Significance of serine threonine tyrosine kinase 1 as a drug resistance factor and therapeutic predictor in acute leukemia

Nirasawa,Shinya; Kobayashi,Daisuke; Kondoh,Takashi; Kuribayashi,Kageaki; Tanaka,Maki; Yanagihara,Nozomi; Watanabe,Naoki

doi:10.3892/ijo.2014.2633

Significance of serine threonine tyrosine kinase 1 as a drug resistance factor and therapeutic predictor in acute leukemia

Authors:
- Shinya Nirasawa
- Daisuke Kobayashi
- Takashi Kondoh
- Kageaki Kuribayashi
- Maki Tanaka
- Nozomi Yanagihara
- Naoki Watanabe
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Affiliations: Department of Clinical Laboratory Medicine, Sapporo Medical University School of Medicine, Sapporo 060-8543, Japan
Published online on: September 3, 2014 https://doi.org/10.3892/ijo.2014.2633
Pages: 1867-1874

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Abstract

Alterations in the mRNA expression or the mutation of previously reported tyrosine kinases have been detected only in a limited number of patients with acute leukemia. In this study, we examined whether the widely expressed serine threonine tyrosine kinase 1 (STYK1)/novel oncogene with kinase domain (NOK) acts as a drug resistance factor in acute leukemia. The transfection of leukemic HL-60 cells with an STYK1 expression vector resulted in the resistance to doxorubicin and etoposide and decreased drug-induced caspase-3/7 activity and sub-G1 population. To investigate the mechanism of STYK1-induced drug resistance, microarray analysis was performed using HL-60 cells transfected with control or STYK1 expression vectors. Three tyrosine kinases (EphA4, FLT4 and STK31), two NF-κB inducers (MAPK4 and TNF-RSF11A), and two genes essential for stem cell replication (SALL4 and NOV) were identified as novel STYK1-induced genes. In addition to the data using cell line, a comparison of the leukemic patients who did and did not respond to therapy revealed that STYK1 expression before therapy was significantly higher in the non-responder group compared with the group that responded completely. These results suggest that STYK1 is a novel drug resistance factor and could be a predictor of the therapeutic response in acute leukemia.

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1	Nakao M, Yokota S, Iwai T, Kaneko H, Horiike S, Kashima K, et al: Internal tandem duplication of the flt3 gene found in acute myeloid leukemia. Leukemia. 10:1911–1918. 1996.PubMed/NCBI
2	Gambacorti-Passerini CB, Gunby RH, Piazza R, Galietta A, Rostagno R and Scapozza L: Molecular mechanisms of resistance to imatinib in Philadelphia-chromosome-positive leukaemias. Lancet Oncol. 4:75–85. 2003. View Article : Google Scholar : PubMed/NCBI
3	Paietta E, Ferrando AA, Neuberg D, et al: Activating FLT3 mutations in CD117/KIT(+) T-cell acute lymphoblastic leukemias. Blood. 104:558–560. 2004. View Article : Google Scholar : PubMed/NCBI
4	Yanada M, Takeuchi J, Sugiura I, et al: High complete remission rate and promising outcome by combination of imatinib and chemotherapy for newly diagnosed BCR-ABL-positive acute lymphoblastic leukemia: a phase II study by the Japan Adult Leukemia Study Group. J Clin Oncol. 24:460–466. 2006. View Article : Google Scholar
5	Wang YY, Zhou GB, Yin T, et al: AML1-ETO and C-KIT mutation/overexpression in t(8;21) leukemia: implication in stepwise leukemogenesis and response to Gleevec. Proc Natl Acad Sci USA. 102:1104–1109. 2005. View Article : Google Scholar : PubMed/NCBI
6	George P, Bali P, Cohen P, et al: Cotreatment with 17-allylamino-demethoxygeldanamycin and FLT-3 kinase inhibitor PKC412 is highly effective against human acute myelogenous leukemia cells with mutant FLT-3. Cancer Res. 64:3645–3652. 2004. View Article : Google Scholar
7	Kondoh T, Kobayashi D, Tsuji N, Kuribayashi K and Watanabe N: Overexpression of serine threonine tyrosine kinase 1/novel oncogene with kinase domain mRNA in patients with acute leukemia. Exp Hematol. 37:824–830. 2009. View Article : Google Scholar : PubMed/NCBI
8	Liu L, Yu XZ, Li TS, et al: A novel protein tyrosine kinase NOK that shares homology with platelet-derived growth factor/fibroblast growth factor receptors induces tumorigenesis and metastasis in nude mice. Cancer Res. 64:3491–3499. 2004. View Article : Google Scholar
9	Chen Y, Li YH, Chen XP, et al: Point mutation at single tyrosine residue of novel oncogene NOK abrogates tumorigenesis in nude mice. Cancer Res. 65:10838–10846. 2005. View Article : Google Scholar : PubMed/NCBI
10	Ma Y, Cui W, Yang J, et al: SALL4, a novel oncogene, is constitutively expressed in human acute myeloid leukemia (AML) and induces AML in transgenic mice. Blood. 108:2726–2735. 2006. View Article : Google Scholar : PubMed/NCBI
11	Gupta R, Hong D, Iborra F, Sarno S and Enver T: NOV (CCN3) functions as a regulator of human hematopoietic stem or progenitor cells. Science. 316:590–593. 2007. View Article : Google Scholar : PubMed/NCBI
12	Jeong HW, Cui W, Yang Y, Lu J, He J, Li A, Song D, Guo Y, Liu BH and Chai L: SALL4, a stem cell factor, affects the side population by regulation of the ATP-binding cassette drug transport genes. PLoS One. 6:e183722011. View Article : Google Scholar : PubMed/NCBI
13	Bard JD, Gelebart P, Amin HM, Young LC, Ma Y and Lai R: Signal transducer and activator of transcription 3 is a transcriptional factor regulating the gene expression of SALL4. FASEB J. 23:1405–1414. 2009. View Article : Google Scholar : PubMed/NCBI
14	Tazzari PL, Cappellini A, Ricci F, et al: Multidrug resistance-associated protein 1 expression is under the control of the phosphoinositide 3 kinase/Akt signal transduction network in human acute myelogenous leukemia blasts. Leukemia. 21:427–438. 2007. View Article : Google Scholar
15	Chiarini F, Del Sole M, Mongiorgi S, et al: The novel Akt inhibitor, perifosine, induces caspase-dependent apoptosis and downregulates P-glycoprotein expression in multidrug-resistant human T-acute leukemia cells by a JNK-dependent mechanism. Leukemia. 22:1106–1116. 2008. View Article : Google Scholar
16	Moriai R, Kobayashi D, Amachika T, Tsuji N and Watanabe N: Diagnostic relevance of overexpressed NOK mRNA in breast cancer. Anticancer Res. 26:4969–4973. 2006.PubMed/NCBI
17	Amachika T, Kobayashi D, Moriai R, Tsuji N and Watanabe N: Diagnostic relevance of overexpressed mRNA of novel oncogene with kinase-domain (NOK) in lung cancers. Lung Cancer. 56:337–340. 2007. View Article : Google Scholar : PubMed/NCBI
18	Harbott J, Viehmann S, Borkhardt A, Henze G and Lampert F: Incidence of TEL/AML1 fusion gene analyzed consecutively in children with acute lymphoblastic leukemia in relapse. Blood. 90:4933–4937. 1997.PubMed/NCBI