Investigating the Correlation Between TGF-β Gene Expression and Disease-Related Prognostic Factors in Bone Marrow Aspiration of Adults With Acute Lymphoblastic Leukemia
Abstract
Acute lymphoblastic leukemia (ALL) is a malignant transformation and proliferation of lymphoid progenitor cells in the bone marrow, blood and extramedullary sites and the second most common acute leukemia in adults. While dose-intensification strategies have led to a significant improvement in outcomes for pediatric patients, the prognosis for the elderly remains very poor. Aberrant or excessive expression of cytokines may be related to the pathogenesis of acute leukemia. TGF-β is a cytokine that plays a role in regulating various cellular processes such as growth, proliferation, and apoptosis. We evaluated the expression of TGF-β mRNA in adults with ALL compared to the control and its relationship with disease-related prognostic factors. Bone marrow specimens were obtained from 90 newly-diagnosed adults with ALL and 33 healthy adults. After immunophenotyping by flow cytometry, RNA was extracted, and RQ-PCR was done. Our result showed that from all patients, 63 (70%) were identified as B-ALL and 27(30%) as T-ALL. TGF-β transcript levels in both T-ALL and B-ALL patients showed a significant decrease compared to the control group (P < 0.001). However, the expression of the TGF-β transcripts was not different between the different immunophenotypic subtypes (P=0.54). The gene expression level of TGF-β was not correlated with age (P=0.47), gender (P=0.29), ALL subtypes (P=0.54), the percentage of bone marrow blasts (P=0.92) and peripheral blood leukocyte count (P=0.38) of ALL patients. In conclusion, since TGF-β has a tumor suppressor role, it seems that leukemic cells may use TGF-β down-regulation to be more freely proliferated and evolve the clone.
2. Dong M, Blobe GC. Role of transforming growth factor-β in hematologic malignancies. Blood 2006;107:4589-96.
3. Terwilliger T, Abdul-Hay M. Acute lymphoblastic leukemia: a comprehensive review and 2017 update. Blood Cancer J 2017;7:e577.
4. Chiaretti S, Zini G, Bassan R. Diagnosis and Subclassification of Acute Lymphoblastic Leukemia. Mediterr J Hematol Infect Dis 2014;6:e2014073.
5. Zuckerman T, Rowe JM. Pathogenesis and prognostication in acute lymphoblastic Leukemia. F1000Prime Rep 2014;59:1-5.
6. Hoelzer D, Bassan R, Dombret H, Fielding A, Ribera JM, Buske C. ESMO Guidelines Committee. Acute lymphoblastic leukaemia in adult patients: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2016;27:v69-82.
7. Kupsa T, Vasatova M, Karesova I, Zak P, Horacek JM. Baseline serum levels of multiple cytokines and adhisin molecules in patients with acute myeloid: results of a pivotal trial. Exp Oncol 2014;36:252-7.
8. Nakase K, Kita K, Kyo T, Ueda T, Tanaka I, and Katayama N. Prognostic Relevance of Cytokine Receptor Expression in Acute Myeloid Leukemia: Interleukin-2 Receptor α-Chain (CD25) Expression Predicts a Poor Prognosis. PLoS One 2015;10:e0128998.
9. Ho MY, Tang SJ, Chuang MJ, Cha TL, Li JY, Sun GH, et al. TNF-α induces epithelial-mesenchymal transition of renal cell carcinoma cells via a GSK3β-dependent mechanism. Mol Cancer Res 2012;10:1109-19.
10. Aomatsu K, Arao T, Sugioka K, Matsumoto K, Tamura D, Kudo K, et al. TGF-β induces sustained upregulation of snai1 and snai2 through smad and non-smad pathways in a human corneal epithelial cell line. Invest Ophthalmol Vis Sci 2011;52:2437-43.
11. Blank U and Karlsson S. TGF-b signaling in the control of hematopoietic stem cells. Blood 2015;125:3542-50.
12. Jing Y, Han Z, Zhang S, Liu Y, Wei L. Epithelial-mesenchymal transition in tumor microenvironment. Cell Biosci 2011;1:29.
13. Gharagozlou S, Kardar GA, Rabbani H, Shokri F. Molecular analysis of the heavy chain variable region genes of human hybridoma clones specific for coagulation factor VIII. Thromb Haemost 2005;94:1131-7.
14. Asgarian Omran H, Shabani M, Shahrestani T, Sarafnejad A, Khoshnoodi J, Vossough P, et al. Immunophenotypic subtyping of leukemic cells from Iranian patients with acute lymphoblastic leukaemia: association to disease outcome. Iran J Immunol 2007;4:15-25.
15. Wolfraim LA, Fernandez TM, Mamura M, Fuller WL, Kumar R, Cole DE, et al. Loss of Smad3 in acute T-cell lymphoblastic leukemia. N Engl J Med 2004;351:552-559.
16. Lucas PJ, McNeil N, Hilgenfeld E, Choudhury B, Kim SJ, Eckhaus MA, et al. Transforming growth factor-beta pathway serves as a primary tumor suppressor in CD8+ T cell tumorigenesis. Cancer Res 2004;64:6524-6529.
17. Kubiczkova L, Sedlarikova L, Hajek R, and Sevcikova S. TGF-beta - an excellent servant but a bad master. J Transl Med 2012;10:183.
18. Douglas RS, Capocasale RJ, Lamb RJ, Nowell PC, Moore JS. Chronic lymphocytic leukemia B cells are resistant to the apoptotic effects of transforming growth factor-beta. Blood 1997;89:941-7.
19. Lagneaux L, Delforge A, Bron D, Massy M, Bernier M, Stryckmans P. Heterogenous response of B lymphocytes to transforming growth factor-beta in B-cell chronic lymphocytic leukaemia: correlation with the expression of TGF-beta receptors. Br J Haematol 1997;97:612-20.
20. Rowe JM. Prognostic factors in adult acute lymphoblastic leukaemia. Br J Haematol 2010;150:389-405.
21. Gokbuget N, Arnold R, Bohme A, Fietkau R, Freund M, Ganser A, et al. Improved outcome in high risk and very high risk ALL by risk adapted SCT and in standard risk ALL by intensive chemotherapy in 713 adult ALL patients treated according to the prospective GMALL study 07/2003. Blood 2007;110:12.
22. Cools J. Improvements in the survival of children and adolescents with acute lymphoblastic leukemia. Haematologica 2012;97:635.
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Issue | Vol 56, No 10 (2018) | |
Section | Original Article(s) | |
Keywords | ||
Acute lymphoblastic leukemia TGF-β Immunophenotyping RQ-PCR |
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