NPM and NPM-MLF1 interact with chromatin remodeling complexes and influence their recruitment to specific genes

Autoři: Anaïs Darracq aff001;  Helen Pak aff001;  Vincent Bourgoin aff001;  Farah Zmiri aff001;  Graham Dellaire aff003;  El Bachir Affar aff001;  Eric Milot aff001
Působiště autorů: Maisonneuve Rosemont Hospital Research Center, CIUSSS Est de l’Île de Montréal, boulevard l’Assomption, Montreal, Quebec, Canada aff001;  Molecular Biology Program, University of Montreal, Montreal, Quebec, Canada aff002;  Departments of Pathology and Biochemistry & Molecular Biology, Dalhousie University, Halifax, Nova Scotia, Canada aff003;  Department of Medicine, University of Montreal, Boulevard Edouard-Montpetit, Montréal, Quebec, Canada, Montreal, Quebec, Canada aff004
Vyšlo v časopise: NPM and NPM-MLF1 interact with chromatin remodeling complexes and influence their recruitment to specific genes. PLoS Genet 15(11): e32767. doi:10.1371/journal.pgen.1008463
Kategorie: Research Article


Nucleophosmin (NPM1) is frequently mutated or subjected to chromosomal translocation in acute myeloid leukemia (AML). NPM protein is primarily located in the nucleus, but the recurrent NPMc+ mutation, which creates a nuclear export signal, is characterized by cytoplasmic localization and leukemogenic properties. Similarly, the NPM-MLF1 translocation product favors the partial cytoplasmic retention of NPM. Regardless of their common cellular distribution, NPM-MLF1 malignancies engender different effects on hematopoiesis compared to NPMc+ counterparts, highlighting possible aberrant nuclear function(s) of NPM in NPMc+ and NPM-MLF1 AML. We performed a proteomic analysis and found that NPM and NPM-MLF1 interact with various nuclear proteins including subunits of the chromatin remodeling complexes ISWI, NuRD and P/BAF. Accordingly, NPM and NPM-MLF1 are recruited to transcriptionally active or repressed genes along with NuRD subunits. Although the overall gene expression program in NPM knockdown cells is similar to that resulting from NPMc+, NPM-MLF1 expression differentially altered gene transcription regulated by NPM. The abnormal gene regulation imposed by NPM-MLF1 can be characterized by the enhanced recruitment of NuRD to gene regulatory regions. Thus, different mechanisms would orchestrate the dysregulation of NPM function in NPMc+- versus NPM1-MLF1-associated leukemia.

Klíčová slova:

Acute myeloid leukemia – Antibodies – Co-immunoprecipitation – DNA transcription – Gene expression – Gene regulation – Chromatin – Transcriptional control


1. Fraga MF, Esteller M. Towards the human cancer epigenome: a first draft of histone modifications. Cell Cycle. 2005;4(10):1377–81. doi: 10.4161/cc.4.10.2113 16205112.

2. Valk-Lingbeek ME, Bruggeman SW, van Lohuizen M. Stem cells and cancer; the polycomb connection. Cell. 2004;118(4):409–18. doi: 10.1016/j.cell.2004.08.005 15315754.

3. Falini B, Mecucci C, Tiacci E, Alcalay M, Rosati R, Pasqualucci L, et al. Cytoplasmic nucleophosmin in acute myelogenous leukemia with a normal karyotype. N Engl J Med. 2005;352(3):254–66. doi: 10.1056/NEJMoa041974 15659725.

4. Verhaak RG, Goudswaard CS, van Putten W, Bijl MA, Sanders MA, Hugens W, et al. Mutations in nucleophosmin (NPM1) in acute myeloid leukemia (AML): association with other gene abnormalities and previously established gene expression signatures and their favorable prognostic significance. Blood. 2005;106(12):3747–54. doi: 10.1182/blood-2005-05-2168 16109776.

5. Alcalay M, Tiacci E, Bergomas R, Bigerna B, Venturini E, Minardi SP, et al. Acute myeloid leukemia bearing cytoplasmic nucleophosmin (NPMc+ AML) shows a distinct gene expression profile characterized by up-regulation of genes involved in stem-cell maintenance. Blood. 2005;106(3):899–902. doi: 10.1182/blood-2005-02-0560 15831697.

6. Grisendi S, Mecucci C, Falini B, Pandolfi PP. Nucleophosmin and cancer. Nat Rev Cancer. 2006;6(7):493–505. doi: 10.1038/nrc1885 16794633.

7. Chen S, Maya-Mendoza A, Zeng K, Tang CW, Sims PF, Loric J, et al. Interaction with checkpoint kinase 1 modulates the recruitment of nucleophosmin to chromatin. J Proteome Res. 2009;8(10):4693–704. doi: 10.1021/pr900396d 19694479.

8. Nichol JN, Galbraith MD, Kleinman CL, Espinosa JM, Miller WH Jr. NPM and BRG1 Mediate Transcriptional Resistance to Retinoic Acid in Acute Promyelocytic Leukemia. Cell Rep. 2016;14(12):2938–49. doi: 10.1016/j.celrep.2016.02.074 26997274; PubMed Central PMCID: PMC4814328.

9. Swaminathan V, Kishore AH, Febitha KK, Kundu TK. Human histone chaperone nucleophosmin enhances acetylation-dependent chromatin transcription. Mol Cell Biol. 2005;25(17):7534–45. doi: 10.1128/MCB.25.17.7534-7545.2005 16107701; PubMed Central PMCID: PMC1190275.

10. Leotoing L, Meunier L, Manin M, Mauduit C, Decaussin M, Verrijdt G, et al. Influence of nucleophosmin/B23 on DNA binding and transcriptional activity of the androgen receptor in prostate cancer cell. Oncogene. 2008;27(20):2858–67. doi: 10.1038/sj.onc.1210942 18037965.

11. Liu H, Tan BC, Tseng KH, Chuang CP, Yeh CW, Chen KD, et al. Nucleophosmin acts as a novel AP2alpha-binding transcriptional corepressor during cell differentiation. EMBO Rep. 2007;8(4):394–400. doi: 10.1038/sj.embor.7400909 17318229; PubMed Central PMCID: PMC1852768.

12. Todd MA, Picketts DJ. PHF6 interacts with the nucleosome remodeling and deacetylation (NuRD) complex. J Proteome Res. 2012;11(8):4326–37. doi: 10.1021/pr3004369 22720776.

13. Hammond CM, Stromme CB, Huang H, Patel DJ, Groth A. Histone chaperone networks shaping chromatin function. Nat Rev Mol Cell Biol. 2017;18(3):141–58. doi: 10.1038/nrm.2016.159 28053344; PubMed Central PMCID: PMC5319910.

14. Lin J, Kato M, Nagata K, Okuwaki M. Efficient DNA binding of NF-kappaB requires the chaperone-like function of NPM1. Nucleic Acids Res. 2017;45(7):3707–23. doi: 10.1093/nar/gkw1285 28003476; PubMed Central PMCID: PMC5397172.

15. Colombo E, Bonetti P, Lazzerini Denchi E, Martinelli P, Zamponi R, Marine JC, et al. Nucleophosmin is required for DNA integrity and p19Arf protein stability. Mol Cell Biol. 2005;25(20):8874–86. doi: 10.1128/MCB.25.20.8874-8886.2005 16199867; PubMed Central PMCID: PMC1265791.

16. Falini B, Bigerna B, Pucciarini A, Tiacci E, Mecucci C, Morris SW, et al. Aberrant subcellular expression of nucleophosmin and NPM-MLF1 fusion protein in acute myeloid leukaemia carrying t(3;5): a comparison with NPMc+ AML. Leukemia. 2006;20(2):368–71. doi: 10.1038/sj.leu.2404068 16341033.

17. Raimondi SC, Dube ID, Valentine MB, Mirro J Jr., Watt HJ, Larson RA, et al. Clinicopathologic manifestations and breakpoints of the t(3;5) in patients with acute nonlymphocytic leukemia. Leukemia. 1989;3(1):42–7. 2642576.

18. Xue Y, Wong J, Moreno GT, Young MK, Cote J, Wang W. NURD, a novel complex with both ATP-dependent chromatin-remodeling and histone deacetylase activities. Mol Cell. 1998;2(6):851–61. doi: 10.1016/s1097-2765(00)80299-3 9885572.

19. Hodges C, Kirkland JG, Crabtree GR. The Many Roles of BAF (mSWI/SNF) and PBAF Complexes in Cancer. Cold Spring Harb Perspect Med. 2016;6(8). doi: 10.1101/cshperspect.a026930 27413115; PubMed Central PMCID: PMC4968166.

20. Kadoch C, Crabtree GR. Mammalian SWI/SNF chromatin remodeling complexes and cancer: Mechanistic insights gained from human genomics. Sci Adv. 2015;1(5):e1500447. doi: 10.1126/sciadv.1500447 26601204; PubMed Central PMCID: PMC4640607.

21. Hota SK, Bruneau BG. ATP-dependent chromatin remodeling during mammalian development. Development. 2016;143(16):2882–97. doi: 10.1242/dev.128892 27531948; PubMed Central PMCID: PMC5004879.

22. Oppikofer M, Bai T, Gan Y, Haley B, Liu P, Sandoval W, et al. Expansion of the ISWI chromatin remodeler family with new active complexes. EMBO Rep. 2017;18(10):1697–706. doi: 10.15252/embr.201744011 28801535; PubMed Central PMCID: PMC5623870.

23. Quentmeier H, Martelli MP, Dirks WG, Bolli N, Liso A, Macleod RA, et al. Cell line OCI/AML3 bears exon-12 NPM gene mutation-A and cytoplasmic expression of nucleophosmin. Leukemia. 2005;19(10):1760–7. doi: 10.1038/sj.leu.2403899 16079892.

24. Brunetti L, Gundry MC, Sorcini D, Guzman AG, Huang YH, Ramabadran R, et al. Mutant NPM1 Maintains the Leukemic State through HOX Expression. Cancer Cell. 2018;34(3):499–512 e9. Epub 2018/09/12. doi: 10.1016/j.ccell.2018.08.005 30205049; PubMed Central PMCID: PMC6159911.

25. Hanissian SH, Akbar U, Teng B, Janjetovic Z, Hoffmann A, Hitzler JK, et al. cDNA cloning and characterization of a novel gene encoding the MLF1-interacting protein MLF1IP. Oncogene. 2004;23(20):3700–7. doi: 10.1038/sj.onc.1207448 15116101.

26. Winteringham LN, Kobelke S, Williams JH, Ingley E, Klinken SP. Myeloid Leukemia Factor 1 inhibits erythropoietin-induced differentiation, cell cycle exit and p27Kip1 accumulation. Oncogene. 2004;23(29):5105–9. doi: 10.1038/sj.onc.1207661 15122318.

27. Bottardi S, Mavoungou L, Pak H, Daou S, Bourgoin V, Lakehal YA, et al. The IKAROS interaction with a complex including chromatin remodeling and transcription elongation activities is required for hematopoiesis. PLoS Genet. 2014;10(12):e1004827. doi: 10.1371/journal.pgen.1004827 25474253; PubMed Central PMCID: PMC4256266.

28. Daou S, Hammond-Martel I, Mashtalir N, Barbour H, Gagnon J, Iannantuono NV, et al. The BAP1/ASXL2 Histone H2A Deubiquitinase Complex Regulates Cell Proliferation and Is Disrupted in Cancer. J Biol Chem. 2015;290(48):28643–63. doi: 10.1074/jbc.M115.661553 26416890; PubMed Central PMCID: PMC4661380.

29. Bozhenok L, Wade PA, Varga-Weisz P. WSTF-ISWI chromatin remodeling complex targets heterochromatic replication foci. EMBO J. 2002;21(9):2231–41. doi: 10.1093/emboj/21.9.2231 11980720; PubMed Central PMCID: PMC125993.

30. Corona DF, Tamkun JW. Multiple roles for ISWI in transcription, chromosome organization and DNA replication. Biochim Biophys Acta. 2004;1677(1–3):113–9. doi: 10.1016/j.bbaexp.2003.09.018 15020052.

31. Blonska M, Lin X. NF-kappaB signaling pathways regulated by CARMA family of scaffold proteins. Cell Res. 2011;21(1):55–70. doi: 10.1038/cr.2010.182 21187856; PubMed Central PMCID: PMC3193407.

32. Yang M, Shao JH, Miao YJ, Cui W, Qi YF, Han JH, et al. Tumor cell-activated CARD9 signaling contributes to metastasis-associated macrophage polarization. Cell Death Differ. 2014;21(8):1290–302. doi: 10.1038/cdd.2014.45 24722209; PubMed Central PMCID: PMC4085533.

33. Fidler C, Strickson A, Boultwood J, Waincoat JS. Mutation analysis of the SPARC gene in the 5q-syndrome. Am J Hematol. 2000;64(4):324. doi: 10.1002/1096-8652(200008)64:4<324::aid-ajh19>;2-6 10911392.

34. DiMartino JF, Lacayo NJ, Varadi M, Li L, Saraiya C, Ravindranath Y, et al. Low or absent SPARC expression in acute myeloid leukemia with MLL rearrangements is associated with sensitivity to growth inhibition by exogenous SPARC protein. Leukemia. 2006;20(3):426–32. doi: 10.1038/sj.leu.2404102 16424866.

35. Fenouille N, Puissant A, Dufies M, Robert G, Jacquel A, Ohanna M, et al. Persistent activation of the Fyn/ERK kinase signaling axis mediates imatinib resistance in chronic myelogenous leukemia cells through upregulation of intracellular SPARC. Cancer Res. 2010;70(23):9659–70. doi: 10.1158/0008-5472.CAN-10-2034 21098700.

36. Framson PE, Sage EH. SPARC and tumor growth: where the seed meets the soil? J Cell Biochem. 2004;92(4):679–90. Epub 2004/06/24. doi: 10.1002/jcb.20091 15211566.

37. Ishibashi K, Suzuki M, Sasaki S, Imai M. Identification of a new multigene four-transmembrane family (MS4A) related to CD20, HTm4 and beta subunit of the high-affinity IgE receptor. Gene. 2001;264(1):87–93. Epub 2001/03/14. doi: 10.1016/s0378-1119(00)00598-9 11245982.

38. Hinai AA, Valk PJ. Review: Aberrant EVI1 expression in acute myeloid leukaemia. Br J Haematol. 2016;172(6):870–8. doi: 10.1111/bjh.13898 26729571.

39. Heller G, Rommer A, Steinleitner K, Etzler J, Hackl H, Heffeter P, et al. EVI1 promotes tumor growth via transcriptional repression of MS4A3. J Hematol Oncol. 2015;8:28. doi: 10.1186/s13045-015-0124-6 25886616; PubMed Central PMCID: PMC4389965.

40. Hu G, Wade PA. NuRD and pluripotency: a complex balancing act. Cell Stem Cell. 2012;10(5):497–503. doi: 10.1016/j.stem.2012.04.011 22560073; PubMed Central PMCID: PMC3348611.

41. Bottardi S, Mavoungou L, Milot E. IKAROS: a multifunctional regulator of the polymerase II transcription cycle. Trends Genet. 2015;31(9):500–8. doi: 10.1016/j.tig.2015.05.003 26049627.

42. Brown SA, Imbalzano AN, Kingston RE. Activator-dependent regulation of transcriptional pausing on nucleosomal templates. Genes Dev. 1996;10(12):1479–90. doi: 10.1101/gad.10.12.1479 8666232.

43. Corey LL, Weirich CS, Benjamin IJ, Kingston RE. Localized recruitment of a chromatin-remodeling activity by an activator in vivo drives transcriptional elongation. Genes Dev. 2003;17(11):1392–401. doi: 10.1101/gad.1071803 12782657; PubMed Central PMCID: PMC196071.

44. Zhou VW, Goren A, Bernstein BE. Charting histone modifications and the functional organization of mammalian genomes. Nat Rev Genet. 2011;12(1):7–18. doi: 10.1038/nrg2905 21116306.

45. Lesch BJ, Page DC. Poised chromatin in the mammalian germ line. Development. 2014;141(19):3619–26. doi: 10.1242/dev.113027 25249456; PubMed Central PMCID: PMC4197577.

46. Bernstein BE, Mikkelsen TS, Xie X, Kamal M, Huebert DJ, Cuff J, et al. A bivalent chromatin structure marks key developmental genes in embryonic stem cells. Cell. 2006;125(2):315–26. Epub 2006/04/25. doi: 10.1016/j.cell.2006.02.041 16630819.

47. Luo Z, Lin C, Shilatifard A. The super elongation complex (SEC) family in transcriptional control. Nat Rev Mol Cell Biol. 2012;13(9):543–7. Epub 2012/08/17. doi: 10.1038/nrm3417 nrm3417 [pii]. 22895430.

48. Kwak H, Lis JT. Control of transcriptional elongation. Annu Rev Genet. 2013;47:483–508. doi: 10.1146/annurev-genet-110711-155440 24050178; PubMed Central PMCID: PMC3974797.

49. Balusu R, Fiskus W, Rao R, Chong DG, Nalluri S, Mudunuru U, et al. Targeting levels or oligomerization of nucleophosmin 1 induces differentiation and loss of survival of human AML cells with mutant NPM1. Blood. 2011;118(11):3096–106. Epub 2011/07/02. blood-2010-09-309674 [pii] doi: 10.1182/blood-2010-09-309674 21719597.

50. Li X, Xu DH, Liu F, Liu GY, Lu K, Deng XL, et al. Relocation of NPM Affects the Malignant Phenotypes of Hepatoma SMMC-7721 Cells. J Cell Biochem. 2017;118(10):3225–36. doi: 10.1002/jcb.25971 28262969.

51. Hein MY, Hubner NC, Poser I, Cox J, Nagaraj N, Toyoda Y, et al. A human interactome in three quantitative dimensions organized by stoichiometries and abundances. Cell. 2015;163(3):712–23. doi: 10.1016/j.cell.2015.09.053 26496610.

52. Dykhuizen EC, Hargreaves DC, Miller EL, Cui K, Korshunov A, Kool M, et al. BAF complexes facilitate decatenation of DNA by topoisomerase IIalpha. Nature. 2013;497(7451):624–7. doi: 10.1038/nature12146 23698369; PubMed Central PMCID: PMC3668793.

53. Miller EL, Hargreaves DC, Kadoch C, Chang CY, Calarco JP, Hodges C, et al. TOP2 synergizes with BAF chromatin remodeling for both resolution and formation of facultative heterochromatin. Nat Struct Mol Biol. 2017;24(4):344–52. doi: 10.1038/nsmb.3384 28250416; PubMed Central PMCID: PMC5395302.

54. Banuelos S, Lectez B, Taneva SG, Ormaza G, Alonso-Marino M, Calle X, et al. Recognition of intermolecular G-quadruplexes by full length nucleophosmin. Effect of a leukaemia-associated mutation. FEBS Lett. 2013;587(14):2254–9. Epub 2013/06/08. doi: 10.1016/j.febslet.2013.05.055 23742937.

55. King HW, Klose RJ. The pioneer factor OCT4 requires the chromatin remodeller BRG1 to support gene regulatory element function in mouse embryonic stem cells. Elife. 2017;6. doi: 10.7554/eLife.22631 28287392; PubMed Central PMCID: PMC5400504.

56. Bottardi S, Ross J, Bourgoin V, Fotouhi-Ardakani N, Affar el B, Trudel M, et al. Ikaros and GATA-1 combinatorial effect is required for silencing of human gamma-globin genes. Mol Cell Biol. 2009;29(6):1526–37. doi: 10.1128/MCB.01523-08 19114560; PubMed Central PMCID: PMC2648246.

57. Mohd-Sarip A, Teeuwssen M, Bot AG, De Herdt MJ, Willems SM, Baatenburg de Jong RJ, et al. DOC1-Dependent Recruitment of NURD Reveals Antagonism with SWI/SNF during Epithelial-Mesenchymal Transition in Oral Cancer Cells. Cell Rep. 2017;20(1):61–75. doi: 10.1016/j.celrep.2017.06.020 28683324.

58. Bornelov S, Reynolds N, Xenophontos M, Gharbi S, Johnstone E, Floyd R, et al. The Nucleosome Remodeling and Deacetylation Complex Modulates Chromatin Structure at Sites of Active Transcription to Fine-Tune Gene Expression. Mol Cell. 2018;71(1):56–72 e4. doi: 10.1016/j.molcel.2018.06.003 30008319; PubMed Central PMCID: PMC6039721.

59. Ho L, Miller EL, Ronan JL, Ho WQ, Jothi R, Crabtree GR. esBAF facilitates pluripotency by conditioning the genome for LIF/STAT3 signalling and by regulating polycomb function. Nat Cell Biol. 2011;13(8):903–13. doi: 10.1038/ncb2285 21785422; PubMed Central PMCID: PMC3155811.

60. Li Y, Schulz VP, Deng C, Li G, Shen Y, Tusi BK, et al. Setd1a and NURF mediate chromatin dynamics and gene regulation during erythroid lineage commitment and differentiation. Nucleic Acids Res. 2016;44(15):7173–88. doi: 10.1093/nar/gkw327 27141965; PubMed Central PMCID: PMC5009724.

61. Tsukiyama T, Palmer J, Landel CC, Shiloach J, Wu C. Characterization of the imitation switch subfamily of ATP-dependent chromatin-remodeling factors in Saccharomyces cerevisiae. Genes Dev. 1999;13(6):686–97. doi: 10.1101/gad.13.6.686 10090725; PubMed Central PMCID: PMC316555.

62. Shilatifard A. Chromatin modifications by methylation and ubiquitination: implications in the regulation of gene expression. Annu Rev Biochem. 2006;75:243–69. doi: 10.1146/annurev.biochem.75.103004.142422 16756492.

63. Lin C, Smith ER, Takahashi H, Lai KC, Martin-Brown S, Florens L, et al. AFF4, a component of the ELL/P-TEFb elongation complex and a shared subunit of MLL chimeras, can link transcription elongation to leukemia. Mol Cell. 2010;37(3):429–37. doi: 10.1016/j.molcel.2010.01.026 20159561; PubMed Central PMCID: PMC2872029.

64. Gurumurthy M, Tan CH, Ng R, Zeiger L, Lau J, Lee J, et al. Nucleophosmin interacts with HEXIM1 and regulates RNA polymerase II transcription. J Mol Biol. 2008;378(2):302–17. doi: 10.1016/j.jmb.2008.02.055 18371977.

65. Yoshida T, Hazan I, Zhang J, Ng SY, Naito T, Snippert HJ, et al. The role of the chromatin remodeler Mi-2beta in hematopoietic stem cell self-renewal and multilineage differentiation. Genes Dev. 2008;22(9):1174–89. doi: 10.1101/gad.1642808 18451107; PubMed Central PMCID: PMC2335314.

66. Zhang J, Jackson AF, Naito T, Dose M, Seavitt J, Liu F, et al. Harnessing of the nucleosome-remodeling-deacetylase complex controls lymphocyte development and prevents leukemogenesis. Nat Immunol. 2011;13(1):86–94. doi: 10.1038/ni.2150 22080921; PubMed Central PMCID: PMC3868219.

67. Shi J, Whyte WA, Zepeda-Mendoza CJ, Milazzo JP, Shen C, Roe JS, et al. Role of SWI/SNF in acute leukemia maintenance and enhancer-mediated Myc regulation. Genes Dev. 2013;27(24):2648–62. doi: 10.1101/gad.232710.113 24285714; PubMed Central PMCID: PMC3877755.

68. Nakatani Y, Ogryzko V. Immunoaffinity purification of mammalian protein complexes. Methods Enzymol. 2003;370:430–44. doi: 10.1016/S0076-6879(03)70037-8 14712665.

69. Shah GM, Shah RG, Poirier GG. Different cleavage pattern for poly(ADP-ribose) polymerase during necrosis and apoptosis in HL-60 cells. Biochem Biophys Res Commun. 1996;229(3):838–44. doi: 10.1006/bbrc.1996.1889 8954981.

70. Fuzesi-Levi MG, Ben-Nissan G, Bianchi E, Zhou H, Deery MJ, Lilley KS, et al. Dynamic regulation of the COP9 signalosome in response to DNA damage. Mol Cell Biol. 2014;34(6):1066–76. doi: 10.1128/MCB.01598-13 24421388; PubMed Central PMCID: PMC3958043.

71. Vizcaino JA, Cote RG, Csordas A, Dianes JA, Fabregat A, Foster JM, et al. The PRoteomics IDEntifications (PRIDE) database and associated tools: status in 2013. Nucleic Acids Res. 2013;41(Database issue):D1063–9. Epub 2012/12/04. doi: 10.1093/nar/gks1262 23203882; PubMed Central PMCID: PMC3531176.

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