Login Register Cart 0
Generic placeholder image

Cardiovascular & Hematological Agents in Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 1871-5257
ISSN (Online): 1875-6182

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

The mRNA Expression of PTEN, LEF1, JAK3, LC3 and p62/SQSTM1 Genes in Patients with Chronic Myeloid Leukemia

Author(s): Elahe Razmara Lak, Gholamhossein Tamaddon, Mani Ramzi, Reza Ranjbaran, Elham Abedi and Sedigheh Sharifzadeh*

Volume 21, Issue 1, 2023

Published on: 02 November, 2022

Page: [67 - 76] Pages: 10

DOI: 10.2174/1871525720666220819123639

Price: $65

Abstract

Introduction: Chronic myeloid leukemia (CML) is a progressive myeloproliferative disorder resulting from forming a chimeric BCR-ABL gene. The proteins derived from this gene can affect some genes from various signaling pathways such as PI3K/AKT/Wnt/catenin/JAK/Stat involved in proliferation, differentiation, cell death, and genes related to autophagy. Imatinib is the first-line treatment for CML patients, with durable and proper responses in Iranian children and adult CML patients. Hence, we aimed to evaluate the mRNA expression of some selected key genes from those pathways in patients with CML before and under treatment.

Methods: In the case-control study, the mRNA expression of PTEN, LEF1, JAK3, LC3 and p62 genes were measured in 51 CML patients (6 patients before treatment and 45 patients under treatment with imatinib mesylate) and 40 healthy controls using the Real-time PCR method.

Results: The mRNA expression of PTEN and P62 were significantly higher in newly diagnosed patients than in controls (P<0.0001 and P = 0.0183, respectively), while the expression of the LC3 gene was significantly lower in the untreated newly diagnosed group than in control subjects (P = 0.0191). The expression level of PTEN, LEF1, JAK3 and P62 genes were significantly decreased in patients under treatment than in the group before treatment (P = 0.0172, P = 0.0002, P = 0.0047 and P = 0.0038, respectively). A positive correlation was seen between the gene expression of P62 and BCR-ABL in the patients under treatment (r 0529, P = 0.016).

Conclusion: Our findings showed that the changes in expression of these genes were related to the patient’s treatment. Due to the key role of these genes in proliferation, differentiation and tumor suppression, it is proposed that these genes may be helpful for follow-up of treatment in CML patients.

Keywords: Autophagy, BCR-ABL, chronic myeloid leukemia, diagnosis, treatment, myeloproliferative disorder.

« Previous Next »
Graphical Abstract

[1]
Quintás-Cardama, A.; Cortes, J. Molecular biology of BCR-ABL1-positive chronic myeloid leukemia. Blood, 2009, 113(8), 1619-1630.
[http://dx.doi.org/10.1182/blood-2008-03-144790] [PMID: 18827185]
[2]
Daley, G.Q.; Van Etten, R.A.; Baltimore, D. Induction of chronic myelogenous leukemia in mice by the P210bcr/ABL gene of the Philadelphia chromosome. Science, 1990, 247(4944), 824-830.
[http://dx.doi.org/10.1126/science.2406902] [PMID: 2406902]
[3]
Skorski, T.; Bellacosa, A.; Nieborowska-Skorska, M.; Majewski, M.; Martinez, R.; Choi, J.K.; Trotta, R.; Wlodarski, P.; Perrotti, D.; Chan, T.O.; Wasik, M.A.; Tsichlis, P.N.; Calabretta, B. Transformation of hematopoietic cells by BCR/ABL requires activation of a PI-3k/Akt-dependent pathway. EMBO J., 1997, 16(20), 6151-6161.
[http://dx.doi.org/10.1093/emboj/16.20.6151] [PMID: 9321394]
[4]
Sawyers, C.L.; McLaughlin, J.; Witte, O.N. Genetic requirement for Ras in the transformation of fibroblasts and hematopoietic cells by the Bcr-Abl oncogene. J. Exp. Med., 1995, 181(1), 307-313.
[http://dx.doi.org/10.1084/jem.181.1.307] [PMID: 7807010]
[5]
Reuther, J.Y.; Reuther, G.W.; Cortez, D.; Pendergast, A.M.; Baldwin, A.S. Jr A requirement for NF-kappaB activation in Bcr-Abl-mediated transformation. Genes Dev., 1998, 12(7), 968-981.
[http://dx.doi.org/10.1101/gad.12.7.968] [PMID: 9531535]
[6]
Carlesso, N.; Frank, D.A.; Griffin, J.D. Tyrosyl phosphorylation and DNA binding activity of SIGNAL Transducers and Activators of Transcription (STAT) proteins in hematopoietic cell lines transformed by Bcr/Abl. J. Exp. Med., 1996, 183(3), 811-820.
[http://dx.doi.org/10.1084/jem.183.3.811] [PMID: 8642285]
[7]
Steelman, L.S.; Pohnert, S.C.; Shelton, J.G.; Franklin, R.A.; Bertrand, F.E.; McCubrey, J.A. JAK/STAT, Raf/MEK/ERK, PI3K/Akt and BCR-ABL in cell cycle progression and leukemogenesis. Leukemia, 2004, 18(2), 189-218.
[http://dx.doi.org/10.1038/sj.leu.2403241] [PMID: 14737178]
[8]
Druker, B.J.; Talpaz, M.; Resta, D.J.; Peng, B.; Buchdunger, E.; Ford, J.M.; Lydon, N.B.; Kantarjian, H.; Capdeville, R.; Ohno-Jones, S.; Sawyers, C.L. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N. Engl. J. Med., 2001, 344(14), 1031-1037.
[http://dx.doi.org/10.1056/NEJM200104053441401] [PMID: 11287972]
[9]
Kantarjian, H.; Sawyers, C.; Hochhaus, A.; Guilhot, F.; Schiffer, C.; Gambacorti-Passerini, C.; Niederwieser, D.; Resta, D.; Capdeville, R.; Zoellner, U.; Talpaz, M.; Druker, B.; Goldman, J.; O’Brien, S.G.; Russell, N.; Fischer, T.; Ottmann, O.; Cony-Makhoul, P.; Facon, T.; Stone, R.; Miller, C.; Tallman, M.; Brown, R.; Schuster, M.; Loughran, T.; Gratwohl, A.; Mandelli, F.; Saglio, G.; Lazzarino, M.; Russo, D.; Baccarani, M.; Morra, E. Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia. N. Engl. J. Med., 2002, 346(9), 645-652.
[http://dx.doi.org/10.1056/NEJMoa011573] [PMID: 11870241]
[10]
Sawyers, C.L.; Hochhaus, A.; Feldman, E.; Goldman, J.M.; Miller, C.B.; Ottmann, O.G.; Schiffer, C.A.; Talpaz, M.; Guilhot, F.; Deininger, M.W.; Fischer, T. Imatinib induces hematologic and cytogenetic responses in patients with chronic myelogenous leukemia in myeloid blast crisis: Results of a phase II studyPresented in part at the 43rd Annual Meeting of The American Society of Hematology, Orlando, FL, December 11, 2001. Blood, 2002, 99(10), 3530-3539.
[http://dx.doi.org/10.1182/blood.V99.10.3530] [PMID: 11986204]
[11]
Benito, R.; Lumbreras, E.; Abáigar, M.; Gutiérrez, N.C.; Delgado, M.; Robledo, C.; García, J.L.; Rodríguez-Vicente, A.E.; Cañizo, M.C.; Rivas, J.M. Imatinib therapy of chronic myeloid leukemia restores the expression levels of key genes for DNA damage and cell-cycle progression. Pharmacogenet. Genomics, 2012, 22(5), 381-388.
[http://dx.doi.org/10.1097/FPC.0b013e328351f3e9] [PMID: 22388797]
[12]
Calabretta, B.; Salomoni, P. Inhibition of autophagy: A new strategy to enhance sensitivity of chronic myeloid leukemia stem cells to tyrosine kinase inhibitors. Leuk. Lymphoma, 2011, 52(Suppl. 1), 54-59.
[http://dx.doi.org/10.3109/10428194.2010.546913]
[13]
Puissant, A.; Robert, G.; Fenouille, N.; Luciano, F.; Cassuto, J.P.; Raynaud, S.; Auberger, P. Resveratrol promotes autophagic cell death in chronic myelogenous leukemia cells via JNK-mediated p62/SQSTM1 expression and AMPK activation. Cancer Res., 2010, 70(3), 1042-1052.
[http://dx.doi.org/10.1158/0008-5472.CAN-09-3537] [PMID: 20103647]
[14]
Kiraz, Y. Expression levels of JAK/STAT signaling genes in newly diagnosed, drug sensitive and resistant chronic myeloid leukemia patients; İzmir Institute of Technology, 2014.
[15]
Håkansson, P.; Lassen, C.; Olofsson, T.; Baldetorp, B.; Karlsson, A.; Gullberg, U.; Fioretos, T. Establishment and phenotypic characterization of human U937 cells with inducible P210 BCR/ABL expression reveals upregulation of CEACAM1 (CD66a). Leukemia, 2004, 18(3), 538-547.
[http://dx.doi.org/10.1038/sj.leu.2403255] [PMID: 14712293]
[16]
Tipping, A.J.; Deininger, M.W.; Goldman, J.M.; Melo, J.V. Comparative gene expression profile of chronic myeloid leukemia cells innately resistant to imatinib mesylate. Exp. Hematol., 2003, 31(11), 1073-1080.
[http://dx.doi.org/10.1016/j.exphem.2003.08.006] [PMID: 14585372]
[17]
Jotta, P.Y.; Ganazza, M.A.; Silva, A.; Viana, M.B.; da Silva, M.J.; Zambaldi, L.J.; Barata, J.T.; Brandalise, S.R.; Yunes, J.A. Negative prognostic impact of PTEN mutation in pediatric T-cell acute lymphoblastic leukemia. Leukemia, 2010, 24(1), 239-242.
[http://dx.doi.org/10.1038/leu.2009.209] [PMID: 19829307]
[18]
Lin, Q.; Prudkin, M.L.; Kantarjian, H.M.; Cortes, J.E.; Lau, E.; Grammatikakis, I.; Thomazy, V.A.; Lai, R.; Amin, H.M. Role of Jak3 in chronic myeloid leukemia: Evidence to identify Jak3 as a potential therapeutic target. Blood, 2005, 106(11), 2870-2870.
[19]
Tsai, B.P.; Jimenez, J.; Lim, S.; Fitzgerald, K.D.; Zhang, M.; Chuah, C.T.; Axelrod, H.; Wilson, L.; Ong, S.T.; Semler, B.L.; Waterman, M.L. A novel Bcr-Abl-mTOR-eIF4A axis regulates IRES-mediated translation of LEF-1. Open Biol., 2014, 4(11), 140180.
[http://dx.doi.org/10.1098/rsob.140180] [PMID: 25392452]
[20]
Lu, Y.; Liu, L.L.; Liu, S.S.; Fang, Z.G.; Zou, Y.; Deng, X.B.; Long, Z.J.; Liu, Q.; Lin, D.J. Celecoxib suppresses autophagy and enhances cytotoxicity of imatinib in imatinib-resistant chronic myeloid leukemia cells. J. Transl. Med., 2016, 14(1), 270.
[http://dx.doi.org/10.1186/s12967-016-1012-8] [PMID: 27645552]
[21]
Pankiv, S.; Clausen, T.H.; Lamark, T.; Brech, A.; Bruun, J.A.; Outzen, H.; Øvervatn, A.; Bjørkøy, G.; Johansen, T. p62/SQSTM1 binds directly to Atg8/LC3 to facilitate degradation of ubiquitinated protein aggregates by autophagy. J. Biol. Chem., 2007, 282(33), 24131-24145.
[http://dx.doi.org/10.1074/jbc.M702824200] [PMID: 17580304]
[22]
Mathew, R.; Karp, C.M.; Beaudoin, B.; Vuong, N.; Chen, G.; Chen, H.Y.; Bray, K.; Reddy, A.; Bhanot, G.; Gelinas, C.; Dipaola, R.S.; Karantza-Wadsworth, V.; White, E. Autophagy suppresses tumorigenesis through elimination of p62. Cell, 2009, 137(6), 1062-1075.
[http://dx.doi.org/10.1016/j.cell.2009.03.048] [PMID: 19524509]
[23]
Elzinga, B.M.; Nyhan, M.J.; Crowley, L.C.; O’Donovan, T.R.; Cahill, M.R.; McKenna, S.L. Induction of autophagy by Imatinib sequesters Bcr-Abl in autophagosomes and down-regulates Bcr-Abl protein. Am. J. Hematol., 2013, 88(6), 455-462.
[http://dx.doi.org/10.1002/ajh.23428] [PMID: 23440701]
[24]
Adams, O.; Dislich, B.; Berezowska, S.; Schläfli, A.M.; Seiler, C.A.; Kröll, D.; Tschan, M.P.; Langer, R. Prognostic relevance of autophagy markers LC3B and p62 in esophageal adenocarcinomas. Oncotarget, 2016, 7(26), 39241-39255.
[http://dx.doi.org/10.18632/oncotarget.9649] [PMID: 27250034]

Rights & Permissions Print Cite
Article Metrics
35
3
© 2024 Bentham Science Publishers | Privacy Policy