Original Article

Involvement Value of FLT-3, c-Myc, STAT3, p27, and HOTAIR Gene Expression in Acute Myeloid Leukemia Patients: A Molecular Perspective to a Novel Leukemogenesis Mechanism

Abstract

Background: The identification of long non-coding RNAs (lncRNAs) in the pathogenesis of acute myeloid leukemia (AML) has marked a new era in the molecular understating of the disease. This study investigated the correlation between the changes in the expression of lncRNAs, including HOTAIR, PVT-1, and CRNDE, and the alteration in the expression profile of FLT-3, c-Myc, STAT3, STAT5, and p27 in AML patients.

Materials and Methods: Blood samples were collected from forty-one newly diagnosed AML patients and ten healthy individuals to evaluate the expression levels of the study genes using qRT-PCR analysis. The probable correlation between the gene expressions was determined using Pearson’s correlation test.

Results: The results showed that while there was a significant elevation in the expression of FLT3, c-Myc, STAT3, and HOTAIR, p27 expression remarkably diminished in AML patients compared to the control group. Also, a correlation was found between the expression of FLT-3 and p27 and the expression of HOTAIR and STAT3. It was assumed that FLT-3 had a role in increasing the proliferative and survival capacity of AML cells, at least partly, through c-Myc-mediated suppression of p27. Moreover, lncRNA HOTAIR showed to be involved in leukemia proliferation assumably by enhancing the expression of STAT3.

Conclusion: Overall, the results of gene profile analysis suggested that studying the expression of HOTAIR, FLT-3, c-Myc, STAT3, and p27 could be helpful to AML patients, and each of these genes could be a valuable target for pharmaceutic intervention.

1. De Kouchkovsky I, Abdul-Hay M. Acute myeloid leukemia: a comprehensive review and 2016 update. Blood Cancer. 2016; 6(7): e441.
2. Wahlin A, Hörnsten P, Jonsson H. Remission rate and survival in acute myeloid leukemia: impact of selection and chemotherapy. Eur J Haematol. 1991 46(4):240-7.
3. Moorman AV, Roman E, Willett EV, et al. Karyotype and age in acute myeloid leukemia.: Are they linked? Cancer Genet Cytogenet. 2001;126(2):155-61
4. Jiang MC, Ni JJ, Cui WY, et al. Emerging roles of lncRNA in cancer and therapeutic opportunities. Am J Cancer Res. 2019;9(7):1354-1366. eCollection 2019.
5. Yang G, Lu X, Yuan L. LncRNA: a link between RNA and cancer. Biochim Biophys Acta. 2014;1839(11):1097-109.
6. Huppi K, Volfovsky N, Runfola T, et al. The identification of microRNAs in a genomically unstable region of human chromosome 8q24. Mol Cancer Res. 2008;6(2):212-21.
7. Yap KL, Li S, Muñoz-Cabello AM, R et al. Molecular interplay of the noncoding RNA ANRIL and methylated histone H3 lysine 27 by polycomb CBX7 in transcriptional silencing of INK4a. Mol Cell. 2010;38(5):662-74.
8. Guo G, Kang Q, Chen Q, , et al. High expression of long non-coding RNA H19 is required for efficient tumorigenesis induced by Bcr-Abl oncogene. FEBS Lett. 2014; 588(9): 1780-6.
9. Sun J, Li W, Sun Y, et al. A novel antisense long noncoding RNA within the IGF1R gene locus is imprinted in hematopoietic malignancies. Nucleic Acids Res. 2014;42(15):9588-601.
10. Chapuis N, Tamburini J, Cornillet-Lefebvre P, et al. Autocrine IGF-1/IGF-1R signaling is responsible for constitutive PI3K/Akt activation in acute myeloid leukemia: therapeutic value of neutralizing anti-IGF-1R antibody. Haematologica. 2010; 95(3): 415-23.
11. Benetatos L, Vartholomatos G, Hatzimichael E. MEG3 imprinted gene contribution in tumorigenesis. Int J Cancer. 2011;129(4):773-9.
12. Khoury H, Suarez-Saiz F, Wu S, et al. An upstream insulator regulates DLK1 imprinting in AML. Blood. 2010; 115(11): 2260-3.
13. Lagunas-Rangel FA, Chávez-Valencia V. FLT3-ITD and its current role in acute myeloid leukaemia. Med Oncol. 2017;34(6):114.
14. Notopuro PB, Nugraha J, Utomo B, et al. The Association of FLT3-ITD Gene Mutation with Bone Marrow Blast Cell Count, CD34, Cyclin D1, Bcl-xL and hENT1 Expression in Acute Myeloid Leukemia Patients. Iran J Pathol. 2020; 15(4): 306-12.
15. Döhner H, Weisdorf DJ, Bloomfield CD. Acute myeloid leukemia. New England Journal of Medicine 2015; 373(12): 1136-52.
16. Deschler B, Lübbert M. Acute myeloid leukemia: epidemiology and etiology. Cancer. 2006; 107(9): 2099-107.
17. Patnaik MM. The importance of FLT3 mutational analysis in acute myeloid leukemia. Leuk Lymphoma. 2018; 59(10): 2273-86.
18. Garg M, Nagata Y, Kanojia D, et al. Profiling of somatic mutations in acute myeloid leukemia with FLT3-ITD at diagnosis and relapse. Blood. 2015; 126(22): 2491-501.
19. McCormick SR, McCormick MJ, Grutkoski PS, , et al. FLT3 mutations at diagnosis and relapse in acute myeloid leukemia: cytogenetic and pathologic correlations, including cuplike blast morphology. Arch Pathol Lab Med. 2010;134(8):1143-51.
20. Kiyoi H, Naoe T. FLT3 in human hematologic malignancies. Leuk Lymphoma. 2002;43(8):1541-7.
21. Mizuki M, Fenski R, Halfter H, et al. Flt3 mutations from patients with acute myeloid leukemia induce transformation of 32D cells mediated by the Ras and STAT5 pathways. Blood. 2000; 96(12): 3907-14.
22. Spiekermann K, Bagrintseva K, Schwab R, et al. Overexpression and constitutive activation of FLT3 induces STAT5 activation in primary acute myeloid leukemia blast cells. Clin Cancer Res. 2003;9(6):2140-50.
23. Tamai M, Furuichi Y, Kasai S, et al. TGFβ1 synergizes with FLT3 ligand to induce chemoresistant quiescence in acute lymphoblastic leukemia with MLL gene rearrangements. Leuk Res. 2017; 61: 68-76.
24. Huang J, Liu T, Shang C, et al. Identification of lncRNAs by microarray analysis reveals the potential role of lncRNAs in cervical cancer pathogenesis. Oncol Lett. 2018; 15(4): 5584-92.
25. Kim T, Croce CM. Long noncoding RNAs: Undeciphered cellular codes encrypting keys of colorectal cancer pathogenesis. Cancer Lett. 2018; 417: 89-95.
26. Malih S, Saidijam M, Malih N. A brief review on long noncoding RNAs: a new paradigm in breast cancer pathogenesis, diagnosis and therapy. Tumour Biol.2016; 37(2): 1479-85.
27. Wu Y, Zhang L, Wang Y, et al. Long noncoding RNA HOTAIR involvement in cancer. Tumour Biol. 2014; 35(10): 9531-8.
28. Xiao Z, Qu Z, Chen Z, et al. LncRNA HOTAIR is a prognostic biomarker for the proliferation and chemoresistance of colorectal cancer via MiR-203a-3p-mediated Wnt/ss-catenin signaling pathway. Cell Physiol Biochem. 2018;46(3):1275-1285.
29. Ono H, Motoi N, Nagano H, et al. Long noncoding RNA HOTAIR is relevant to cellular proliferation, invasiveness, and clinical relapse in small‐cell lung cancer. Cancer Med. 2014; 3(3): 632-42.
30. Qiu Jj, Wang Y, Ding Jx, et al. The long non-coding RNA HOTAIR promotes the proliferation of serous ovarian cancer cells through the regulation of cell cycle arrest and apoptosis. Exp Cell Res. 2015; 333(2): 238-48.
31. Zhang Y, Cheng X, Liang H, et al. Long non-coding RNA HOTAIR and STAT3 synergistically regulate the cervical cancer cell migration and invasion. Chem Biol Interact. 2018;286:106-110.
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IssueVol 17, No 3 (2023) QRcode
SectionOriginal Article(s)
DOI https://doi.org/10.18502/ijhoscr.v17i3.13304
Keywords
Acute myeloid leukemia; LncRNAs; Gene expression; HOTAIR; FLT-3

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How to Cite
1.
Shagerdi Esmaeli N, Asadi S, Bashash D, Salari S, Hamidpour M. Involvement Value of FLT-3, c-Myc, STAT3, p27, and HOTAIR Gene Expression in Acute Myeloid Leukemia Patients: A Molecular Perspective to a Novel Leukemogenesis Mechanism. Int J Hematol Oncol Stem Cell Res. 2023;17(3):145-155.