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Open Access 01-12-2014 | Review

Pim kinases in hematological malignancies: where are we now and where are we going?

Authors: Patrizia Mondello, Salvatore Cuzzocrea, Michael Mian

Published in: Journal of Hematology & Oncology | Issue 1/2014

Abstract

The proviral insertion in murine (PIM) lymphoma proteins are a serine/threonine kinase family composed of three isoformes: Pim-1, Pim-2 and Pim-3. They play a critical role in the control of cell proliferation, survival, homing and migration. Recently, overexpression of Pim kinases has been reported in human tumors, mainly in hematologic malignancies. In vitro and in vivo studies have confirmed their oncogenic potential. Indeed, PIM kinases have shown to be involved in tumorgenesis, to enhance tumor growth and to induce chemo-resistance, which is why they have become an attractive therapeutic target for cancer therapy. Novel molecules inhibiting Pim kinases have been evaluated in preclinical studies, demonstrating to be effective and with a favorable toxicity profile. Given the promising results, some of these compounds are currently under investigation in clinical trials. Herein, we provide an overview of the biological activity of PIM-kinases, their role in hematologic malignancies and future therapeutic opportunities.

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Nawijn MC, Alendar A, Berns A: For better or for worse: the role of Pim oncogenes in tumorigenesis. Nat Rev Cancer. 2011, 11: 23-34.PubMed

Fox CJ, Hammerman PS, Cinalli RM, Master SR, Chodosh LA, Thompson CB: The serine/threonine kinase Pim- 2 is a transcriptionally regulated apoptotic inhibitor. Genes Dev. 2003, 17: 1841-1854.PubMedCentralPubMed

Qian KC, Wang L, Hickey ER, Studts J, Barringer K, Peng C, Kronkaitis A, Li J, White A, Mische S, Farmer B: Structural basis of constitutive activity and a unique nucleotide binding mode of human Pim-1 kinase. J Biol Chem. 2005, 280: 6130-6137.PubMed

Allen JD, Verhoeven E, Domen J, van der Valk M, Berns A: Pim-2 transgene induces lymphoid tumors, exhibiting potent synergy with c-myc. Oncogene. 1997, 15: 1133-1141.PubMed

Dautry F, Weil D, Yu J, Dautry-Varsat A: Regulation of pim and myb mRNA accumulation by interleukin 2 and interleukin 3 in murine hematopoietic cell lines. J Biol Chem. 1988, 263: 17615-17620.PubMed

Lilly M, Le T, Holland P, Hendrickson SL: Sustained expression of the pim-1 kinase is specifically induced in myeloid cells by cytokines whose receptors are structurally related. Oncogene. 1992, 7: 727-732.PubMed

Pratt WB: The role of the hsp90-based chaperone system in signal transduction by nuclear receptors and receptors signaling via MAP kinase. Annu Rev Pharmacol Toxicol. 1997, 37: 297-326.PubMed

Mizuno K, Shirogane T, Shinohara A, Iwamatsu A, Hibi M, Hirano T: Regulation of Pim-1 by Hsp90. Biochem Biophys Res Commun. 2001, 281: 663-669.PubMed

Nieborowska-Skorska M, Hoser G, Kossev P, Wasik MA, Skorski T: Complementary functions of the antiapoptotic protein A1 and serine/threonine kinase pim-1 in the BCR/ABL-mediated leukemogenesis. Blood. 2002, 99: 4531-4539.PubMed

10.

Wernig G, Gonneville JR, Crowley BJ, Rodrigues MS, Reddy MM, Hudon HE, Walz C, Reiter A, Podar K, Royer Y, Constantinescu SN, Tomasson MH, Griffin JD, Gilliland DG, Sattler M: The Jak2V617F oncogene associated with myeloproliferative diseases requires a functional FERM domain for transformation and for expression of the Myc and Pim proto-oncogenes. Blood. 2008, 111: 3751-3759.PubMedCentralPubMed

11.

Kim KT, Baird K, Ahn JY, Meltzer P, Lilly M, Levis M, Small D: Pim-1 is up-regulated by constitutively activated FLT3 and plays a role in FLT3-mediated cell survival. Blood. 2005, 105: 1759-1767.PubMed

12.

Mikkers H, Nawijn M, Allen J, Brouwers C, Verhoeven E, Jonkers J, Berns A: Mice deficient for all PIM kinases display reduced body size and impaired responses to hematopoietic growth factors. Mol Cell Biol. 2004, 24: 6104-6115.PubMedCentralPubMed

13.

Eichmann A, Yuan L, Bréant C, Alitalo K, Koskinen PJ: Developmental expression of pim kinases suggests functions also outside of the hematopoietic system. Oncogene. 2000, 19: 1215-1224.PubMed

14.

Bachmann M, Möröy T: The serine/threoninekinasePim-1. Int J Biochem Cell Biol. 2005, 37: 726-730.PubMed

15.

Feldman JD, Vician L, Crispino M, Tocco G, Marcheselli VL, Bazan NG, Baudry M, Herschman HR: KID-1, a protein kinase induced by depolarization in brain. J Biol Chem. 1998, 273: 16535-16543.PubMed

16.

Alizadeh AA, Eisen MB, Davis RE, Ma C, Lossos IS, Rosenwald A, Boldrick JC, Sabet H, Tran T, Yu X, Powell JI, Yang L, Marti GE, Moore T, Hudson J, Lu L, Lewis DB, Tibshirani R, Sherlock G, Chan WC, Greiner TC, Weisenburger DD, Armitage JO, Warnke R, Levy R, Wilson W, Grever MR, Byrd JC, Botstein D, Brown PO, Staudt LM: Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature. 2000, 403: 503-511.PubMed

17.

Cohen AM, Grinblat B, Bessler H, Kristt D, Kremer A, Schwartz A, Halperin M, Shalom S, Merkel D, Don J: Increased expression of the hPim-2 gene in human chronic lymphocytic leukemia and non-Hodgkin lymphoma. Leuk Lymphoma. 2004, 45: 951-955.PubMed

18.

Wingett D, Long A, Kelleher D, Magnuson NS: Pim-1 proto-oncogene expression in anti-CD3- mediated T-cell activation is associated with pro- tein kinase C activation and is independent of Raf-1. J Immunol. 1996, 156: 549-557.PubMed

19.

Cibull TL, Jones TD, Li L, Eble JN, Ann Baldridge L, Malott SR, Luo Y, Cheng L: Overexpression of Pim-1 during progression of prostatic adenocarcinoma. J Clin Pathol. 2006, 59: 285-288.PubMedCentralPubMed

20.

Shah N, Pang B, Yeoh KG, Thorn S, Chen CS, Lilly MB, Salto-Tellez M: Potential roles for the PIM1 kinase in human cancer - a molecular and therapeuticappraisal. Eur J Cancer. 2008, 44: 2144-2151.PubMed

21.

Van Lohuizen M, Verbeek S, Krimpenfort P, Domen J, Saris C, Radaszkiewicz T, Berns A: Predisposition to lymphomagenesis in pim-1 transgenic mice: cooperation with c-myc and N-myc in murine leukemia virus-induced tumors. Cell. 1989, 56: 673-682.PubMed

22.

van Lohuizen M, Verbeek S, Scheijen B, Wientjens E, van der Gulden H, Berns A: Identification of cooperating oncogenes in E mu-myc transgenic mice by provirus tagging. Cell. 1991, 65: 737-752.PubMed

23.

Berns A: Tumorigenesis in transgenic mice: identification and characterization of synergizing oncogenes. J Cell Biochem. 1991, 47: 130-135.PubMed

24.

Verbeek S, van Lohuizen M, van der Valk M, Domen J, Kraal G, Berns A: Mice bearing the E mu-myc and E mu-pim-1 transgenes develop pre-B-cell leukemia prenatally. Mol Cell Biol. 1991, 11: 1176-1179.PubMedCentralPubMed

25.

Kim J, Roh M, Abdulkadir SA: Pim1 promotes human prostate cancer cell tumorigenicity and c-MYC transcriptional activity. BMC Cancer. 2010, 10: 248-PubMedCentralPubMed

26.

Shinto Y, Morimoto M, Katsumata M, Uchida A, Aozasa K, Okamoto M, Kurosawa T, Ochi T, Greene MI, Tsujimoto Y: Moloney murine leukemia virus infection accelerates lymphomagenesis in E mu-bcl-2 transgenic mice. Oncogene. 1995, 11: 1729-1736.PubMed

27.

Baron BW, Anastasi J, Hyjek EM, Bies J, Reddy PL, Dong J, Joseph L, Thirman MJ, Wroblewski K, Wolff L, Baron JM: PIM1 gene cooperates with human BCL6 gene to promote the development of lymphomas. Proc Natl Acad Sci U S A. 2012, 109: 5735-5739.PubMedCentralPubMed

28.

Blyth K, Terry A, Mackay N, Vaillant F, Bell M, Cameron ER, Neil JC, Stewart M: Runx2: a novel oncogenic effector revealed by in vivo complementation and retroviral tagging. Oncogene. 2001, 20: 295-302.PubMed

29.

Feldman BJ, Reid TR, Cleary ML: Pim1 cooperates with E2a-Pbx1 to facilitate the progression of thymic lymphomas in transgenic mice. Oncogene. 1997, 15: 2735-2742.PubMed

30.

Jonkers J, Korswagen HC, Acton D, Breuer M, Berns A: Activation of a novel proto-oncogene, Frat1, contributes to progression of mouse T-cell lymphomas. EMBO J. 1997, 16: 441-450.PubMedCentralPubMed

31.

An N, Kraft AS, Kang Y: Abnormal hematopoietic phenotypes in Pim kinase triple knockout mice. J Hematol Oncol. 2013, 29: 6-12.

32.

Fox CJ, Hammerman PS, Thompson CB: The Pim kinases control rapamycin-resistant T cell survival and activation. J Exp Med. 2005, 201: 259-266.PubMedCentralPubMed

33.

Wang Z, Bhattacharya N, Weaver M, Petersen K, Meyer M, Gapter L, Magnuson NS: Pim-1: A serine/threonine kinase with a role in cell survival, proliferation, differentiation and tumorigenesis. J Vet Sci. 2001, 2: 167-179.PubMed

34.

Cuypers HT, Selten G, Berns A, van Kessel AH G: Assignment of the human homologue of Pim-1, a mouse gene implicated in leukemogenesis, to the pter-q12 region of chromosome 6. Hum Genet. 1986, 72: 262-265.PubMed

35.

Aho TL, Sandholm J, Peltola KJ, Mankonen HP, Lilly M, Koskinen PJ: Pim-1 kinase promotes inactivation of the pro-apoptotic Bad protein by phosphorylating it on the Ser112 gatekeeper site. FEBS Lett. 2004, 571: 43-49.PubMed

36.

Macdonald A, Campbell DG, Toth R, McLauchlan H, Hastie CJ, Arthur JS: Pim kinases phosphorylate multiple sites on Bad and promote 14-3-3 binding and dissociation from Bcl-XL. BMC Cell Biol. 2006, 7: 1-PubMedCentralPubMed

37.

Yan B, Zemskova M, Holder S, Chin V, Kraft A, Koskinen PJ, Lilly M: The PIM-2 kinase phosphorylates BAD on serine 112 and reverses BAD-induced cell death. J Biol Chem. 2003, 278: 45358-45367.PubMed

38.

Li YY, Popivanova BK, Nagai Y, Ishikura H, Fujii C, Mukaida N: Pim-3, a proto-oncogene with serine/ threonine kinase activity, is aberrantly expressed in human pancreatic cancer and phosphorylates bad to block bad-mediated apoptosis in human pancreatic cancer cell lines. Cancer Res. 2006, 66: 6741-6747.PubMed

39.

Gu JJ, Wang Z, Reeves R, Magnuson NS: PIM1 phosphorylates and negatively regulates ASK1-mediated apoptosis. Oncogene. 2009, 28: 4261-4271.PubMedCentralPubMed

40.

Hogan C, Hutchison C, Marcar L, Milne D, Saville M, Goodlad J, Kernohan N, Meek D: Elevated levels of oncogenic protein kinase Pim-1 induce the p53 pathway in cultured cells and correlate with increased Mdm2 in mantle cell lymphoma. J Biol Chem. 2008, 283: 18012-18023.PubMedCentralPubMed

41.

Zhou BP, Liao Y, Xia W, Zou Y, Spohn B, Hung MC: HER-2/neu induces p53 ubiquitination via Akt-mediated MDM2 phosphorylation. Nat Cell Biol. 2001, 3: 973-982.PubMed

42.

Mayo LD, Donner DB: A phosphatidylinositol 3-kinase/Akt pathway promotes translocation of Mdm2 from the cytoplasm to the nucleus. Proc Natl Acad Sci U S A. 2001, 98: 11598-11603.PubMedCentralPubMed

43.

Ashcroft M, Ludwig RL, Woods DB, Copeland TD, Weber HO, MacRae EJ, Vousden KH: Phosphorylation of HDM2 by Akt. Oncogene. 2002, 21: 1955-1962.PubMed

44.

Gottlieb TM, Leal JF, Seger R, Taya Y, Oren M: Cross-talk between Akt, p53 and Mdm2: possible implications for the regulation of apoptosis. Oncogene. 2002, 21: 1299-1303.PubMed

45.

Jackson MW, Patt LE, LaRusch GA, Donner DB, Stark GR, Mayo LD: Hdm2 nuclear export, regulated by insulin-like growth factor-I/MAPK/p90Rsk signaling, mediates the transformation of human cells. J Biol Chem. 2006, 281: 16814-16820.PubMed

46.

Weber HO, Ludwig RL, Morrison D, Kotlyarov A, Gaestel M, Vousden KH: HDM2 phosphorylation by MAPKAP kinase 2. Oncogene. 2005, 24: 1965-1972.PubMed

47.

Stott FJ, Bates S, James MC, McConnell BB, Starborg M, Brookes S, Palmero I, Ryan K, Hara E, Vousden KH, Peters G: The alternative product from the human CDKN2A locus, p14(ARF), participates in a regulatory feedback loop with p53 and MDM2. EMBO J. 1998, 17: 5001-5014.PubMedCentralPubMed

48.

Llanos S, Clark PA, Rowe J, Peters G: Stabilization of p53 by p14ARF without relocation of MDM2 to the nucleolus. Nat Cell Biol. 2001, 3: 445-452.PubMed

49.

Hammerman PS, Fox CJ, Cinalli RM, Xu A, Wagner JD, Lindsten T, Thompson CB: Lymphocyte transformation by Pim-2 is dependent on nuclear factor-kappaB activation. Cancer Res. 2004, 64: 8341-8348.PubMed

50.

Nihira K, Ando Y, Yamaguchi T, Kagami Y, Miki Y, Yoshida K: Pim-1 controls NF-kappaB signalling by stabilizing RelA/p65. Cell Death Differ. 2010, 17: 689-698.PubMed

51.

Wang Z, Bhattacharya N, Mixter PF, Wei W, Sedivy J, Magnuson NS: Phosphorylation of the cell cycle inhibitor p21Cip1/WAF1 by Pim-1 kinase. Biochim Biophys Acta. 2002, 1593: 45-55.PubMed

52.

Wang Z, Zhang Y, Gu JJ, Davitt C, Reeves R, Magnuson NS: Pim-2 phosphorylation of p21(Cip1/WAF1) enhances its stability and inhibits cell proliferation in HCT116 cells. Int J Biochem Cell Biol. 2010, 42: 1030-1038.PubMedCentralPubMed

53.

Morishita D, Katayama R, Sekimizu K, Tsuruo T, Fujita N: Pim kinases promote cell cycle progression by phosphorylating and down-regulating p27Kip1 at the transcriptional and posttranscriptional levels. Cancer Res. 2008, 68: 5076-5085.PubMed

54.

Xia W, Chen JS, Zhou X, Sun PR, Lee DF, Liao Y, Zhou BP, Hung MC: Phosphorylation/cytoplasmic localization of p21Cip1/WAF1 is associated with HER2/neu overexpression and provides a novel combination predictor for poor prognosis in breast cancer patients. Clin Cancer Res. 2004, 10: 3815-3824.PubMed

55.

Zhou BP, Liao Y, Xia W, Spohn B, Lee MH, Hung MC: Cytoplasmic localization of p21Cip1/WAF1 by Akt-induced phosphorylation in HER-2/neu-overexpressing cells. Nat Cell Biol. 2001, 3: 245-252.PubMed

56.

Mumenthaler SM, Ng PY, Hodge A, Bearss D, Berk G, Kanekal S, Redkar S, Taverna P, Agus DB, Jain A: Pharmacologic inhibition of Pim kinases alters prostate cancer cell growth and resensitizes chemoresistant cells to taxanes. Mol Cancer Ther. 2009, 8: 2882-2893.PubMedCentralPubMed

57.

Mochizuki T, Kitanaka C, Noguchi K, Muramatsu T, Asai A, Kuchino Y: Physical and functional interactions between Pim-1 kinase and Cdc25A phosphatase. Implications for the Pim-1-mediated activation of the c-Myc signaling pathway. J Biol Chem. 1999, 274: 18659-18666.PubMed

58.

Bachmann M, Hennemann H, Xing PX, Hoffmann I, Moroy T: The oncogenic ser- ine/threonine kinase Pim-1 phosphorylates and inhibits the activity of Cdc25C-associated kinase 1 (C-TAK1): a novel role for Pim-1 at the G2/M cell cycle checkpoint. J Biol Chem. 2004, 279: 48319-48328.PubMed

59.

Bhattacharya N, Wang Z, Davitt C, McKenzie IF, Xing PX, Magnuson NS: Pim-1 associates with protein complexes necessary for mitosis. Chromosoma. 2002, 111: 80-95.PubMed

60.

Yip-Schneider MT, Horie M, Broxmeyer HE: Transcriptional induction of pim-1 protein kinase gene expression by interferon gamma and posttranscriptional effects on costimulation with steel factor. Blood. 1995, 85: 3494-3502.PubMed

61.

Chen XP, Losman JA, Cowan S, Donahue E, Fay S, Vuong BQ, Nawijn MC, Capece D, Cohan VL, Rothman P: Pim serine/threonine kinases regulate the stability of Socs-1 protein. Proc Natl Acad Sci U S A. 2002, 99: 2175-2180.PubMedCentralPubMed

62.

Peltola KJ, Paukku K, Aho TL, Ruuska M, Silvennoinen O, Koskinen PJ: Pim-1 kinase inhibits STAT5-dependent transcription via its interactions with SOCS1 and SOCS3. Blood. 2004, 103: 3744-3750.PubMed

63.

Chen JL, Limnander A, Rothman PB: Pim-1 and Pim-2 kinases are required for efficient pre-B-cell transformation by v-Abl oncogene. Blood. 2008, 111: 1677-1685.PubMed

64.

Berns A, Mikkers H, Krimpenfort P, Allen J, Scheijen B, Jonkers J: Identification and characterization of collaborating oncogenes in compound mutant mice. Cancer Res. 1999, 59 (Suppl): 1773-1777.

65.

Shirogane T, Fukada T, Muller JM, Shima DT, Hibi M, Hirano T: Synergistic roles for Pim-1 and c-Myc in STAT3-mediated cell cycle progression and antiapoptosis. Immunity. 1999, 11: 709-719.PubMed

66.

Zhang Y, Wang Z, Li X, Magnuson NS: Pim kinase‐dependent inhibition of c‐Myc degradation. Oncogene. 2008, 27: 4809-4819.PubMed

67.

Zippo A, De Robertis A, Serafini R, Oliviero S: PIM1-dependent phosphorylation of histone H3 at serine 10 is required for MYC-dependent transcriptional activation and oncogenic transformation. Nat Cell Biol. 2007, 9: 932-944.PubMed

68.

Winter S, Simboeck E, Fischle W, Zupkovitz G, Dohnal I, Mechtler K, Ammerer G, Seiser C: 14‐3‐3 proteins recognize a histone code at histone H3 and are required for transcriptional activation. EMBO J. 2008, 27: 88-99.PubMedCentralPubMed

69.

Zippo A, Serafini R, Rocchigiani M, Pennacchini S, Krepelova A, Oliviero S: Histone crosstalk between H3S10ph and H4K16ac generates a histone code that mediates transcription elongation. Cell. 2009, 138: 1122-1136.PubMed

70.

Nakayama KI, Nakayama K: Ubiquitin ligases: cell-cycle control and cancer. Nat Rev Cancer. 2006, 6: 369-381.PubMed

71.

Matsumoto A, Onoyama I, Nakayama KI: Expression of mouse Fbxw7 isoforms is regulated in a cell cycle- or p53-dependent manner. Biochem Biophys Res Commun. 2006, 350: 114-119.PubMed

72.

Yoshida GJ, Saya H: Inversed relationship between CD44 variant and c-Myc due to oxidative stress-induced canonical Wnt activation. Biochem Biophys Res Commun. 2014, 443: 622-627.PubMed

73.

Reavie L, Della Gatta G, Crusio K, Aranda-Orgilles B, Buckley SM, Thompson B, Lee E, Gao J, Bredemeyer AL, Helmink BA, Zavadil J, Sleckman BP, Palomero T, Ferrando A, Aifantis I: Regulation of hematopoietic stem cell differentiation by a single ubiquitin ligase-substrate complex. Nat Immunol. 2010, 11: 207-215.PubMedCentralPubMed

74.

Reavie L, Buckley SM, Loizou E, Takeishi S, Aranda-Orgilles B, Ndiaye-Lobry D, Abdel-Wahab O, Ibrahim S, Nakayama KI, Aifantis I: Regulation of c-Myc ubiquitination controls chronic myelogenous leukemia initiation and progression. Cancer Cell. 2013, 23: 362-375.PubMedCentralPubMed

75.

Kwak EL, Moberg KH, Wahrer DC, Quinn JE, Gilmore PM, Graham CA, Hariharan IK, Harkin DP, Haber DA, Bell DW: Infrequent mutations of Archipelago (hAGO, hCDC4, Fbw7) in primary ovarian cancer. Gynecol Oncol. 2005, 98: 124-128.PubMed

76.

Strohmaier H, Spruck CH, Kaiser P, Won KA, Sangfelt O, Reed SI: Human F-box protein hCdc4 targets cyclin E for proteolysis and is mutated in a breast cancer cell line. Nature. 2001, 413: 316-322.PubMed

77.

Spruck CH, Strohmaier H, Sangfelt O, Muller HM, Hubalek M, Muller-Holzner E, Marth C, Widschwendter M, Reed SI: hCDC4 gene mutations in endometrial cancer. Cancer Res. 2002, 62: 4535-4539.PubMed

78.

Rajagopalan H, Jallepalli PV, Rago C, Velculescu VE, Kinzler KW, Vogelstein B, Lengauer C: Inactivation of hCDC4 can cause chromosomal instability. Nature. 2004, 428: 77-81.PubMed

79.

Siu KT, Xu Y, Swartz KL, Bhattacharyya M, Gurbuxani S, Hua Y, Minella AC: Chromosome instability underlies hematopoietic stem cell dysfunction and lymphoid neoplasia associated with impaired Fbw7- mediated cyclin E regulation. Mol Cell Biol. 2014, 34: 3244-3258.PubMedCentralPubMed

80.

Chang TC, Yu D, Lee YS, Wentzel EA, Arking DE, West KM, Dang CV, Thomas-Tikhonenko A, Mendell JT: Widespread microRNA repression by Myc contributes to tumorigenesis. Nat Genet. 2008, 40: 43-50.PubMedCentralPubMed

81.

Liu L, Wang S, Chen R, Wu Y, Zhang B, Huang S, Zhang J, Xiao F, Wang M, Liang Y: Myc induced miR-144/451 contributes to the acquired imatinib resistance in chronic myelogenous leukemia cell K562. Biochem Biophys Res Commun. 2012, 425: 368-373.PubMed

82.

Hammerman PS, Fox CJ, Brinbaum MJ, Thompson CB: Pim and Akt oncogenes are independent regulators of hematopoietic cell growth and survival. Blood. 2005, 105: 4477-4483.PubMedCentralPubMed

83.

Schatz JH, Oricchio E, Wolfe AL, Jiang M, Linkov I, Maragulia J, Shi W, Zhang Z, Rajasekhar VK, Pagano NC, Porco JA, Teruya-Feldstein J, Rosen N, Zelenetz AD, Pelletier J, Wendel HG: Targeting cap-dependent translation blocks converging survival signals by AKT and PIM kinases in lymphoma. J Exp Med. 2011, 208: 1799-1807.PubMedCentralPubMed

84.

Cen B, Xiong Y, Song JH, Mahajan S, DuPont R, McEachern K, DeAngelo DJ, Cortes JE, Minden MD, Ebens A, Mims A, LaRue AC, Kraft AS: The Pim-1 Protein Kinase Is an Important Regulator of MET Receptor Tyrosine Kinase Levels and Signaling. Mol Cell Biol. 2014, 34: 2517-2532.PubMedCentralPubMed

85.

Kucia M, Jankowski K, Reca R, Wysoczynski M, Bandura L, Allendorf D, Zhang J, Ratajczak J, Ratajczak M: CXCR4–SDF-1 signaling, locomotion, chemotaxis and adhesion. J Mol Histol. 2004, 35: 233-245.PubMed

86.

Lapidot T, Dar A, Kollet O: How do stem cells find their way home?. Blood. 2005, 106: 1901-1910.PubMed

87.

Busillo JM, Benovic JL: Regulation of CXCR4 signaling. Biochim Biophys Acta. 2007, 1768: 952-963.PubMedCentralPubMed

88.

Boudot A, Kerdivel G, Lecomte S, Flouriot G, Desille M, Godey F, Leveque J, Tas P, Le Dréan Y, Pakdel F: COUP-TFI modifies CXCL12 and CXCR4 expression by activating EGF signaling and stimulates breast cancer cell migration. BMC Cancer. 2014, 14: 407-PubMedCentralPubMed

89.

Matteucci E, Locati M, Desiderio MA: Hepatocyte growth factor enhances CXCR4 expression favoring breast cancer cell invasiveness. Exp Cell Res. 2005, 310: 176-185.PubMed

90.

Chetram MA, Don-Salu-Hewage AS, Hinton CV: ROS enhances CXCR4-mediated functions through inactivation of PTEN in prostate cancer cells. Biochem Biophys Res Commun. 2011, 410: 195-200.PubMedCentralPubMed

91.

Matsusaka S, Tohyama Y, He J, Shi Y, Hazama R, Kadono T, Kurihara R, Tohyama K, Yamamura H: Protein-tyrosine kinase, Syk, is required for CXCL12-induced polarization of B cells. Biochem Biophys Res Commun. 2005, 328: 1163-1169.PubMed

92.

Croker AK, Allan AL: Cancer stem cells: implications for the progression and treatment of metastatic disease. J Cell Mol Med. 2008, 12: 374-390.PubMedCentralPubMed

93.

Grundler R, Brault L, Gasser C, Bullock AN, Dechow T, Woetzel S, Pogacic V, Villa A, Ehret S, Berridge G, Spoo A, Dierks C, Biondi A, Knapp S, Duyster J, Schwaller J: Dissection of PIM serine/threonine kinases in FLT3-ITD- induced leukemogenesis reveals PIM1 as regulator of CXCL12-CXCR4-mediated homing and migration. J Exp Med. 2009, 206: 1957-1970.PubMedCentralPubMed

94.

Decker S, Finter J, Forde AJ, Kissel S, Schwaller J, Mack TS, Kuhn A, Gray N, Follo M, Jumaa H, Burger M, Zirlik K, Pfeifer D, Miduturu CV, Eibel H, Veelken H, Dierks C: PIM kinases are essential for chronic lymphocytic leukemia cell survival (PIM2/3) and CXCR4-mediated microenvironmental interactions (PIM1). Mol Cancer Ther. 2014, 13: 1231-1245.PubMed

95.

Chen W, Kumar AR, Hudson WA, Li Q, Wu B, Staggs RA, Lund EA, Sam TN, Kersey JH: Gene dosage and critical target cells. Cancer Cell. 2008, 13: 432-440.PubMedCentralPubMed

96.

Mizuki M, Schwable J, Steur C, Choudhary C, Agrawal S, Sargin B, Steffen B, Matsumura I, Kanakura Y, Böhmer FD, Müller-Tidow C, Berdel WE, Serve H: Suppression of myeloid transcription factors and induction of STAT response genes by AML-specific Flt3 mutations. Blood. 2003, 101: 3164-3173.PubMed

97.

Hu YL, Passegue E, Fong S, Largman C, Lawrence HJ: Evidence that the Pim1 kinase gene is a direct target of HOXA9. Blood. 2007, 109: 4732-4738.PubMedCentralPubMed

98.

Vu HA, Xinh PT, Kano Y, Tokunaga K, Sato Y: The juxtamembrane domain in ETV6/FLT3 is critical for PIM-1 up-regulation and cell proliferation. Biochem Biophys Res Commun. 2009, 383: 308-313.PubMed

99.

Gomez-Abad C, Pisonero H, Blanco-Aparicio C, Roncador G, González-Menchén A, Martinez-Climent JA, Mata E, Rodríguez ME, Muñoz-González G, Sánchez-Beato M, Leal JF, Bischoff JR, Piris MA: PIM2 inhibition as a rational therapeutic approach in B-cell lymphoma. Blood. 2011, 118: 5517-5527.PubMed

100.

Brault L, Menter T, Obermann EC, Knapp S, Thommen S, Schwaller J, Tzankov A: PIM kinases are progression markers and emerging therapeutic targets in diffuse large B-cell lymphoma. Br J Cancer. 2012, 107: 491-500.PubMedCentralPubMed

101.

Hsi ED, Jung SH, Lai R, Johnson JL, Cook JR, Jones D, Devos S, Cheson BD, Damon LE, Said J: Ki67 and PIM1 expression predict outcome in mantle cell lymphoma treated with high dose therapy, stem cell transplantation and rituximab: a Cancer and Leukemia Group B 59909 correlative science study. Leuk Lymphoma. 2008, 49: 2081-2090.PubMedCentralPubMed

102.

Pasqualucci L, Neumeister P, Goossens T, Nanjangud G, Chaganti RS, Küppers R, Dalla-Favera R: Hypermutation of multiple proto-oncogenes in B-cell diffuse large-cell lymphomas. Nature. 2001, 412: 341-346.PubMed

103.

Claudio JO, Masih-Khan E, Tang H, Gonçalves J, Voralia M, Li ZH, Nadeem V, Cukerman E, Francisco-Pabalan O, Liew CC, Woodgett JR, Stewart AK: A molecular compendium of genes expressed in multiple myeloma. Blood. 2002, 100: 2175-2186.PubMed

104.

Pogacic V, Bullock AN, Fedorov O, Filippakopoulos P, Gasser C, Biondi A, Meyer-Monard S, Knapp S, Schwaller J: Structural analysis identifies imidazo[1,2-b]pyridazines as PIM kinase inhibitors with in vitro antileukemic activity. Cancer Res. 2007, 67: 6916-6924.PubMed

105.

Blanco-Aparicio C, Collazo AM, Oyarzabal J, Leal JF, Albarán MI, Lima FR, Pequeño B, Ajenjo N, Becerra M, Alfonso P, Reymundo MI, Palacios I, Mateos G, Quiñones H, Corrionero A, Carnero A, Pevarello P, Lopez AR, Fominaya J, Pastor J, Bischoff JR: Pim 1 kinase inhibitor ETP-45299 suppresses cellular proliferation and synergizes with PI3K inhibition. Cancer Lett. 2011, 300: 145-153.PubMed

106.

Garcia PD, Langowski JL, Wang Y, Chen M, Castillo J, Fanton C, Ison M, Zavorotinskaya T, Dai Y, Lu J, Niu XH, Basham S, Chan J, Yu J, Doyle M, Feucht P, Warne R, Narberes J, Tsang T, Fritsch C, Kauffmann A, Pfister E, Drueckes P, Trappe J, Wilson C, Han W, Lan J, Nishiguchi G, Lindvall M, Bellamacina C, Aycinena JA, Zang R, Holash J, Burger MT: Pan-PIM kinase inhibition provides a novel therapy for treating hematologic cancers. Clin Cancer Res. 2014, 20: 1834-1845.PubMed

107.

Chen LS, Redkar S, Bearss D, Wierda WG, Gandhi V: Pim kinase inhibitor, SGI-1776, induces apoptosis in chronic lymphocytic leukemia cells. Blood. 2009, 114: 4150-4157.PubMedCentralPubMed

108.

Chen LS, Redkar S, Taverna P, Cortes JE, Gandhi V: Mechanisms of cytotoxicity to Pim kinase inhibitor, SGI-1776, in acute myeloid leukemia. Blood. 2011, 118: 693-702.PubMedCentralPubMed

109.

Yang Q, Chen LS, Neelapu SS, Miranda RN, Medeiros LJ, Gandhi V: Transcription and translation are primary targets of Pim kinase inhibitor SGI-1776 in mantle cell lymphoma. Blood. 2012, 120: 3491-3500.PubMedCentralPubMed

110.

Hospital MA, Green AS, Lacombe C, Mayeux P, Bouscary D, Tamburini J: The FLT3 and Pim kinases inhibitor SGI-1776 preferentially target FLT3-ITD AML cells. Blood. 2012, 119: 1791-1792.PubMed

111.

Fischer KM, Cottage CT, Konstandin MH, Völkers M, Khan M, Sussman MA: Pim-1 kinase inhibits pathological injury by promoting cardioprotective signaling. J Mol Cell Cardiol. 2011, 51: 554-558.PubMedCentralPubMed

112.

Quijada P, Toko H, Fischer KM, Bailey B, Reilly P, Hunt KD, Gude NA, Avitabile D, Sussman MA: Preservation of myocardial structure is enhanced by pim-1 engineering of bone marrow cells. Circ Res. 2012, 111: 77-86.PubMedCentralPubMed

113.

Lin YW, Beharry ZM, Hill EG, Song JH, Wang W, Xia Z, Zhang Z, Aplan PD, Aster JC, Smith CD, Kraft AS: A small molecule inhibitor of Pim protein kinases blocks the growth of precursor T-cell lymphoblastic leukemia/lymphoma. Blood. 2010, 115: 824-833.PubMedCentralPubMed

114.

Beharry Z, Zemskova M, Mahajan S, Zhang F, Ma J, Xia Z, Lilly M, Smith CD, Kraft AS: Novel benzylidene-thiazolidine-2,4-diones inhibit Pim protein kinase activity and induce cell cycle arrest in leukemia and prostate cancer cells. Mol Cancer Ther. 2009, 8: 1473-1483.PubMedCentralPubMed

115.

Dakin LA, Block MH, Chen H, Code E, Dowling JE, Feng X, Ferguson AD, Green I, Hird AW, Howard T, Keeton EK, Lamb ML, Lyne PD, Pollard H, Read J, Wu AJ, Zhang T, Zheng X: Discovery of novel benzylidene-1,3-thiazolidine-2,4-diones as potent and selective inhibitors of the PIM-1, PIM-2, and PIM-3 protein kinases. Bioorg Med Chem Lett. 2012, 22: 4599-4604.PubMed

116.

Meja K, Stengel C, Sellar R, Huszar D, Davies BR, Gale RE, Linch DC, Khwaja A: PIM and AKT kinase inhibitors show synergistic cytotoxicity in acute myeloid leukaemia that is associated with convergence on mTOR and MCL1 pathways. Br J Haematol. 2014, 167: 69-79.PubMed

117.

Brzózka K, Windak R, Guratowska M, Krawczyńska K, Kłosowska-Wardęga A, Zurawska M, Trębacz E, Sabiniarz A, Czardybon W, Chołody M, Horvath R, Szamborska-Gbur A, Prymula K, Milik M, Kowalczyk P, Rzymski T, Beuzen N: Preclinical development of a Pim kinase inhibitor for cancer treatment. [abstract]. Cancer Res. 2012, 72: s1-

118.

Keeton EK, McEachern K, Dillman KS, Palakurthi S, Cao Y, Grondine MR, Kaur S, Wang S, Chen Y, Wu A, Shen M, Gibbons FD, Lamb ML, Zheng X, Stone RM, Deangelo DJ, Platanias LC, Dakin LA, Chen H, Lyne PD, Huszar D: AZD1208, a potent and selective pan-Pim kinase inhibitor, demonstrates efficacy in preclinical models of acute myeloid leukemia. Blood. 2014, 123: 905-913.PubMedCentralPubMed

119.

Fathi AT, Arowojolu O, Swinnen I, Sato T, Rajkhowa T, Small D, Marmsater F, Robinson JE, Gross SD, Martinson M, Allen S, Kallan NC, Levis M: A potential therapeutic target for FLT3-ITD AML: PIM1 kinase. Leuk Res. 2012, 36: 224-231.PubMedCentralPubMed

Title: Pim kinases in hematological malignancies: where are we now and where are we going?
Authors: Patrizia Mondello
Salvatore Cuzzocrea
Michael Mian
Publication date: 01-12-2014
Publisher: BioMed Central
Published in: Journal of Hematology & Oncology / Issue 1/2014
Electronic ISSN: 1756-8722
DOI: https://doi.org/10.1186/s13045-014-0095-z

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