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CC BY-NC-ND 4.0 · South Asian J Cancer 2022; 11(04): 346-352
DOI: 10.1055/s-0042-1742593
Original Article
Leukemia, Lymphoma, Myeloma

Dysregulated Expression of MiR-19b, MiR-25, MiR-17, WT1, and CEBPA in Patients with Acute Myeloid Leukemia and Association with Graft versus Host Disease after Hematopoietic Stem Cell Transplantation

Mahdiyar Iravani Saadi
1   Colorectal Research Center, Iran University of Medical Sciences, Tehran, Iran
,
Fatemeh Tahmasebijaroubi
2   Hematology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
,
Esmat Noshadi
2   Hematology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
,
Raha Rahimikian
3   Department of Biochemistry, Bushehr University of Medical Sciences, Bushehr, Iran
,
Zahed Karimi
4   Hematology and Oncology Department, Shiraz University of Medical Sciences, Shiraz, Iran
,
Maryam Owjfard
5   Clinical Neurology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
6   Shiraz University of Applied Science and Technology (UAST), Shiraz, Iran
,
Ahmad Niknam
2   Hematology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
,
Ehsan Nabi Abdolyousefi
2   Hematology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
,
Sanaz Salek
2   Hematology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
,
Reza Tabrizi
7   Health Policy Research Center, Institute of Health, Shiraz University of Medical Sciences, Shiraz, Iran
8   Non Communicable Diseases Research Center (NCDC), Fasa University of Medical Sciences, Fasa, Iran
,
Elham Jamali
2   Hematology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
› Author Affiliations Funding Dr. Elham Jamali reports this work was financially supported by Shiraz University of Medical Sciences, Shiraz, Iran and grants from grant number 94–01–104–11279.
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Abstract

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Elham Jamali

Objectives Acute myeloid leukemia (AML) is a blood malignancy characterized by the proliferation of aberrant cells in the bone marrow and blood that interfere with normal blood cells. We have investigated whether changes in the level of micro-ribonucleic acid (miR)-19b, miR-17, and miR-25, Wilms' tumor (WT1), and CCAAT enhancer-binding protein α (CEBPA) genes expression affect disease prognosis and clinical outcome in AML patients.

Materials and Methods The expression level of miR-19-b, miR-17, and miR-25, as well as WT1 and CEBPA genes in a group of patients and controls as well as different risk groups (high, intermediate, and favorite risk), M3 versus non-M3, and graft-versus-host disease (GvHD) versus non-GvHD patients were assessed using a quantitative SYBR Green real-time polymerase chain reaction method.

Results When compared with the baseline level at the period of diagnosis before chemotherapy, the expression of miR-19b and miR-17 in AML patients increased significantly after chemotherapy. The level of miR-19b and miR-25 expression in AML patients with M3 and non-M3 French–American–British subgroups differ significantly. MiR-19b and miR-25 expression was elevated in GvHD patients, while miR-19b and miR-25 expression was somewhat decreased in GvHD patients compared with non-GvHD patients, albeit the difference was not statistically significant. Also, patients with different cytogenetic aberrations had similar levels of miR-19-b and miR-25 expression.

Conclusion MiR-19b, miR-17, and miR-25 are aberrantly expressed in AML patients' peripheral blood leukocytes, which may play a role in the development of acute GvHD following hematopoietic stem cell transplantation.

Keywords

acute myeloid leukemia - microRNA - chemotherapy - stem cell transplantation - acute graft versus host disease


Publication History

Article published online:
25 April 2022

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  • References

  • 1 Basilico S, Göttgens B. Dysregulation of haematopoietic stem cell regulatory programs in acute myeloid leukaemia. J Mol Med (Berl) 2017; 95 (07) 719-727
    CrossrefPubMedGoogle Scholar
  • 2 Döhner H, Estey E, Grimwade D. et al. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood 2017; 129 (04) 424-447
    CrossrefPubMedGoogle Scholar
  • 3 De Kouchkovsky I, Abdul-Hay M. Acute myeloid leukemia: a comprehensive review and 2016 update. Blood Cancer J 2016; 6 (07) e441
    CrossrefPubMedGoogle Scholar
  • 4 Mueller BU, Pabst T. C/EBPalpha and the pathophysiology of acute myeloid leukemia. Curr Opin Hematol 2006; 13 (01) 7-14
    CrossrefPubMedGoogle Scholar
  • 5 Saadi MI, Ramzi M, Hosseinzadeh M. et al. Expression levels of Il-6 and Il-18 in acute myeloid leukemia and its relation with response to therapy and acute GvHD after bone marrow transplantation. Indian J Surg Oncol 2021; 12 (03) 465-471
    CrossrefPubMedGoogle Scholar
  • 6 Eisfeld AK, Mrózek K, Kohlschmidt J. et al. The mutational oncoprint of recurrent cytogenetic abnormalities in adult patients with de novo acute myeloid leukemia. Leukemia 2017; 31 (10) 2211-2218
    CrossrefPubMedGoogle Scholar
  • 7 Welch JS, Ley TJ, Link DC. et al. The origin and evolution of mutations in acute myeloid leukemia. Cell 2012; 150 (02) 264-278
    CrossrefPubMedGoogle Scholar
  • 8 Seca H, Almeida GM, Guimaraes JE, Vasconcelos MH. miR signatures and the role of miRs in acute myeloid leukaemia. Eur J Cancer 2010; 46 (09) 1520-1527
    CrossrefPubMedGoogle Scholar
  • 9 Jongen-Lavrencic M, Sun SM, Dijkstra MK, Valk PJ, Löwenberg B. MicroRNA expression profiling in relation to the genetic heterogeneity of acute myeloid leukemia. Blood 2008; 111 (10) 5078-5085
    CrossrefPubMedGoogle Scholar
  • 10 Eyholzer M, Schmid S, Wilkens L, Mueller BU, Pabst T. The tumour-suppressive miR-29a/b1 cluster is regulated by CEBPA and blocked in human AML. Br J Cancer 2010; 103 (02) 275-284
    CrossrefPubMedGoogle Scholar
  • 11 Chen H, Liu T, Liu J. et al. Circ-ANAPC7 is upregulated in acute myeloid leukemia and appears to target the MiR-181 family. Cell Physiol Biochem 2018; 47 (05) 1998-2007
    CrossrefPubMedGoogle Scholar
  • 12 Pinweha P, Rattanapornsompong K, Charoensawan V, Jitrapakdee S. MicroRNAs and oncogenic transcriptional regulatory networks controlling metabolic reprogramming in cancers. Comput Struct Biotechnol J 2016; 14: 223-233
    CrossrefPubMedGoogle Scholar
  • 13 Zhang TJ, Lin J, Zhou JD. et al. High bone marrow miR-19b level predicts poor prognosis and disease recurrence in de novo acute myeloid leukemia. Gene 2018; 640: 79-85
    CrossrefPubMedGoogle Scholar
  • 14 Mogilyansky E, Rigoutsos I. The miR-17/92 cluster: a comprehensive update on its genomics, genetics, functions and increasingly important and numerous roles in health and disease. Cell Death Differ 2013; 20 (12) 1603-1614
    CrossrefPubMedGoogle Scholar
  • 15 Olive V, Bennett MJ, Walker JC. et al. miR-19 is a key oncogenic component of mir-17-92. Genes Dev 2009; 23 (24) 2839-2849
    CrossrefPubMedGoogle Scholar
  • 16 Yan W, Xu L, Sun Z. et al. MicroRNA biomarker identification for pediatric acute myeloid leukemia based on a novel bioinformatics model. Oncotarget 2015; 6 (28) 26424-26436
    CrossrefPubMedGoogle Scholar
  • 17 Niu M, Feng Y, Zhang N. et al. High expression of miR-25 predicts favorable chemotherapy outcome in patients with acute myeloid leukemia. Cancer Cell Int 2019; 19 (01) 122
    CrossrefPubMedGoogle Scholar
  • 18 Miwa H, Beran M, Saunders GF. Expression of the Wilms' tumor gene (WT1) in human leukemias. Leukemia 1992; 6 (05) 405-409
    PubMedGoogle Scholar
  • 19 King-Underwood L, Renshaw J, Pritchard-Jones K. Mutations in the Wilms' tumor gene WT1 in leukemias. Blood 1996; 87 (06) 2171-2179
    CrossrefPubMedGoogle Scholar
  • 20 Ariyaratana S, Loeb DM. The role of the Wilms tumour gene (WT1) in normal and malignant haematopoiesis. Expert Rev Mol Med 2007; 9 (14) 1-17
    CrossrefPubMedGoogle Scholar
  • 21 Nerlov C. C/EBPalpha mutations in acute myeloid leukaemias. Nat Rev Cancer 2004; 4 (05) 394-400
    CrossrefPubMedGoogle Scholar
  • 22 King-Underwood L, Pritchard-Jones K. Wilms' tumor (WT1) gene mutations occur mainly in acute myeloid leukemia and may confer drug resistance. Blood 1998; 91 (08) 2961-2968
    CrossrefPubMedGoogle Scholar
  • 23 Zhang Q, Bai S, Vance GH. Molecular genetic tests for FLT3, NPM1, and CEBPA in acute myeloid leukemia. In: Czader M. ed. Hematological Malignancies. Totowa, NJ: Humana Press; 2013: 105-121
    Google Scholar
  • 24 Silverman LB, Sallan SE. Newly diagnosed childhood acute lymphoblastic leukemia: update on prognostic factors and treatment. Curr Opin Hematol 2003; 10 (04) 290-296
    CrossrefPubMedGoogle Scholar
  • 25 August KJ, Chiang KY, Bostick RM. et al. Biomarkers of immune activation to screen for severe, acute GVHD. Bone Marrow Transplant 2011; 46 (04) 601-604
    CrossrefPubMedGoogle Scholar
  • 26 Choi SW, Kitko CL, Braun T. et al. Change in plasma tumor necrosis factor receptor 1 levels in the first week after myeloablative allogeneic transplantation correlates with severity and incidence of GVHD and survival. Blood 2008; 112 (04) 1539-1542
    CrossrefPubMedGoogle Scholar
  • 27 Iravani Saadi M, Arandi N, Yaghobi R, Azarpira N, Geramizadeh B, Ramzi M. Aberrant expression of the miR-181b/miR-222 after hematopoietic stem cell transplantation in patients with acute myeloid leukemia. Indian J Hematol Blood Transfus 2019; 35 (03) 446-450
    CrossrefPubMedGoogle Scholar
  • 28 Saadi MI, Arandi N, Yaghobi R. et al. Up-regulation of the miR-92a and miR-181a in patients with acute myeloid leukemia and their inhibition with locked nucleic acid (LNA)-antimiRNA; introducing c-Kit as a new target gene. Intl J Hematol Oncol 2018; 28 (03) 001-009
    Google Scholar
  • 29 Iravani Saadi M, Babaee Beigi MA, Ghavipishe M. et al. The circulating level of interleukins 6 and 18 in ischemic and idiopathic dilated cardiomyopathy. J Cardiovasc Thorac Res 2019; 11 (02) 132-137
    CrossrefPubMedGoogle Scholar
  • 30 Ramzi M, Iravani Saadi M, Yaghobi R, Arandi N. Dysregulated expression of CD28 and CTLA-4 molecules in patients with acute myeloid leukemia and possible association with development of graft versus host disease after hematopoietic stem cell transplantation. Int J Organ Transplant Med 2019; 10 (02) 84-90
    PubMedGoogle Scholar
  • 31 Glucksberg H, Storb R, Fefer A. et al. Clinical manifestations of graft-versus-host disease in human recipients of marrow from HL-A-matched sibling donors. Transplantation 1974; 18 (04) 295-304
    CrossrefPubMedGoogle Scholar
  • 32 Bozorgi H, Ramzi M, Noshadi E. et al. Characterization of MiR-92b,1275 and 551 in patients with acute myeloid leukemia and their association with acute graft versus host disease after hematopoietic stem cell. Transplantation 2020
    PubMedGoogle Scholar
  • 33 Kumar CC. Genetic abnormalities and challenges in the treatment of acute myeloid leukemia. Genes Cancer 2011; 2 (02) 95-107
    CrossrefPubMedGoogle Scholar
  • 34 Danen-van Oorschot AA, Kuipers JE, Arentsen-Peters S. et al. Differentially expressed miRNAs in cytogenetic and molecular subtypes of pediatric acute myeloid leukemia. Pediatr Blood Cancer 2012; 58 (05) 715-721
    CrossrefPubMedGoogle Scholar
  • 35 Iravani Saadi M, Ramzi M, Hesami Z. et al. MiR-181a and -b expression in acute lymphoblastic leukemia and its correlation with acute graft-versus-host disease after hematopoietic stem cell transplantation, COVID-19 and torque teno viruses. Virusdisease 2021; 1-10
    PubMedGoogle Scholar
  • 36 Niktoreh N, Walter C, Zimmermann M. et al. Mutated WT1, FLT3-ITD, and NUP98–NSD1 fusion in various combinations define a poor prognostic group in pediatric acute myeloid leukemia. J Oncol 2019; 2019: 1609128
    CrossrefPubMedGoogle Scholar
  • 37 Hou H-A, Huang T-C, Lin L-I. et al. WT1 mutation in 470 adult patients with acute myeloid leukemia: stability during disease evolution and implication of its incorporation into a survival scoring system. Blood 2010; 115 (25) 5222-5231
    CrossrefPubMedGoogle Scholar
  • 38 Toska E, Roberts SG. Mechanisms of transcriptional regulation by WT1 (Wilms' tumour 1). Biochem J 2014; 461 (01) 15-32
    CrossrefPubMedGoogle Scholar
  • 39 Cilloni D, Gottardi E, De Micheli D. et al. Quantitative assessment of WT1 expression by real time quantitative PCR may be a useful tool for monitoring minimal residual disease in acute leukemia patients. Leukemia 2002; 16 (10) 2115-2121
    CrossrefPubMedGoogle Scholar
  • 40 Krauth MT, Alpermann T, Bacher U. et al. WT1 mutations are secondary events in AML, show varying frequencies and impact on prognosis between genetic subgroups. Leukemia 2015; 29 (03) 660-667
    CrossrefPubMedGoogle Scholar
  • 41 Weisser M, Kern W, Rauhut S. et al. Prognostic impact of RT-PCR-based quantification of WT1 gene expression during MRD monitoring of acute myeloid leukemia. Leukemia 2005; 19 (08) 1416-1423
    CrossrefPubMedGoogle Scholar
  • 42 Jacobsohn DA, Tse WT, Chaleff S. et al. High WT1 gene expression before haematopoietic stem cell transplant in children with acute myeloid leukaemia predicts poor event-free survival. Br J Haematol 2009; 146 (06) 669-674
    CrossrefPubMedGoogle Scholar
  • 43 Gianfaldoni G, Mannelli F, Ponziani V. et al. Early reduction of WT1 transcripts during induction chemotherapy predicts for longer disease free and overall survival in acute myeloid leukemia. Haematologica 2010; 95 (05) 833-836
    CrossrefPubMedGoogle Scholar
  • 44 Hickey CJ, Schwind S, Radomska HS. et al. Lenalidomide-mediated enhanced translation of C/EBPα-p30 protein up-regulates expression of the antileukemic microRNA-181a in acute myeloid leukemia. Blood 2013; 121 (01) 159-169
    CrossrefPubMedGoogle Scholar
  • 45 Johnson PF. Molecular stop signs: regulation of cell-cycle arrest by C/EBP transcription factors. J Cell Sci 2005; 118 (Pt 12): 2545-2555
    CrossrefPubMedGoogle Scholar
  • 46 Gholami M, Bayat S, Manoochehrabadi S. et al. Investigation of CEBPA and CEBPA-AS genes expression in acute myeloid leukemia. Rep Biochem Mol Biol 2019; 7 (02) 136-141
    PubMedGoogle Scholar
  • 47 Fuchs O. Growth-inhibiting activity of transcription factor C/EBPalpha, its role in haematopoiesis and its tumour suppressor or oncogenic properties in leukaemias. Folia Biol (Praha) 2007; 53 (03) 97-108
    Google Scholar
  • 48 Green CL, Koo KK, Hills RK, Burnett AK, Linch DC, Gale RE. Prognostic significance of CEBPA mutations in a large cohort of younger adult patients with acute myeloid leukemia: impact of double CEBPA mutations and the interaction with FLT3 and NPM1 mutations. J Clin Oncol 2010; 28 (16) 2739-2747
    CrossrefPubMedGoogle Scholar
  • 49 Trivedi AK, Pal P, Behre G, Singh SM. Multiple ways of C/EBPalpha inhibition in myeloid leukaemia. Eur J Cancer 2008; 44 (11) 1516-1523
    CrossrefPubMedGoogle Scholar
  • 50 Marcucci G, Maharry K, Radmacher MD. et al. Prognostic significance of, and gene and microRNA expression signatures associated with, CEBPA mutations in cytogenetically normal acute myeloid leukemia with high-risk molecular features: a Cancer and Leukemia Group B Study. J Clin Oncol 2008; 26 (31) 5078-5087
    CrossrefPubMedGoogle Scholar
  • 51 Eyholzer M, Schmid S, Schardt JA, Haefliger S, Mueller BU, Pabst T. Complexity of miR-223 regulation by CEBPA in human AML. Leuk Res 2010; 34 (05) 672-676
    CrossrefPubMedGoogle Scholar
  • 52 Kumar M, Lu Z, Takwi AAL. et al. Negative regulation of the tumor suppressor p53 gene by microRNAs. Oncogene 2011; 30 (07) 843-853
    CrossrefPubMedGoogle Scholar
  • 53 Xiong Q, Yang Y, Wang H. et al. Characterization of miRNomes in acute and chronic myeloid leukemia cell lines. Genomics Proteomics Bioinformatics 2014; 12 (02) 79-91
    CrossrefPubMedGoogle Scholar
  • 54 Garzon R, Volinia S, Liu C-G. et al. MicroRNA signatures associated with cytogenetics and prognosis in acute myeloid leukemia. Blood 2008; 111 (06) 3183-3189
    CrossrefPubMedGoogle Scholar
  • 55 Fujino T, Yamazaki Y, Largaespada DA. et al. Inhibition of myeloid differentiation by Hoxa9, Hoxb8, and Meis homeobox genes. Exp Hematol 2001; 29 (07) 856-863
    CrossrefPubMedGoogle Scholar
  • 56 Starczynowski DT, Morin R, McPherson A. et al. Genome-wide identification of human microRNAs located in leukemia-associated genomic alterations. Blood 2011; 117 (02) 595-607
    CrossrefPubMedGoogle Scholar
  • 57 Vaz C, Ahmad HM, Sharma P. et al. Analysis of microRNA transcriptome by deep sequencing of small RNA libraries of peripheral blood. BMC Genomics 2010; 11 (01) 288
    CrossrefPubMedGoogle Scholar
  • 58 Marcucci G, Mrózek K, Radmacher MD, Garzon R, Bloomfield CD. The prognostic and functional role of microRNAs in acute myeloid leukemia. Blood 2011; 117 (04) 1121-1129
    CrossrefPubMedGoogle Scholar
  • 59 Fuziwara CS, Kimura ET. Insights into regulation of the miR-17–92 cluster of miRNAs in cancer. Front Med (Lausanne) 2015; 2: 64
    PubMedGoogle Scholar