Acute myeloid leukemia (AML), caused by abnormal proliferation and accumulation of hematopoietic progenitor cells, is one of the most common malignancies in adults. We reported here DYRK1A expression level was reduced in the bone marrow of adult AML patients, comparing to normal controls. Overexpression of DYRK1A inhibited the proliferation of AML cell lines by increasing the proportion of cells undergoing G0/G1 phase. We reasoned that the proliferative inhibition was due to downregulation of c-Myc by DYRK1A, through mediating its degradation. Moreover, overexpression of c-Myc markedly reversed AML cell growth inhibition induced by DYRK1A. DYRK1A also had significantly lower expression in relapsed/refractory AML patients, comparing to newly-diagnosed AML patients, which indicated the role of DYRK1A in chemoresistance of AML. Our study provided functional evidences for DYRK1A as a potential tumor suppressor in AML.
References
[1]
Oran B, Weisdorf DJ (2012) Survival for older patients with acute myeloid leukemia: a population-based study. Haematologica 97: 1916–1924. doi: 10.3324/haematol.2012.066100
[2]
Pulte D, Redaniel MT, Jansen L, Brenner H, Jeffreys M (2013) Recent trends in survival of adult patients with acute leukemia: overall improvements, but persistent and partly increasing disparity in survival of patients from minority groups. Haematologica 98: 222–229. doi: 10.3324/haematol.2012.063602
[3]
Licht JD, Sternberg DW (2005) The molecular pathology of acute myeloid leukemia. Hematology Am Soc Hematol Educ Program: 137–142.
[4]
Becker W, Weber Y, Wetzel K, Eirmbter K, Tejedor FJ, et al. (1998) Sequence characteristics, subcellular localization, and substrate specificity of DYRK-related kinases, a novel family of dual specificity protein kinases. J Biol Chem 273: 25893–25902. doi: 10.1074/jbc.273.40.25893
[5]
Yoshida K (2008) Role for DYRK family kinases on regulation of apoptosis. Biochem Pharmacol 76: 1389–1394. doi: 10.1016/j.bcp.2008.05.021
[6]
Aranda S, Laguna A, de la Luna S (2011) DYRK family of protein kinases: evolutionary relationships, biochemical properties, and functional roles. FASEB J 25: 449–462. doi: 10.1096/fj.10-165837
[7]
Taira N, Nihira K, Yamaguchi T, Miki Y, Yoshida K (2007) DYRK2 is targeted to the nucleus and controls p53 via Ser46 phosphorylation in the apoptotic response to DNA damage. Mol Cell 25: 725–738. doi: 10.1016/j.molcel.2007.02.007
[8]
Gwack Y, Sharma S, Nardone J, Tanasa B, Iuga A, et al. (2006) A genome-wide Drosophila RNAi screen identifies DYRK-family kinases as regulators of NFAT. Nature 441: 646–650. doi: 10.1038/nature04631
[9]
Arron JR, Winslow MM, Polleri A, Chang CP, Wu H, et al. (2006) NFAT dysregulation by increased dosage of DSCR1 and DYRK1A on chromosome 21. Nature 441: 595–600. doi: 10.1038/nature04678
[10]
Yiu GK, Toker A (2006) NFAT induces breast cancer cell invasion by promoting the induction of cyclooxygenase-2. J Biol Chem 281: 12210–12217. doi: 10.1074/jbc.m600184200
[11]
Gregory MA, Phang TL, Neviani P, Alvarez-Calderon F, Eide CA, et al. (2010) Wnt/Ca2+/NFAT signaling maintains survival of Ph+ leukemia cells upon inhibition of Bcr-Abl. Cancer Cell 18: 74–87. doi: 10.1016/j.ccr.2010.04.025
[12]
Altafaj X, Dierssen M, Baamonde C, Marti E, Visa J, et al. (2001) Neurodevelopmental delay, motor abnormalities and cognitive deficits in transgenic mice overexpressing Dyrk1A (minibrain), a murine model of Down's syndrome. Hum Mol Genet 10: 1915–1923. doi: 10.1093/hmg/10.18.1915
[13]
Park J, Song WJ, Chung KC (2009) Function and regulation of Dyrk1A: towards understanding Down syndrome. Cell Mol Life Sci 66: 3235–3240. doi: 10.1007/s00018-009-0123-2
[14]
Satge D, Sasco AJ, Carlsen NL, Stiller CA, Rubie H, et al. (1998) A lack of neuroblastoma in Down syndrome: a study from 11 European countries. Cancer Res 58: 448–452.
[15]
Malinge S, Izraeli S, Crispino JD (2009) Insights into the manifestations, outcomes, and mechanisms of leukemogenesis in Down syndrome. Blood 113: 2619–2628. doi: 10.1182/blood-2008-11-163501
[16]
Birger Y, Izraeli S (2012) DYRK1A in Down syndrome: an oncogene or tumor suppressor? J Clin Invest 122: 807–810. doi: 10.1172/jci62372
[17]
Lu M, Zheng L, Han B, Wang L, Wang P, et al. (2011) REST regulates DYRK1A transcription in a negative feedback loop. J Biol Chem 286: 10755–10763. doi: 10.1074/jbc.m110.174540
[18]
Adams JM, Harris AW, Pinkert CA, Corcoran LM, Alexander WS, et al. (1985) The c-myc oncogene driven by immunoglobulin enhancers induces lymphoid malignancy in transgenic mice. Nature 318: 533–538. doi: 10.1038/318533a0
[19]
Nesbit CE, Tersak JM, Prochownik EV (1999) MYC oncogenes and human neoplastic disease. Oncogene 18: 3004–3016. doi: 10.1038/sj.onc.1202746
[20]
Zhang J, Ma D, Ye J, Zang S, Lu F, et al. (2012) Prognostic impact of delta-like ligand 4 and Notch1 in acute myeloid leukemia. Oncol Rep 28: 1503–1511. doi: 10.3892/or.2012.1943
[21]
Welcker M, Orian A, Jin J, Grim JE, Harper JW, et al. (2004) The Fbw7 tumor suppressor regulates glycogen synthase kinase 3 phosphorylation-dependent c-Myc protein degradation. Proc Natl Acad Sci U S A 101: 9085–9090. doi: 10.1073/pnas.0402770101
[22]
Jung MS, Park JH, Ryu YS, Choi SH, Yoon SH, et al. (2011) Regulation of RCAN1 protein activity by Dyrk1A protein-mediated phosphorylation. J Biol Chem 286: 40401–40412. doi: 10.1074/jbc.m111.253971
[23]
Scales TM, Lin S, Kraus M, Goold RG, Gordon-Weeks PR (2009) Nonprimed and DYRK1A-primed GSK3 beta-phosphorylation sites on MAP1B regulate microtubule dynamics in growing axons. J Cell Sci 122: 2424–2435. doi: 10.1242/jcs.040162
[24]
Kurabayashi N, Hirota T, Sakai M, Sanada K, Fukada Y (2010) DYRK1A and glycogen synthase kinase 3beta, a dual-kinase mechanism directing proteasomal degradation of CRY2 for circadian timekeeping. Mol Cell Biol 30: 1757–1768. doi: 10.1128/mcb.01047-09
[25]
Chen JY, Lin JR, Tsai FC, Meyer T (2013) Dosage of Dyrk1a shifts cells within a p21-cyclin D1 signaling map to control the decision to enter the cell cycle. Mol Cell 52: 87–100. doi: 10.1016/j.molcel.2013.09.009
[26]
Hammerle B, Ulin E, Guimera J, Becker W, Guillemot F, et al. (2011) Transient expression of Mnb/Dyrk1a couples cell cycle exit and differentiation of neuronal precursors by inducing p27KIP1 expression and suppressing NOTCH signaling. Development 138: 2543–2554. doi: 10.1242/dev.066167
[27]
Park J, Oh Y, Yoo L, Jung MS, Song WJ, et al. (2010) Dyrk1A phosphorylates p53 and inhibits proliferation of embryonic neuronal cells. J Biol Chem 285: 31895–31906. doi: 10.1074/jbc.m110.147520
[28]
Litovchick L, Florens LA, Swanson SK, Washburn MP, DeCaprio JA (2011) DYRK1A protein kinase promotes quiescence and senescence through DREAM complex assembly. Genes Dev 25: 801–813. doi: 10.1101/gad.2034211
[29]
Ruggero D, Montanaro L, Ma L, Xu W, Londei P, et al. (2004) The translation factor eIF-4E promotes tumor formation and cooperates with c-Myc in lymphomagenesis. Nat Med 10: 484–486. doi: 10.1038/nm1042
[30]
Reavie L, Buckley SM, Loizou E, Takeishi S, Aranda-Orgilles B, et al. (2013) Regulation of c-Myc ubiquitination controls chronic myelogenous leukemia initiation and progression. Cancer Cell 23: 362–375. doi: 10.1016/j.ccr.2013.01.025
[31]
Mateyak MK, Obaya AJ, Adachi S, Sedivy JM (1997) Phenotypes of c-Myc-deficient rat fibroblasts isolated by targeted homologous recombination. Cell Growth Differ 8: 1039–1048.
[32]
Adhikary S, Eilers M (2005) Transcriptional regulation and transformation by Myc proteins. Nat Rev Mol Cell Biol 6: 635–645. doi: 10.1038/nrm1703
[33]
Daksis JI, Lu RY, Facchini LM, Marhin WW, Penn LJ (1994) Myc induces cyclin D1 expression in the absence of de novo protein synthesis and links mitogen-stimulated signal transduction to the cell cycle. Oncogene 9: 3635–3645.
[34]
Seoane J, Le HV, Massague J (2002) Myc suppression of the p21(Cip1) Cdk inhibitor influences the outcome of the p53 response to DNA damage. Nature 419: 729–734. doi: 10.1038/nature01119
[35]
Du J, Widlund HR, Horstmann MA, Ramaswamy S, Ross K, et al. (2004) Critical role of CDK2 for melanoma growth linked to its melanocyte-specific transcriptional regulation by MITF. Cancer Cell 6: 565–576. doi: 10.1016/j.ccr.2004.10.014
[36]
Xie RL, Gupta S, Miele A, Shiffman D, Stein JL, et al. (2003) The tumor suppressor interferon regulatory factor 1 interferes with SP1 activation to repress the human CDK2 promoter. J Biol Chem 278: 26589–26596. doi: 10.1074/jbc.m301491200
[37]
de Wit NJ, Burtscher HJ, Weidle UH, Ruiter DJ, van Muijen GN (2002) Differentially expressed genes identified in human melanoma cell lines with different metastatic behaviour using high density oligonucleotide arrays. Melanoma Res 12: 57–69. doi: 10.1097/00008390-200202000-00009
[38]
Teague TK, Hildeman D, Kedl RM, Mitchell T, Rees W, et al. (1999) Activation changes the spectrum but not the diversity of genes expressed by T cells. Proc Natl Acad Sci U S A 96: 12691–12696. doi: 10.1073/pnas.96.22.12691
[39]
Hammerle B, Vera-Samper E, Speicher S, Arencibia R, Martinez S, et al. (2002) Mnb/Dyrk1A is transiently expressed and asymmetrically segregated in neural progenitor cells at the transition to neurogenic divisions. Dev Biol 246: 259–273. doi: 10.1006/dbio.2002.0675
[40]
Jung P, Menssen A, Mayr D, Hermeking H (2008) AP4 encodes a c-MYC-inducible repressor of p21. Proc Natl Acad Sci U S A 105: 15046–15051. doi: 10.1073/pnas.0801773105
[41]
Kim MY, Jeong BC, Lee JH, Kee HJ, Kook H, et al. (2006) A repressor complex, AP4 transcription factor and geminin, negatively regulates expression of target genes in nonneuronal cells. Proc Natl Acad Sci U S A 103: 13074–13079. doi: 10.1073/pnas.0601915103
[42]
Maenz B, Hekerman P, Vela EM, Galceran J, Becker W (2008) Characterization of the human DYRK1A promoter and its regulation by the transcription factor E2F1. BMC Mol Biol 9: 30. doi: 10.1186/1471-2199-9-30
[43]
Strom DK, Cleveland JL, Chellappan S, Nip J, Hiebert SW (1998) E2F-1 and E2F-3 are functionally distinct in their ability to promote myeloid cell cycle progression and block granulocyte differentiation. Cell Growth Differ 9: 59–69.
[44]
Lee Y, Ha J, Kim HJ, Kim YS, Chang EJ, et al. (2009) Negative feedback Inhibition of NFATc1 by DYRK1A regulates bone homeostasis. J Biol Chem 284: 33343–33351. doi: 10.1074/jbc.m109.042234
[45]
Reddy BY, Greco SJ, Patel PS, Trzaska KA, Rameshwar P (2009) RE-1-silencing transcription factor shows tumor-suppressor functions and negatively regulates the oncogenic TAC1 in breast cancer cells. Proc Natl Acad Sci U S A 106: 4408–4413. doi: 10.1073/pnas.0809130106
[46]
Wagoner MP, Gunsalus KT, Schoenike B, Richardson AL, Friedl A, et al. (2010) The transcription factor REST is lost in aggressive breast cancer. PLoS Genet 6: e1000979. doi: 10.1371/journal.pgen.1000979