Skip to main content
Hauptrubriken
CME Facharzt-Training Webinare Zeitschriften Bücher e.Medpedia Podcast
Service
Jobbörse Info & Hilfe
Fachgebiete
Anästhesiologie Allgemeinmedizin Arbeitsmedizin Augenheilkunde Chirurgie Dermatologie Gynäkologie und Geburtshilfe HNO Innere Medizin Kardiologie Neurologie Onkologie und Hämatologie Orthopädie und Unfallchirurgie Pädiatrie Pathologie Psychiatrie Radiologie Rechtsmedizin Urologie Zahnmedizin
Themen
Klimawandel und Gesundheit Neues aus dem Markt COVID-19 Praxis und Beruf Seltene Erkrankungen GOÄ & EBM Panorama
Sammlungen
Kasuistiken Algorithmen & Infografiken Blickdiagnosen Arthropedia FlapFinder (für Dermatochirurgen) Videos Kongressberichterstattung Medizin für Apothekerinnen und Apotheker Für Ärztinnen und Ärzte in Weiterbildung Für Medizinstudierende
Erweiterte Suche
Anmelden
nach oben
International Journal of Hematology
Erschienen in: International Journal of Hematology 4/2015

01.04.2015 | Progress in Hematology

Molecular mechanisms of MLL-associated leukemia

verfasst von: Akihiko Yokoyama

Erschienen in: International Journal of Hematology | Ausgabe 4/2015

Einloggen, um Zugang zu erhalten

Abstract

Gene rearrangements of the mixed lineage leukemia (MLL) gene cause aggressive leukemia. The fusion of MLL and its partner genes generates various MLL fusion genes, and their gene products trigger aberrant self-renewal of hematopoietic progenitors leading to leukemia. Since the identification of the MLL gene two decades ago, a substantial amount of information has been obtained regarding the mechanisms by which MLL mutations cause leukemia. Wild-type MLL maintains the expression of Homeobox (HOX) genes during development. MLL activates the expression of posterior HOX-A genes in the hematopoietic lineage to stimulate the expansion of immature progenitors. MLL fusion proteins constitutively activate the HOX genes, causing aberrant self-renewal. The modes of transcriptional activation vary depending on the fusion partners and can be categorized into at least four groups. Here I review the recent progress in research related to the molecular mechanisms of MLL fusion-dependent leukemogenesis.
Literatur
1.
Tkachuk DC, Kohler S, Cleary ML. Involvement of a homolog of Drosophila trithorax by 11q23 chromosomal translocations in acute leukemias. Cell. 1992;71:691–700.CrossRefPubMed
2.
Gu Y, Nakamura T, Alder H, et al. The t(4;11) chromosome translocation of human acute leukemias fuses the ALL-1 gene, related to Drosophila trithorax, to the AF-4 gene. Cell. 1992;71:701–8.CrossRefPubMed
3.
Djabali M, Selleri L, Parry P, Bower M, Young BD, Evans GA. A trithorax-like gene is interrupted by chromosome 11q23 translocations in acute leukaemias. Nat Genet. 1992;2:113–8.CrossRefPubMed
4.
5.
Dimartino JF, Cleary ML. Mll rearrangements in haematological malignancies: lessons from clinical and biological studies. Br J Haematol. 1999;106:614–26.CrossRefPubMed
6.
Lavau C, Szilvassy SJ, Slany R, Cleary ML. Immortalization and leukemic transformation of a myelomonocytic precursor by retrovirally transduced HRX-ENL. EMBO J. 1997;16:4226–37.CrossRefPubMedCentralPubMed
7.
Corral J, Lavenir I, Impey H, et al. An Mll-AF9 fusion gene made by homologous recombination causes acute leukemia in chimeric mice: a method to create fusion oncogenes. Cell. 1996;85:853–61.CrossRefPubMed
8.
Dobson CL, Warren AJ, Pannell R, et al. The mll-AF9 gene fusion in mice controls myeloproliferation and specifies acute myeloid leukaemogenesis. EMBO J. 1999;18:3564–74.CrossRefPubMedCentralPubMed
9.
Chen W, Li Q, Hudson WA, Kumar A, Kirchhof N, Kersey JH. A murine Mll-AF4 knock-in model results in lymphoid and myeloid deregulation and hematologic malignancy. Blood. 2006;108:669–77.CrossRefPubMedCentralPubMed
10.
Metzler M, Forster A, Pannell R, et al. A conditional model of MLL-AF4 B-cell tumourigenesis using invertor technology. Oncogene. 2006;25:3093–103.CrossRefPubMed
11.
Drynan LF, Pannell R, Forster A, et al. Mll fusions generated by Cre-loxP-mediated de novo translocations can induce lineage reassignment in tumorigenesis. EMBO J. 2005;24:3136–46.CrossRefPubMedCentralPubMed
12.
13.
Barabe F, Kennedy JA, Hope KJ, Dick JE. Modeling the initiation and progression of human acute leukemia in mice. Science. 2007;316:600–4.CrossRefPubMed
14.
15.
Li BE, Ernst P. Two decades of leukemia oncoprotein epistasis: the MLL1 paradigm for epigenetic deregulation in leukemia. Exp Hematol. 2014;42:995–1012.CrossRefPubMed
16.
Yu BD, Hess JL, Horning SE, Brown GA, Korsmeyer SJ. Altered Hox expression and segmental identity in Mll-mutant mice. Nature. 1995;378:505–8.CrossRefPubMed
17.
Yagi H, Deguchi K, Aono A, Tani Y, Kishimoto T, Komori T. Growth disturbance in fetal liver hematopoiesis of Mll-mutant mice. Blood. 1998;92:108–17.PubMed
18.
Sedkov Y, Tillib S, Mizrokhi L, Mazo A. The bithorax complex is regulated by trithorax earlier during Drosophila embryogenesis than is the Antennapedia complex, correlating with a bithorax-like expression pattern of distinct early trithorax transcripts. Development. 1994;120:1907–17.PubMed
19.
Breen TR, Harte PJ. Trithorax regulates multiple homeotic genes in the bithorax and Antennapedia complexes and exerts different tissue-specific, parasegment-specific and promoter-specific effects on each. Development. 1993;117:119–34.PubMed
20.
Deschamps J, van Nes J. Developmental regulation of the Hox genes during axial morphogenesis in the mouse. Development. 2005;132:2931–42.CrossRefPubMed
21.
Wang KC, Helms JA, Chang HY. Regeneration, repair and remembering identity: the three Rs of Hox gene expression. Trends Cell Biol. 2009;19:268–75.CrossRefPubMedCentralPubMed
22.
Yu BD, Hanson RD, Hess JL, Horning SE, Korsmeyer SJ. MLL, a mammalian trithorax-group gene, functions as a transcriptional maintenance factor in morphogenesis. Proc Natl Acad Sci USA. 1998;95:10632–6.CrossRefPubMedCentralPubMed
23.
Blobel GA, Kadauke S, Wang E, et al. A reconfigured pattern of MLL occupancy within mitotic chromatin promotes rapid transcriptional reactivation following mitotic exit. Mol Cell. 2009;36:970–83.CrossRefPubMedCentralPubMed
24.
Jude CD, Climer L, Xu D, Artinger E, Fisher JK, Ernst P. Unique and independent roles for MLL in adult hematopoietic stem cells and progenitors. Cell Stem Cell. 2007;1:324–37.CrossRefPubMedCentralPubMed
25.
Forsberg EC, Prohaska SS, Katzman S, Heffner GC, Stuart JM, Weissman IL. Differential expression of novel potential regulators in hematopoietic stem cells. PLoS Genet. 2005;1:e28.CrossRefPubMedCentralPubMed
26.
Yokoyama A, Ficara F, Murphy MJ, et al. MLL becomes functional through intra-molecular interaction not by proteolytic processing. PLoS One. 2013;8:e73649.CrossRefPubMedCentralPubMed
27.
Somervaille TC, Cleary ML. Identification and characterization of leukemia stem cells in murine MLL-AF9 acute myeloid leukemia. Cancer Cell. 2006;10:257–68.CrossRefPubMed
28.
Kroon E, Krosl J, Thorsteinsdottir U, Baban S, Buchberg AM, Sauvageau G. Hoxa9 transforms primary bone marrow cells through specific collaboration with Meis1a but not Pbx1b. EMBO J. 1998;17:3714–25.CrossRefPubMedCentralPubMed
29.
Yokoyama A, Ficara F, Murphy MJ, et al. Proteolytically cleaved MLL subunits are susceptible to distinct degradation pathways. J Cell Sci. 2011;124:2208–19.CrossRefPubMedCentralPubMed
30.
McMahon KA, Hiew SY, Hadjur S, et al. Mll has a critical role in fetal and adult hematopoietic stem cell self-renewal. Cell Stem Cell. 2007;1:338–45.CrossRefPubMed
31.
Milne TA, Briggs SD, Brock HW, et al. MLL targets SET domain methyltransferase activity to Hox gene promoters. Mol Cell. 2002;10:1107–17.CrossRefPubMed
32.
Nakamura T, Mori T, Tada S, et al. ALL-1 is a histone methyltransferase that assembles a supercomplex of proteins involved in transcriptional regulation. Mol Cell. 2002;10:1119–28.CrossRefPubMed
33.
Patel A, Dharmarajan V, Vought VE, Cosgrove MS. On the mechanism of multiple lysine methylation by the human mixed lineage leukemia protein-1 (MLL1) core complex. J Biol Chem. 2009;284:24242–56.CrossRefPubMedCentralPubMed
34.
Cao F, Chen Y, Cierpicki T, et al. An Ash2L/RbBP5 heterodimer stimulates the MLL1 methyltransferase activity through coordinated substrate interactions with the MLL1 SET domain. PLoS One. 2010;5:e14102.CrossRefPubMedCentralPubMed
35.
Dou Y, Milne TA, Tackett AJ, et al. Physical association and coordinate function of the H3 K4 methyltransferase MLL1 and the H4 K16 acetyltransferase MOF. Cell. 2005;121:873–85.CrossRefPubMed
36.
Dou Y, Milne TA, Ruthenburg AJ, et al. Regulation of MLL1 H3K4 methyltransferase activity by its core components. Nat Struct Mol Biol. 2006;13:713–9.CrossRefPubMed
37.
Terranova R, Agherbi H, Boned A, Meresse S, Djabali M. Histone and DNA methylation defects at Hox genes in mice expressing a SET domain-truncated form of Mll. Proc Natl Acad Sci USA. 2006;103:6629–34.CrossRefPubMedCentralPubMed
38.
Mishra BP, Zaffuto KM, Artinger EL, et al. The histone methyltransferase activity of MLL1 is dispensable for hematopoiesis and leukemogenesis. Cell Rep. 2014;7:1239–47.CrossRefPubMedCentralPubMed
39.
Yokoyama A, Kitabayashi I, Ayton PM, Cleary ML, Ohki M. Leukemia proto-oncoprotein MLL is proteolytically processed into 2 fragments with opposite transcriptional properties. Blood. 2002;100:3710–8.CrossRefPubMed
40.
Hsieh JJ, Ernst P, Erdjument-Bromage H, Tempst P, Korsmeyer SJ. Proteolytic cleavage of MLL generates a complex of N- and C-terminal fragments that confers protein stability and subnuclear localization. Mol Cell Biol. 2003;23:186–94.CrossRefPubMedCentralPubMed
41.
Yokoyama A, Wang Z, Wysocka J, et al. Leukemia proto-oncoprotein MLL forms a SET1-like histone methyltransferase complex with menin to regulate Hox gene expression. Mol Cell Biol. 2004;24:5639–49.CrossRefPubMedCentralPubMed
42.
Yokoyama A, Somervaille TC, Smith KS, Rozenblatt-Rosen O, Meyerson M, Cleary ML. The menin tumor suppressor protein is an essential oncogenic cofactor for MLL-associated leukemogenesis. Cell. 2005;123:207–18.CrossRefPubMed
43.
Ernst P, Wang J, Huang M, Goodman RH, Korsmeyer SJ. MLL and CREB bind cooperatively to the nuclear coactivator CREB-binding protein. Mol Cell Biol. 2001;21:2249–58.CrossRefPubMedCentralPubMed
44.
Fair K, Anderson M, Bulanova E, Mi H, Tropschug M, Diaz MO. Protein interactions of the MLL PHD fingers modulate MLL target gene regulation in human cells. Mol Cell Biol. 2001;21:3589–97.CrossRefPubMedCentralPubMed
45.
Xia ZB, Anderson M, Diaz MO, Zeleznik-Le NJ. MLL repression domain interacts with histone deacetylases, the polycomb group proteins HPC2 and BMI-1, and the corepressor C-terminal-binding protein. Proc Natl Acad Sci USA. 2003;100:8342–7.CrossRefPubMedCentralPubMed
46.
Wang Z, Song J, Milne TA, et al. Pro isomerization in MLL1 PHD3-bromo cassette connects H3K4me readout to CyP33 and HDAC-mediated repression. Cell. 2010;141:1183–94.CrossRefPubMed
47.
Hughes CM, Rozenblatt-Rosen O, Milne TA, et al. Menin associates with a trithorax family histone methyltransferase complex and with the hoxc8 locus. Mol Cell. 2004;13:587–97.CrossRefPubMed
48.
49.
Milne TA, Kim J, Wang GG, et al. Multiple interactions recruit MLL1 and MLL1 fusion proteins to the HOXA9 locus in leukemogenesis. Mol Cell. 2010;38:853–63.CrossRefPubMedCentralPubMed
50.
Krivtsov AV, Twomey D, Feng Z, et al. Transformation from committed progenitor to leukaemia stem cell initiated by MLL-AF9. Nature. 2006;442:818–22.CrossRefPubMed
51.
52.
Slany RK, Lavau C, Cleary ML. The oncogenic capacity of HRX-ENL requires the transcriptional transactivation activity of ENL and the DNA binding motifs of HRX. Mol Cell Biol. 1998;18:122–9.PubMedCentralPubMed
53.
Ayton PM, Chen EH, Cleary ML. Binding to nonmethylated CpG DNA is essential for target recognition, transactivation, and myeloid transformation by an MLL oncoprotein. Mol Cell Biol. 2004;24:10470–8.CrossRefPubMedCentralPubMed
54.
55.
Botbol Y, Raghavendra NK, Rahman S, Engelman A, Lavigne M. Chromatinized templates reveal the requirement for the LEDGF/p75 PWWP domain during HIV-1 integration in vitro. Nucleic Acids Res. 2008;36(4):1237–46.CrossRefPubMedCentralPubMed
56.
Okuda H, Kawaguchi M, Kanai A, et al. MLL fusion proteins link transcriptional coactivators to previously active CpG-rich promoters. Nucleic Acids Res. 2014;42:4241–56.CrossRefPubMedCentralPubMed
57.
Eidahl JO, Crowe BL, North JA, et al. Structural basis for high-affinity binding of LEDGF PWWP to mononucleosomes. Nucleic Acids Res. 2013;41:3924–36.CrossRefPubMedCentralPubMed
58.
Vezzoli A, Bonadies N, Allen MD, et al. Molecular basis of histone H3K36me3 recognition by the PWWP domain of Brpf1. Nat Struct Mol Biol. 2010;17:617–9.CrossRefPubMed
59.
Lukasik SM, Cierpicki T, Borloz M, Grembecka J, Everett A, Bushweller JH. High resolution structure of the HDGF PWWP domain: a potential DNA binding domain. Protein Sci. 2006;15:314–23.CrossRefPubMedCentralPubMed
60.
61.
Barski A, Cuddapah S, Cui K, et al. High-resolution profiling of histone methylations in the human genome. Cell. 2007;129:823–37.CrossRefPubMed
62.
Birke M, Schreiner S, Garcia-Cuellar MP, Mahr K, Titgemeyer F, Slany RK. The MT domain of the proto-oncoprotein MLL binds to CpG-containing DNA and discriminates against methylation. Nucleic Acids Res. 2002;30:958–65.CrossRefPubMedCentralPubMed
63.
Allen MD, Grummitt CG, Hilcenko C, et al. Solution structure of the nonmethyl-CpG-binding CXXC domain of the leukaemia-associated MLL histone methyltransferase. EMBO J. 2006;25:4503–12.CrossRefPubMedCentralPubMed
64.
Cierpicki T, Risner LE, Grembecka J, et al. Structure of the MLL CXXC domain-DNA complex and its functional role in MLL-AF9 leukemia. Nat Struct Mol Biol. 2010;17:62–8.CrossRefPubMedCentralPubMed
65.
Muntean AG, Tan J, Sitwala K, et al. The PAF complex synergizes with MLL fusion proteins at HOX loci to promote leukemogenesis. Cancer Cell. 2010;17:609–21.CrossRefPubMedCentralPubMed
66.
67.
Thiel AT, Blessington P, Zou T, et al. MLL-AF9-induced leukemogenesis requires coexpression of the wild-type Mll allele. Cancer Cell. 2010;17:148–59.CrossRefPubMedCentralPubMed
68.
Yokoyama A, Lin M, Naresh A, Kitabayashi I, Cleary ML. A higher-order complex containing AF4 and ENL family proteins with P-TEFb facilitates oncogenic and physiologic MLL-dependent transcription. Cancer Cell. 2010;17:198–212.CrossRefPubMedCentralPubMed
69.
Peterlin BM, Price DH. Controlling the elongation phase of transcription with P-TEFb. Mol Cell. 2006;23:297–305.CrossRefPubMed
70.
Shilatifard A, Lane WS, Jackson KW, Conaway RC, Conaway JW. An RNA polymerase II elongation factor encoded by the human ELL gene. Science. 1996;271:1873–6.CrossRefPubMed
71.
Lin C, Smith ER, Takahashi H, 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;37:429–37.CrossRefPubMedCentralPubMed
72.
He N, Liu M, Hsu J, et al. HIV-1 Tat and host AFF4 recruit two transcription elongation factors into a bifunctional complex for coordinated activation of HIV-1 transcription. Mol Cell. 2010;38:428–38.CrossRefPubMedCentralPubMed
73.
Sobhian B, Laguette N, Yatim A, et al. HIV-1 Tat assembles a multifunctional transcription elongation complex and stably associates with the 7SK snRNP. Mol Cell. 2010;38:439–51.CrossRefPubMedCentralPubMed
74.
Mueller D, Bach C, Zeisig D, et al. A role for the MLL fusion partner ENL in transcriptional elongation and chromatin modification. Blood. 2007;110:4445–54.CrossRefPubMedCentralPubMed
75.
Biswas D, Milne TA, Basrur V, et al. Function of leukemogenic mixed lineage leukemia 1 (MLL) fusion proteins through distinct partner protein complexes. Proc Natl Acad Sci USA. 2011;108:15751–6.CrossRefPubMedCentralPubMed
76.
77.
Nguyen AT, Taranova O, He J, Zhang Y. DOT1L, the H3K79 methyltransferase, is required for MLL-AF9-mediated leukemogenesis. Blood. 2011;117:6912–22.CrossRefPubMedCentralPubMed
78.
Jo SY, Granowicz EM, Maillard I, Thomas D, Hess JL. Requirement for Dot1 l in murine postnatal hematopoiesis and leukemogenesis by MLL translocation. Blood. 2011;117:4759–68.CrossRefPubMedCentralPubMed
79.
Deshpande AJ, Deshpande A, Sinha AU, et al. AF10 Regulates Progressive H3K79 Methylation and HOX Gene Expression in Diverse AML Subtypes. Cancer Cell. 2014;26:896–908.CrossRefPubMed
80.
Maethner E, Garcia-Cuellar MP, Breitinger C, et al. MLL-ENL inhibits polycomb repressive complex 1 to achieve efficient transformation of hematopoietic cells. Cell Rep. 2013;3:1553–66.CrossRefPubMedCentralPubMed
81.
82.
Mohan M, Herz HM, Takahashi YH, et al. Linking H3K79 trimethylation to Wnt signaling through a novel Dot1-containing complex (DotCom). Genes Dev. 2010;24:574–89.CrossRefPubMedCentralPubMed
83.
Okada Y, Feng Q, Lin Y, et al. hDOT1L links histone methylation to leukemogenesis. Cell. 2005;121:167–78.CrossRefPubMed
84.
Chen L, Deshpande AJ, Banka D, et al. Abrogation of MLL-AF10 and CALM-AF10-mediated transformation through genetic inactivation or pharmacological inhibition of the H3K79 methyltransferase Dot1l. Leukemia. 2013;27:813–22.CrossRefPubMedCentralPubMed
85.
Daigle SR, Olhava EJ, Therkelsen CA, et al. Selective killing of mixed lineage leukemia cells by a potent small-molecule DOT1L inhibitor. Cancer Cell. 2011;20:53–65.CrossRefPubMedCentralPubMed
86.
Lavau C, Du C, Thirman M, Zeleznik-Le N. Chromatin-related properties of CBP fused to MLL generate a myelodysplastic-like syndrome that evolves into myeloid leukemia. EMBO J. 2000;19:4655–64.CrossRefPubMedCentralPubMed
87.
So CW, Cleary ML. MLL-AFX requires the transcriptional effector domains of AFX to transform myeloid progenitors and transdominantly interfere with forkhead protein function. Mol Cell Biol. 2002;22:6542–52.CrossRefPubMedCentralPubMed
88.
So CW, Cleary ML. Dimerization: a versatile switch for oncogenesis. Blood. 2004;104:919–22.CrossRefPubMed
89.
Martin ME, Milne TA, Bloyer S, et al. Dimerization of MLL fusion proteins immortalizes hematopoietic cells. Cancer Cell. 2003;4:197–207.CrossRefPubMed
90.
So CW, Karsunky H, Passegue E, Cozzio A, Weissman IL, Cleary ML. MLL-GAS7 transforms multipotent hematopoietic progenitors and induces mixed lineage leukemias in mice. Cancer Cell. 2003;3:161–71.CrossRefPubMed
91.
Liedtke M, Ayton PM, Somervaille TC, Smith KS, Cleary ML. Self-association mediated by the Ras association 1 domain of AF6 activates the oncogenic potential of MLL-AF6. Blood. 2010;116:63–70.CrossRefPubMedCentralPubMed
92.
Ono R, Nakajima H, Ozaki K, et al. Dimerization of MLL fusion proteins and FLT3 activation synergize to induce multiple-lineage leukemogenesis. J Clin Invest. 2005;115:919–29.CrossRefPubMedCentralPubMed
93.
Eguchi M, Eguchi-Ishimae M, Greaves M. The small oligomerization domain of gephyrin converts MLL to an oncogene. Blood. 2004;103:3876–82.CrossRefPubMed
94.
Deshpande AJ, Chen L, Fazio M, et al. Leukemic transformation by the MLL-AF6 fusion oncogene requires the H3K79 methyltransferase Dot1l. Blood. 2013;121:2533–41.CrossRefPubMedCentralPubMed
95.
Grembecka J, He S, Shi A, et al. Menin-MLL inhibitors reverse oncogenic activity of MLL fusion proteins in leukemia. Nat Chem Biol. 2012;8:277–84.CrossRefPubMedCentralPubMed
Metadaten
Titel
Molecular mechanisms of MLL-associated leukemia
verfasst von
Akihiko Yokoyama
Publikationsdatum
01.04.2015
Verlag
Springer Japan
Erschienen in
International Journal of Hematology / Ausgabe 4/2015
Print ISSN: 0925-5710
Elektronische ISSN: 1865-3774
DOI
https://doi.org/10.1007/s12185-015-1774-4

Weitere Artikel der Ausgabe 4/2015

International Journal of Hematology 4/2015 Zur Ausgabe

Original Article

Reactivation of hepatitis B virus (HBV) infection in adult T-cell leukemia–lymphoma patients with resolved HBV infection following systemic chemotherapy

Original Article

Third allogeneic stem cell transplantation (SCT) using unrelated cord blood for relapsed acute leukemia after second allogeneic SCT

Original Article

A randomized controlled study evaluating the efficacy of aprepitant for highly/moderately emetogenic chemotherapies in hematological malignancies

Progress in Hematology

Regulation of myelopoiesis by the transcription factor IRF8

Progress in Hematology

Guest editorial: Transcriptional control in myeloid cell development and related diseases

Original Article

Clinical significance of IPF% or RP% measurement in distinguishing primary immune thrombocytopenia from aplastic thrombocytopenic disorders

Neu im Fachgebiet Onkologie

24.04.2024 | DGIM 2024 | Nachrichten

Bei Senioren mit Prostatakarzinom auf Anämie achten!

23.04.2024 | Medikamente in Schwangerschaft und Stillzeit | Nachrichten

ICI-Therapie in der Schwangerschaft wird gut toleriert

22.04.2024 | DGIM 2024 | Kongressbericht | Nachrichten

Krebspatienten impfen: Was? Wen? Und wann nicht?

22.04.2024 | DGIM 2024 | Kongressbericht | Nachrichten

Müde im Alter? Auch an die Nebenniere denken
weitere anzeigen

Update Onkologie

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.

Newsletter bestellen