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Published in: Journal of Translational Medicine 1/2017

Open Access 01-12-2017 | Research

PIM-1 mRNA expression is a potential prognostic biomarker in acute myeloid leukemia

Authors: Hui Cheng, Chongmei Huang, Xiaoqian Xu, Xiaoxia Hu, Shenglan Gong, Gusheng Tang, Xianmin Song, Weiping Zhang, Jianmin Wang, Li Chen, Jianmin Yang

Published in: Journal of Translational Medicine | Issue 1/2017

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Abstract

Background

High expression of proviral integration site for Moloney murine leukemia virus-1 (PIM-1), a serine/threonine kinase, is associated with many cancers. The main purpose of this study were to investigate that the correlation between PIM-1 mRNA levels and clinicopathologic features and its clinical significance in acute myeloid leukemia (AML).

Methods

qRT-PCR was performed for 118 de novo AML and 20 AML complete remission patients and 15 normal individuals. All statistical analysis were performed using Graphpad Prism5 software.

Results

We observed that expression of PIM-1 mRNA was higher in AML patients than in healthy individuals and in complete remission AML patients (P = 0.0177). Further, high PIM-1 mRNA levels were more associated with high-risk FLT3+ AML patients than the FLT3− group (P = 0.0001) and were also associated with clinical factors such as risk stratification (P = 0.0029) and vital status (P = 0.0322). Kaplan–Meier survival analysis indicated that PIM-1 mRNA expression correlated with overall survival (OS), disease free survival (DFS), and relapse rate (RR) in AML patients. Most importantly, the high PIM-1-expressing patients took longer to achieve complete remission than the low expression group (P = 0.001). In addition, the complete remission rate was significantly lower in the high PIM-1 group (P = 0.0277) after induction therapy.

Conclusions

Above results suggest that PIM-1 mRNA levels may be an independent prognostic factor in AML.
Appendix
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Literature
1.
go back to reference Narlik-Grassow M, Blanco-Aparici C, Carnero A. The PIM family of serine/threonine kinases in cancer. Med Res Rev. 2014;34:136–59.CrossRefPubMed Narlik-Grassow M, Blanco-Aparici C, Carnero A. The PIM family of serine/threonine kinases in cancer. Med Res Rev. 2014;34:136–59.CrossRefPubMed
2.
go back to reference Saris CJ, Domen J, Berns A. The pim-1 oncogene encodes two related protein-serine/threonine kinases by alternative initiation at AUG and CUG. EMBO J. 1991;10:655–64.PubMedPubMedCentral Saris CJ, Domen J, Berns A. The pim-1 oncogene encodes two related protein-serine/threonine kinases by alternative initiation at AUG and CUG. EMBO J. 1991;10:655–64.PubMedPubMedCentral
4.
go back to reference Santio NM, Vahakoski RL, Rainio EM, Sandholm JA, Virtanen SS, Prudhomme M, et al. Pim selective inhibitor DHPCC-9 reveals Pim kinases as potent stimulators of cancer cell migration and invasion. Mol Cancer. 2010;19:279.CrossRef Santio NM, Vahakoski RL, Rainio EM, Sandholm JA, Virtanen SS, Prudhomme M, et al. Pim selective inhibitor DHPCC-9 reveals Pim kinases as potent stimulators of cancer cell migration and invasion. Mol Cancer. 2010;19:279.CrossRef
5.
go back to reference Santio NM, Eerola SK, Paatero I, Yli-Kauhaluoma J, Anizon F, Moreau P, et al. Pim kinases promote migration and metastatic growth of prostate cancer xenografts. PLoS ONE. 2015;6:e0130340.CrossRef Santio NM, Eerola SK, Paatero I, Yli-Kauhaluoma J, Anizon F, Moreau P, et al. Pim kinases promote migration and metastatic growth of prostate cancer xenografts. PLoS ONE. 2015;6:e0130340.CrossRef
6.
go back to reference Zhao Y, Hamza MS, Leong HS, Lim CB, Pan YF, Cheung E, et al. Kruppel-like factor 5 modulates p53 independent apoptosis through Pim-1 survival kinase in cancer cells. Oncogene. 2008;27:1–8.CrossRefPubMed Zhao Y, Hamza MS, Leong HS, Lim CB, Pan YF, Cheung E, et al. Kruppel-like factor 5 modulates p53 independent apoptosis through Pim-1 survival kinase in cancer cells. Oncogene. 2008;27:1–8.CrossRefPubMed
7.
go back to reference Santio NM, Salmela M, Arola H, Eerola SK, Heino J, Rainio EM, et al. The PIM-1 kinase promotes prostate cancer cell migration and adhesion via multiple signaling pathways. Exp Cell Res. 2016;342:113–24.CrossRefPubMed Santio NM, Salmela M, Arola H, Eerola SK, Heino J, Rainio EM, et al. The PIM-1 kinase promotes prostate cancer cell migration and adhesion via multiple signaling pathways. Exp Cell Res. 2016;342:113–24.CrossRefPubMed
8.
go back to reference Cen B, Mahajan S, Wang W, Kraft AS. Elevation of receptor tyrosine kinases by small molecule AKT inhibitors in prostate cancer is mediated by Pim-1. Cancer Res. 2013;73:3402–11.CrossRefPubMedPubMedCentral Cen B, Mahajan S, Wang W, Kraft AS. Elevation of receptor tyrosine kinases by small molecule AKT inhibitors in prostate cancer is mediated by Pim-1. Cancer Res. 2013;73:3402–11.CrossRefPubMedPubMedCentral
9.
go back to reference Tursynbay Y, Zhang J, Li Z, Tokay T, Zhumadilov Z, Wu D, et al. Pim-1 kinase as cancer drug target: an update. Biomed Rep. 2016;4:140–6.CrossRefPubMed Tursynbay Y, Zhang J, Li Z, Tokay T, Zhumadilov Z, Wu D, et al. Pim-1 kinase as cancer drug target: an update. Biomed Rep. 2016;4:140–6.CrossRefPubMed
11.
go back to reference Liu HT, Wang N, Wang X, Li SL. Overexpression of Pim-1 is associated with poor prognosis in patients with esophageal squamous cell carcinoma. J Surg Oncol. 2010;102:683–8.CrossRefPubMed Liu HT, Wang N, Wang X, Li SL. Overexpression of Pim-1 is associated with poor prognosis in patients with esophageal squamous cell carcinoma. J Surg Oncol. 2010;102:683–8.CrossRefPubMed
12.
go back to reference Yamamoto JF, Goodman MT. Patterns of leukemia incidence in the United States by subtype and demographic characteristics, 1997–2002. Cancer Causes Control. 2008;19:379–90.CrossRefPubMed Yamamoto JF, Goodman MT. Patterns of leukemia incidence in the United States by subtype and demographic characteristics, 1997–2002. Cancer Causes Control. 2008;19:379–90.CrossRefPubMed
13.
go back to reference Mrózek K, Marcucci G, Nicolet D, Maharry KS, Becker H, Whitman SP, et al. Prognostic significance of the European Leukemia Net standardized system for reporting cytogenetic and molecular alterations in adults with acute myeloid leukemia. J Clin Oncol. 2012;30:4515–23.CrossRefPubMedPubMedCentral Mrózek K, Marcucci G, Nicolet D, Maharry KS, Becker H, Whitman SP, et al. Prognostic significance of the European Leukemia Net standardized system for reporting cytogenetic and molecular alterations in adults with acute myeloid leukemia. J Clin Oncol. 2012;30:4515–23.CrossRefPubMedPubMedCentral
14.
go back to reference Patel JP, Gönen M, Figueroa ME, Fernandez H, Sun Z, Racevskis J, et al. Prognostic relevance of integrated genetic profiling in acute myeloid leukemia. N Engl J Med. 2012;366:1079–89.CrossRefPubMedPubMedCentral Patel JP, Gönen M, Figueroa ME, Fernandez H, Sun Z, Racevskis J, et al. Prognostic relevance of integrated genetic profiling in acute myeloid leukemia. N Engl J Med. 2012;366:1079–89.CrossRefPubMedPubMedCentral
15.
go back to reference Cancer Genome Atlas Research Network. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N Engl J Med. 2013;368:2059–74.CrossRef Cancer Genome Atlas Research Network. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N Engl J Med. 2013;368:2059–74.CrossRef
16.
17.
go back to reference Medinger M, Lengerke C, Passweg J. Novel prognostic and therapeutic mutations in acute myeloid leukemia. Cancer Genom Proteom. 2016;13:317–29. Medinger M, Lengerke C, Passweg J. Novel prognostic and therapeutic mutations in acute myeloid leukemia. Cancer Genom Proteom. 2016;13:317–29.
18.
go back to reference Abutalib SA, Tallman MS. Monoclonal antibodies for the treatment of acute myeloid leukemia. Curr Pharm Biotechnol. 2006;7:343–69.CrossRefPubMed Abutalib SA, Tallman MS. Monoclonal antibodies for the treatment of acute myeloid leukemia. Curr Pharm Biotechnol. 2006;7:343–69.CrossRefPubMed
19.
20.
go back to reference Rau RE, Rodriguez BA, Luo M, Jeong M, Rosen A, Rogers JH, et al. DOT1L as a therapeutic target for the treatment of DNMT3A mutant acute myeloid leukemia. Blood. 2016;128:971–81.CrossRefPubMedPubMedCentral Rau RE, Rodriguez BA, Luo M, Jeong M, Rosen A, Rogers JH, et al. DOT1L as a therapeutic target for the treatment of DNMT3A mutant acute myeloid leukemia. Blood. 2016;128:971–81.CrossRefPubMedPubMedCentral
22.
go back to reference Kim KT, Levis M, Small D. Constitutively activated FLT3 phosphorylates BAD partially through pim-1. Br J Haematol. 2006;134:500–9.CrossRefPubMed Kim KT, Levis M, Small D. Constitutively activated FLT3 phosphorylates BAD partially through pim-1. Br J Haematol. 2006;134:500–9.CrossRefPubMed
23.
go back to reference Kim KT, Baird K, Ahn JY, Meltzer P, Lilly M, Levis M, et al. Pim-1 is up-regulated by constitutively activated FLT3 and plays a role in FLT3− mediated cell survival. Blood. 2005;105:1759–67.CrossRefPubMed Kim KT, Baird K, Ahn JY, Meltzer P, Lilly M, Levis M, et al. Pim-1 is up-regulated by constitutively activated FLT3 and plays a role in FLT3− mediated cell survival. Blood. 2005;105:1759–67.CrossRefPubMed
24.
go back to reference Papaemmanuil E, Gerstung M, Bullinger L, Gaidzik VI, Paschka P, Roberts ND, et al. Genomic clssification and prognosis in acute myeloid leukemia. N Engl J Med. 2016;374:2209–21.CrossRefPubMedPubMedCentral Papaemmanuil E, Gerstung M, Bullinger L, Gaidzik VI, Paschka P, Roberts ND, et al. Genomic clssification and prognosis in acute myeloid leukemia. N Engl J Med. 2016;374:2209–21.CrossRefPubMedPubMedCentral
25.
go back to reference Büchner T, Schlenk RF, Schaich M, Döhner K, Krahl R, Krauter J, et al. Acute myeloid leukemia (AML): different treatment strategies versus a common standard arm-combined prospective analysis by the German AML Intergroup. J Clin Oncol. 2012;30:3604–10.CrossRefPubMed Büchner T, Schlenk RF, Schaich M, Döhner K, Krahl R, Krauter J, et al. Acute myeloid leukemia (AML): different treatment strategies versus a common standard arm-combined prospective analysis by the German AML Intergroup. J Clin Oncol. 2012;30:3604–10.CrossRefPubMed
27.
go back to reference Schetelig J, Schaich M, Schäfer-Eckart K, Hänel M, Aulitzky WE, Einsele H, et al. Study-Alliance-Leukemia: hematopoietic cell transplantation in patients with intermediate and high risk AML: results from the randomized Study Alliance Leukemia (SAL) AML 2003 trial. Leukemia. 2015;29:1060–8.CrossRefPubMed Schetelig J, Schaich M, Schäfer-Eckart K, Hänel M, Aulitzky WE, Einsele H, et al. Study-Alliance-Leukemia: hematopoietic cell transplantation in patients with intermediate and high risk AML: results from the randomized Study Alliance Leukemia (SAL) AML 2003 trial. Leukemia. 2015;29:1060–8.CrossRefPubMed
28.
go back to reference Chen J, Kobayashi M, Darmanin S, Qiao Y, Gully C, Zhao R, et al. Hypoxia-mediated up-regulation of Pim-1 contributes to solid tumor formation. Am J Pathol. 2009;175:400–11.CrossRefPubMedPubMedCentral Chen J, Kobayashi M, Darmanin S, Qiao Y, Gully C, Zhao R, et al. Hypoxia-mediated up-regulation of Pim-1 contributes to solid tumor formation. Am J Pathol. 2009;175:400–11.CrossRefPubMedPubMedCentral
29.
go back to reference Mizuki M, Schwable J, Steur C, Choudhary C, Agrawal S, Sargin B, et al. Suppression of myeloid transcription factors and induction of STAT response genes by AML specific Flt3 mutations. Blood. 2003;101:3164–73.CrossRefPubMed Mizuki M, Schwable J, Steur C, Choudhary C, Agrawal S, Sargin B, et al. Suppression of myeloid transcription factors and induction of STAT response genes by AML specific Flt3 mutations. Blood. 2003;101:3164–73.CrossRefPubMed
30.
go back to reference Fathi AT, Arowojolu O, Swinnen I, Sato T, Rajkhowa T, Small D, et al. A potential therapeutic target for FLT3-ITD AML: PIM-1 kinase. Leuk Res. 2012;36:224–31.CrossRefPubMed Fathi AT, Arowojolu O, Swinnen I, Sato T, Rajkhowa T, Small D, et al. A potential therapeutic target for FLT3-ITD AML: PIM-1 kinase. Leuk Res. 2012;36:224–31.CrossRefPubMed
31.
go back to reference Block KM, Hanke NT, Maine EA, Baker AF. IL-6 stimulates STAT3 and Pim-1 kinase in pancreatic cancer cell lines. Pancreas. 2012;41:773–81.PubMedPubMedCentral Block KM, Hanke NT, Maine EA, Baker AF. IL-6 stimulates STAT3 and Pim-1 kinase in pancreatic cancer cell lines. Pancreas. 2012;41:773–81.PubMedPubMedCentral
32.
go back to reference Li Z, Lin F, Zhuo C, Deng G, Chen Z, Yin S, Gao Z, et al. PIM-1 kinase phosphorylates the human transcri-ption factor FOXP3 at serine 422 to negatively regulate its activity under inflammation. J Biol Chem. 2014;289:26872–81.CrossRefPubMedPubMedCentral Li Z, Lin F, Zhuo C, Deng G, Chen Z, Yin S, Gao Z, et al. PIM-1 kinase phosphorylates the human transcri-ption factor FOXP3 at serine 422 to negatively regulate its activity under inflammation. J Biol Chem. 2014;289:26872–81.CrossRefPubMedPubMedCentral
33.
go back to reference Natarajan K, Bhullar J, Shukla S, Burcu M, Chen ZS, Ambudkar SV, et al. The Pim kinase inhibitor SGI-1776 decreases cell surface expression of P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) and drug transport by Pim-1 dependent and independent mechanisms. Biochem Pharmacol. 2013;85:514–24.CrossRefPubMed Natarajan K, Bhullar J, Shukla S, Burcu M, Chen ZS, Ambudkar SV, et al. The Pim kinase inhibitor SGI-1776 decreases cell surface expression of P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) and drug transport by Pim-1 dependent and independent mechanisms. Biochem Pharmacol. 2013;85:514–24.CrossRefPubMed
34.
go back to reference Goldberg L, Tijssen MR, Birger Y, Hannah RL, Kinston SJ, Schütte J, et al. Genome-scale expression and transcription factor binding profiles reveal therapeutic targets in transgenic ERG myeloid leukemia. Blood. 2013;122:2694–703.CrossRefPubMedPubMedCentral Goldberg L, Tijssen MR, Birger Y, Hannah RL, Kinston SJ, Schütte J, et al. Genome-scale expression and transcription factor binding profiles reveal therapeutic targets in transgenic ERG myeloid leukemia. Blood. 2013;122:2694–703.CrossRefPubMedPubMedCentral
35.
go back to reference Bonin S, Larese FF, Trevisan G, Avian A, Rui F, Stanta G, et al. Gene expression changes in peripheral blood mononuclear cells in occupational exposure to nickel. Exp Dermatol. 2011;20:147–8.CrossRefPubMed Bonin S, Larese FF, Trevisan G, Avian A, Rui F, Stanta G, et al. Gene expression changes in peripheral blood mononuclear cells in occupational exposure to nickel. Exp Dermatol. 2011;20:147–8.CrossRefPubMed
36.
go back to reference Fu L, Fu H, Wu Q, Pang Y, Xu K, Zhou L, et al. High expression of ETS2 predicts poor prognosis in acute myeloid leukemia and may guide treatment decisions. J Transl Med. 2017. doi:10.1186/s12967-017-1260-2. Fu L, Fu H, Wu Q, Pang Y, Xu K, Zhou L, et al. High expression of ETS2 predicts poor prognosis in acute myeloid leukemia and may guide treatment decisions. J Transl Med. 2017. doi:10.​1186/​s12967-017-1260-2.
37.
go back to reference Wu YB, Lu D, He ZF, Jin CG. PIM-1 polymorphism and PIM-1 expression as predisposing factors of esophageal squamous cell carcinoma in the Asian population. Onco Targets Ther. 2016;17:2919–25. Wu YB, Lu D, He ZF, Jin CG. PIM-1 polymorphism and PIM-1 expression as predisposing factors of esophageal squamous cell carcinoma in the Asian population. Onco Targets Ther. 2016;17:2919–25.
Metadata
Title
PIM-1 mRNA expression is a potential prognostic biomarker in acute myeloid leukemia
Authors
Hui Cheng
Chongmei Huang
Xiaoqian Xu
Xiaoxia Hu
Shenglan Gong
Gusheng Tang
Xianmin Song
Weiping Zhang
Jianmin Wang
Li Chen
Jianmin Yang
Publication date
01-12-2017
Publisher
BioMed Central
Published in
Journal of Translational Medicine / Issue 1/2017
Electronic ISSN: 1479-5876
DOI
https://doi.org/10.1186/s12967-017-1287-4

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