.30
CXCR4C-X-C motif chemokine receptor 4Viral receptor3.42.96
EF2Eukaryotic translation elongation factor 2Transcription0.23-0.72
STAT6Signal transducer and activator of transcription 6Transcription-1.26-0.19
IL-15Interleukin 15Inflammation-0.250.13
SRFSerum response factorTranscription0.450.51
BCL2B-cell lymphoma 2Cell survive0.771.13
CASP9Caspase 9 (apoptotic inducer)-1.27-0.98
IFNGInterferon gammaInflammation1.761.78

According to PPIN, PI3K/Akt, mTOR, JAK-STAT, NF_kB, and transactivation genes have central roles in ATL pathogenesis, which are located in central nodes. Cytokines, cyclin, T cell surface molecules, and anti-apoptosis genes are located in external nodes, which influenced by central nods (Figure 1).

The protein-protein interaction networks among ATLs analyzed group
Figure 1. The protein-protein interaction networks among ATLs analyzed group

Based on the signaling network, HBZ and Tax can promote T cells for cell growth and proliferation using several signaling pathways including NF_kB, PI3K, and MAPK signaling pathway, which lead to ATL during lengthy induction by HTLV-1 (Figure 2).

The signaling network in ATL pathogenesis in CD4+ T cells
Figure 2. The signaling network in ATL pathogenesis in CD4+ T cells

In summary, there is limited information regarding ATL pathogenesis; KEGG pathway (hsa05166) is not enriched enough and future investigation for ATL pathogenesis is needed. This information can be useful for the development of diagnosis, monitoring, and treatment of ATL patients. According to the present analysis, the immune-system changes, particularly cytokines, can have influenced several vital signaling pathways such as NF-kB, MAPK, and PI3K-Akt/mTOR signaling pathways, which regulate cell proliferation and is responsible for developing to adult T-cell leukemia/lymphoma.

Footnotes

References

  • 1.

    Kanzaki LIB. HTLV-1: A real pathogen or a runaway guest of a diseased cell? J Biosci. 2018;43(4):785-95. [PubMed: 30207322].

  • 2.

    Mozhgani SH, Zarei-Ghobadi M, Teymoori-Rad M, Mokhtari-Azad T, Mirzaie M, Sheikhi M, et al. Human T-lymphotropic virus 1 (HTLV-1) pathogenesis: A systems virology study. J Cell Biochem. 2018;119(5):3968-79. doi: 10.1002/jcb.26546. [PubMed: 29227540].

  • 3.

    Futsch N, Prates G, Mahieux R, Casseb J, Dutartre H. Cytokine networks dysregulation during HTLV-1 infection and associated diseases. Viruses. 2018;10(12). doi: 10.3390/v10120691. [PubMed: 30563084]. [PubMed Central: PMC6315340].

  • 4.

    Yamagishi M, Watanabe T. Molecular hallmarks of adult T cell leukemia. Front Microbiol. 2012;3:334. doi: 10.3389/fmicb.2012.00334. [PubMed: 23060864]. [PubMed Central: PMC3444139].

  • 5.

    Watanabe T. Adult T-cell leukemia: Molecular basis for clonal expansion and transformation of HTLV-1-infected T cells. Blood. 2017;129(9):1071-81. doi: 10.1182/blood-2016-09-692574. [PubMed: 28115366]. [PubMed Central: PMC5374731].

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