Unlike Its Paralog LEDGF/p75, HRP-2 Is Dispensable for MLL-R Leukemogenesis but Important for Leukemic Cell Survival

. 2021 Jan 19 ; 10 (1) : . [epub] 20210119

Jazyk angličtina Země Švýcarsko Médium electronic

Typ dokumentu časopisecké články, Research Support, N.I.H., Extramural, práce podpořená grantem

Perzistentní odkaz   https://www.medvik.cz/link/pmid33477970

Grantová podpora
R00 CA187565 NCI NIH HHS - United States

HDGF-related protein 2 (HRP-2) is a member of the Hepatoma-Derived Growth Factor-related protein family that harbors the structured PWWP and Integrase Binding Domain, known to associate with methylated histone tails or cellular and viral proteins, respectively. Interestingly, HRP-2 is a paralog of Lens Epithelium Derived Growth Factor p75 (LEDGF/p75), which is essential for MLL-rearranged (MLL-r) leukemia but dispensable for hematopoiesis. Sequel to these findings, we investigated the role of HRP-2 in hematopoiesis and MLL-r leukemia. Protein interactions were investigated by co-immunoprecipitation and validated using recombinant proteins in NMR. A systemic knockout mouse model was used to study normal hematopoiesis and MLL-ENL transformation upon the different HRP-2 genotypes. The role of HRP-2 in MLL-r and other leukemic, human cell lines was evaluated by lentiviral-mediated miRNA targeting HRP-2. We demonstrate that MLL and HRP-2 interact through a conserved interface, although this interaction proved less dependent on menin than the MLL-LEDGF/p75 interaction. The systemic HRP-2 knockout mice only revealed an increase in neutrophils in the peripheral blood, whereas the depletion of HRP-2 in leukemic cell lines and transformed primary murine cells resulted in reduced colony formation independently of MLL-rearrangements. In contrast, primary murine HRP-2 knockout cells were efficiently transformed by the MLL-ENL fusion, indicating that HRP-2, unlike LEDGF/p75, is dispensable for the transformation of MLL-ENL leukemogenesis but important for leukemic cell survival.

Zobrazit více v PubMed

Mohan M., Lin C., Guest E., Shilatifard A. Licensed to elongate: A molecular mechanism for MLL-based leukaemogenesis. Nat. Rev. Cancer. 2010;10:721–728. doi: 10.1038/nrc2915. PubMed DOI

Balgobind B.V., Hollink I.H.I.M., Arentsen-Peters S.T.C.J.M., Zimmermann M., Harbott J., Berna Beverloo H., von Bergh A.R.M., Cloos J., Kaspers G.J.L., de Haas V., et al. Integrative analysis of type-I and type-II aberrations underscores the genetic heterogeneity of pediatric acute myeloid leukemia. Haematologica. 2011;96:1478–1487. doi: 10.3324/haematol.2010.038976. PubMed DOI PMC

Hilden J.M., Dinndorf P.A., Meerbaum S.O., Sather H., Villaluna D., Heerema N.A., McGlennen R., Smith F.O., Woods W.G., Salzer W.L., et al. Analysis of prognostic factors of acute lymphoblastic leukemia in infants: Report on CCG 1953 from the Children’s Oncology Group. Blood. 2006;108:441–451. doi: 10.1182/blood-2005-07-3011. PubMed DOI PMC

Masetti R., Rondelli R., Fagioli F., Mastronuzzi A., Pierani P., Togni M., Menna G., Pigazzi M., Putti M.C., Basso G., et al. Infants with acute myeloid leukemia treated according to the Associazione Italiana di Ematologia e Oncologia Pediatrica 2002/01 protocol have an outcome comparable to that of older children. Haematologica. 2014;99:e127. doi: 10.3324/haematol.2014.106526. PubMed DOI PMC

Chessells J.M., Harrison C.J., Kempski H., Webb D.K. Clinical features, cytogenetics and outcome in acute lymphoblastic and myeloid leukaemia of infancy: Report from the MRC Childhood Leukaemia working party. Leukemia. 2002;12:776–784. doi: 10.1038/sj.leu.2402468. PubMed DOI

Steinhilber D., Marschalek R. How to effectively treat acute leukemia patients bearing MLL-rearrangements? Biochem. Pharmacol. 2018;147:183–190. doi: 10.1016/j.bcp.2017.09.007. PubMed DOI

Meyer C., Schneider B., Jakob S., Strehl S., Attarbaschi A., Schnittger S., Schoch C., Jansen M.W.J.C., van Dongen J.J.M., den Boer M.L., et al. The MLL recombinome of acute leukemias. Leuk. Off. J. Leuk. Soc. Am. Leuk. Res. Fund UK. 2006;20:777–784. doi: 10.1038/sj.leu.2404150. PubMed DOI

Slany R.K. The molecular mechanics of mixed lineage leukemia. Oncogene. 2016;35:5215–5223. doi: 10.1038/onc.2016.30. PubMed DOI

Yokoyama A., Cleary M.L. Menin Critically Links MLL Proteins with LEDGF on Cancer-Associated Target Genes. Cancer Cell. 2008;14:36–46. doi: 10.1016/j.ccr.2008.05.003. PubMed DOI PMC

Yokoyama A., Somervaille T.C.P., Smith K.S., Rozenblatt-Rosen O., Meyerson M., Cleary M.L. The menin tumor suppressor protein is an essential oncogenic cofactor for MLL-associated leukemogenesis. Cell. 2005;123:207–218. doi: 10.1016/j.cell.2005.09.025. PubMed DOI

Caslini C., Yang Z., El-Osta M., Milne T.A., Slany R.K., Hess J.L. Interaction of MLL Amino Terminal Sequences with Menin Is Required for Transformation. Cancer Res. 2007;67:7275–7283. doi: 10.1158/0008-5472.CAN-06-2369. PubMed DOI PMC

El Ashkar S., Schwaller J., Pieters T., Goossens S., Demeulemeester J., Christ F., Van Belle S., Juge S., Boeckx N., Engelman A., et al. LEDGF/p75 is dispensable for hematopoiesis but essential for MLL-rearranged leukemogenesis. Blood. 2018;131:95–107. doi: 10.1182/blood-2017-05-786962. PubMed DOI PMC

Dietz F., Franken S., Yoshida K., Nakamura H., Kappler J., Gieselmann V. The family of hepatoma-derived growth factor proteins: Characterization of a new member HRP-4 and classification of its subfamilies. Biochem. J. 2002;366:491–500. doi: 10.1042/bj20011811. PubMed DOI PMC

El-Tahir H., Dietz F., Dringen R., Schwabe K., Strenge K., Kelm S., Abouzied M., Gieselmann V., Franken S. Expression of hepatoma-derived growth factor family members in the adult central nervous system. BMC Neurosci. 2006;7:6. doi: 10.1186/1471-2202-7-6. PubMed DOI PMC

Izumoto Y., Kuroda T., Harada H., Kishimoto T., Nakamura H. Hepatoma-derived growth factor belongs to a gene family in mice showing significant homology in the amino terminus. Biochem. Biophys. Res. Commun. 1997;238:26–32. doi: 10.1006/bbrc.1997.7233. PubMed DOI

Wu H., Zeng H., Lam R., Tempel W., Amaya M.F., Xu C., Dombrovski L., Qiu W., Wang Y., Min J. Structural and histone binding ability characterizations of human PWWP domains. PLoS ONE. 2011;6:e18919. doi: 10.1371/journal.pone.0018919. PubMed DOI PMC

Daugaard M., Baude A., Fugger K., Povlsen L.K., Beck H., Sørensen C.S., Petersen N.H.T., Sorensen P.H.B., Lukas C., Bartek J., et al. LEDGF (p75) promotes DNA-end resection and homologous recombination. Nat. Struct. Mol. Biol. 2012;19:803–810. doi: 10.1038/nsmb.2314. PubMed DOI

Daugaard M., Kirkegaard-Sørensen T., Ostenfeld M.S., Aaboe M., Høyer-Hansen M., Ørntoft T.F., Rohde M., Jäättelä M. Lens epithelium-derived growth factor is an Hsp70-2 regulated guardian of lysosomal stability in human cancer. Cancer Res. 2007;67:2559–2567. doi: 10.1158/0008-5472.CAN-06-4121. PubMed DOI

Wu X., Daniels T., Molinaro C., Lilly M.B., Casiano C.A. Caspase cleavage of the nuclear autoantigen LEDGF/p75 abrogates its pro-survival function: Implications for autoimmunity in atopic disorders. Cell Death Differ. 2002;9:915–925. doi: 10.1038/sj.cdd.4401063. PubMed DOI

Singh D.P., Ohguro N., Chylack L.T., Shinohara T. Lens epithelium-derived growth factor: Increased resistance to thermal and oxidative stresses. Investig. Ophthalmol. Vis. Sci. 1999;40:1444–1451. PubMed

Basu A., Drame A., Muñoz R., Gijsbers R., Debyser Z., De Leon M., Casiano C.A. Pathway specific gene expression profiling reveals oxidative stress genes potentially regulated by transcription co-activator LEDGF/p75 in prostate cancer cells. Prostate. 2012;72:597–611. doi: 10.1002/pros.21463. PubMed DOI PMC

Basu A., Rojas H., Banerjee H., Cabrera I.B., Perez K.Y., de León M., Casiano C.A. Expression of the stress response oncoprotein LEDGF/p75 in human cancer: A study of 21 tumor types. PLoS ONE. 2012;7 doi: 10.1371/journal.pone.0030132. PubMed DOI PMC

Sapoznik S., Cohen B., Tzuman Y., Meir G., Ben-Dor S., Harmelin A., Neeman M. Gonadotropin-regulated lymphangiogenesis in ovarian cancer is mediated by LEDGF-induced expression of VEGF-C. Cancer Res. 2009;69:9306–9314. doi: 10.1158/0008-5472.CAN-09-1213. PubMed DOI PMC

Huang T.S., Myklebust L.M., Kjarland E., Gjertsen B.T., Pendino F., Bruserud Ø., Døskeland S.O., Lillehaug J.R. LEDGF/p75 has increased expression in blasts from chemotherapy-resistant human acute myelogenic leukemia patients and protects leukemia cells from apoptosis in vitro. Mol. Cancer. 2007;6:31. doi: 10.1186/1476-4598-6-31. PubMed DOI PMC

Singh D.K., Gholamalamdari O., Jadaliha M., Li X.L., Lin Y.C., Zhang Y., Guang S., Hashemikhabir S., Tiwari S., Zhu Y.J., et al. PSIP1/p75 promotes tumorigenicity in breast cancer cells by promoting the transcription of cell cycle genes. Carcinogenesis. 2017;38:966–975. doi: 10.1093/carcin/bgx062. PubMed DOI PMC

Maertens G.N., Cherepanov P., Engelman A. Transcriptional co-activator p75 binds and tethers the Myc-interacting protein JPO2 to chromatin. J. Cell Sci. 2006;119:2563–2571. doi: 10.1242/jcs.02995. PubMed DOI

Bartholomeeusen K., Christ F., Hendrix J., Rain J.-C., Emiliani S., Benarous R., Debyser Z., Gijsbers R., De Rijck J. Lens epithelium-derived growth factor/p75 interacts with the transposase-derived DDE domain of PogZ. J. Biol. Chem. 2009;284:11467–11477. doi: 10.1074/jbc.M807781200. PubMed DOI PMC

Hughes S., Jenkins V., Dar M.J., Engelman A., Cherepanov P. Transcriptional co-activator LEDGF interacts with Cdc7-activator of S-phase kinase (ASK) and stimulates its enzymatic activity. J. Biol. Chem. 2010;285:541–554. doi: 10.1074/jbc.M109.036491. PubMed DOI PMC

Tesina P., Čermáková K., Hořejší M., Procházková K., Fábry M., Sharma S., Christ F., Demeulemeester J., Debyser Z., De Rijck J., et al. Multiple cellular proteins interact with LEDGF/p75 through a conserved unstructured consensus motif. Nat. Commun. 2015;6:7968. doi: 10.1038/ncomms8968. PubMed DOI

Sharma S., Čermáková K., De Rijck J., Demeulemeester J., Fábry M., El Ashkar S., Van Belle S., Lepšík M., Tesina P., Duchoslav V., et al. Affinity switching of the LEDGF/p75 IBD interactome is governed by kinase-dependent phosphorylation. Proc. Natl. Acad. Sci. USA. 2018;115:E7053–E7062. doi: 10.1073/pnas.1803909115. PubMed DOI PMC

Gao K., Xu C., Jin X., Wumaier R., Ma J., Peng J., Wang Y., Tang Y., Yu L., Zhang P. HDGF-related protein-2 (HRP-2) acts as an oncogene to promote cell growth in hepatocellular carcinoma. Biochem. Biophys. Res. Commun. 2015;458:849–855. doi: 10.1016/j.bbrc.2015.02.042. PubMed DOI

Cherepanov P., Maertens G., Proost P., Devreese B., Van Beeumen J., Engelborghs Y., De Clercq E., Debyser Z. HIV-1 integrase forms stable tetramers and associates with LEDGF/p75 protein in human cells. J. Biol. Chem. 2003;278:372–381. doi: 10.1074/jbc.M209278200. PubMed DOI

Cherepanov P., Devroe E., Silver P.A., Engelman A. Identification of an evolutionarily conserved domain in human lens epithelium-derived growth factor/transcriptional co-activator p75 (LEDGF/p75) that binds HIV-1 integrase. J. Biol. Chem. 2004;279:48883–48892. doi: 10.1074/jbc.M406307200. PubMed DOI

Ciuffi A., Llano M., Poeschla E., Hoffmann C., Leipzig J., Shinn P., Ecker J.R., Bushman F. A role for LEDGF/p75 in targeting HIV DNA integration. Nat. Med. 2005;11:1287–1289. doi: 10.1038/nm1329. PubMed DOI

Llano M., Saenz D.T., Meehan A., Wongthida P., Peretz M., Walker W.H., Teo W., Poeschla E.M. An Essential Role for LEDGF/p75 in HIV Integration. Science (80-.) 2006;314:461–464. doi: 10.1126/science.1132319. PubMed DOI

Shun M.C., Raghavendra N.K., Vandegraaff N., Daigle J.E., Hughes S., Kellam P., Cherepanov P., Engelman A. LEDGF/p75 functions downstream from preintegration complex formation to effect gene-specific HIV-1 integration. Genes Dev. 2007;21:1767–1778. doi: 10.1101/gad.1565107. PubMed DOI PMC

Schrijvers R., De Rijck J., Demeulemeester J., Adachi N., Vets S., Ronen K., Christ F., Bushman F.D., Debyser Z., Gijsbers R. LEDGF/p75-independent HIV-1 replication demonstrates a role for HRP-2 and remains sensitive to inhibition by LEDGINs. PLoS Pathog. 2012;8 doi: 10.1371/journal.ppat.1002558. PubMed DOI PMC

Baude A., Aaes T.L., Zhai B., Al-Nakouzi N., Oo H.Z., Daugaard M., Rohde M., Jäättelä M. Hepatoma-derived growth factor-related protein 2 promotes DNA repair by homologous recombination. Nucleic Acids Res. 2016;44:2214–2226. doi: 10.1093/nar/gkv1526. PubMed DOI PMC

LeRoy G., Oksuz O., Descostes N., Aoi Y., Ganai R.A., Kara H.O., Yu J.-R., Lee C.-H., Stafford J., Shilatifard A., et al. LEDGF and HDGF2 relieve the nucleosome-induced barrier to transcription in differentiated cells. Sci. Adv. 2019;5:eaay3068. doi: 10.1126/sciadv.aay3068. PubMed DOI PMC

Zhang X., Chen Y., Pan J., Liu X., Chen H., Zhou X., Yuan Z., Wang X., Mo D. iTRAQ-based quantitative proteomic analysis reveals the distinct early embryo myofiber type characteristics involved in landrace and miniature pig. BMC Genomics. 2016;17:137. doi: 10.1186/s12864-016-2464-1. PubMed DOI PMC

Hu Y., He C., Liu J.P., Li N.S., Peng C., Yang-Ou Y.B., Yang X.Y., Lu N.H., Zhu Y. Analysis of key genes and signaling pathways involved in Helicobacter pylori-associated gastric cancer based on The Cancer Genome Atlas database and RNA sequencing data. Helicobacter. 2018;23 doi: 10.1111/hel.12530. PubMed DOI

Geraerts M., Michiels M., Baekelandt V., Debyser Z., Gijsbers R. Upscaling of lentiviral vector production by tangential flow filtration. J. Gene Med. 2005;7:1299–1310. doi: 10.1002/jgm.778. PubMed DOI

Maertens G., Cherepanov P., Pluymers W., Busschots K., De Clercq E., Debyser Z., Engelborghs Y. LEDGF/p75 is essential for nuclear and chromosomal targeting of HIV-1 integrase in human cells. J. Biol. Chem. 2003;278:33528–33539. doi: 10.1074/jbc.M303594200. PubMed DOI

De Rijck J., Vandekerckhove L., Gijsbers R., Hombrouck A., Hendrix J., Vercammen J., Engelborghs Y., Christ F., Debyser Z. Overexpression of the lens epithelium-derived growth factor/p75 integrase binding domain inhibits human immunodeficiency virus replication. J. Virol. 2006;80:11498–11509. doi: 10.1128/JVI.00801-06. PubMed DOI PMC

Méreau H., De Rijck J., Čermáková K., Kutz A., Juge S., Demeulemeester J., Gijsbers R., Christ F., Debyser Z., Schwaller J. Impairing MLL-fusion gene-mediated transformation by dissecting critical interactions with the lens epithelium-derived growth factor (LEDGF/p75) Leukemia. 2013;27:1245–1253. doi: 10.1038/leu.2013.10. PubMed DOI

Cermakova K., Tesina P., Demeulemeester J., El Ashkar S., Méreau H., Schwaller J., \vRezáčová P., Veverka V., De Rijck J. Validation and structural characterization of the LEDGF/p75-MLL interface as a new target for the treatment of MLL-dependent leukemia. Cancer Res. 2014;74:5139–5151. doi: 10.1158/0008-5472.CAN-13-3602. PubMed DOI

Renshaw P.S., Veverka V., Kelly G., Frenkiel T.A., Williamson R.A., Gordon S.V., Hewinson R.G., Carr M.D. Sequence-specific assignment and secondary structure determination of the 195-residue complex formed by the Mycobacterium tuberculosis proteins CFP-10 and ESAT-6. J. Biomol. NMR. 2004;30:225–226. doi: 10.1023/B:JNMR.0000048852.40853.5c. PubMed DOI

Veverka V., Lennie G., Crabbe T., Bird I., Taylor R.J., Carr M.D. NMR assignment of the mTOR domain responsible for rapamycin binding. J. Biomol. NMR. 2006;36(Suppl. 1):3. doi: 10.1007/s10858-005-4324-1. PubMed DOI

Herrmann T., Güntert P., Wüthrich K. Protein NMR structure determination with automated NOE assignment using the new software CANDID and the torsion angle dynamics algorithm DYANA. J. Mol. Biol. 2002;319:209–227. doi: 10.1016/S0022-2836(02)00241-3. PubMed DOI

Shen Y., Delaglio F., Cornilescu G., Bax A. TALOS+: A hybrid method for predicting protein backbone torsion angles from NMR chemical shifts. J. Biomol. NMR. 2009;44:213–223. doi: 10.1007/s10858-009-9333-z. PubMed DOI PMC

Harjes E., Harjes S., Wohlgemuth S., Müller K.-H., Krieger E., Herrmann C., Bayer P. GTP-Ras Disrupts the Intramolecular Complex of C1 and RA Domains of Nore1. Structure. 2006;14:881–888. doi: 10.1016/j.str.2006.03.008. PubMed DOI

Yokogawa M., Kobashigawa Y., Yoshida N., Ogura K., Harada K., Inagaki F. NMR Analyses of the Interaction between the FYVE Domain of Early Endosome Antigen 1 (EEA1) and Phosphoinositide Embedded in a Lipid Bilayer. J. Biol. Chem. 2012;287:34936–34945. doi: 10.1074/jbc.M112.398255. PubMed DOI PMC

NorCOMM2-Phenotyping-Project. [(accessed on 18 January 2020)]; Available online: http://www.norcomm2.org/norcomm2/index.php.

Moll P., Ante M., Seitz A., Reda T. QuantSeq 3′ mRNA sequencing for RNA quantification. Nat. Methods. 2014;11:i–iii. doi: 10.1038/nmeth.f.376. DOI

Dobin A., Davis C.A., Schlesinger F., Drenkow J., Zaleski C., Jha S., Batut P., Chaisson M., Gingeras T.R. STAR: Ultrafast universal RNA-seq aligner. Bioinformatics. 2013;29:15–21. doi: 10.1093/bioinformatics/bts635. PubMed DOI PMC

Love M.I., Huber W., Anders S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 2014;15:550. doi: 10.1186/s13059-014-0550-8. PubMed DOI PMC

Grembecka J., He S., Shi A., Purohit T., Muntean A.G., Sorenson R.J., Showalter H.D., Murai M.J., Belcher A.M., Hartley T., et al. Menin-MLL inhibitors reverse oncogenic activity of MLL fusion proteins in leukemia. Nat. Chem. Biol. 2012;8:277–284. doi: 10.1038/nchembio.773. PubMed DOI PMC

Borkin D., Pollock J., Kempinska K., Purohit T., Li X., Wen B., Zhao T., Miao H., Shukla S., He M., et al. Property Focused Structure-Based Optimization of Small Molecule Inhibitors of the Protein-Protein Interaction between Menin and Mixed Lineage Leukemia (MLL) J. Med. Chem. 2016;59:892–913. doi: 10.1021/acs.jmedchem.5b01305. PubMed DOI PMC

Huang J., Gurung B., Wan B., Matkar S., Veniaminova N.A., Wan K., Merchant J.L., Hua X., Lei M. The same pocket in menin binds both MLL and JUND but has opposite effects on transcription. Nature. 2012;482:542–546. doi: 10.1038/nature10806. PubMed DOI PMC

Blokken J., De Rijck J., Christ F., Debyser Z. Protein–protein and protein–chromatin interactions of LEDGF/p75 as novel drug targets. Drug Discov. Today Technol. 2017;24:25–31. doi: 10.1016/j.ddtec.2017.11.002. PubMed DOI

Wang H., Shun M.-C., Dickson A.K., Engelman A.N. Embryonic Lethality Due to Arrested Cardiac Development in Psip1/Hdgfrp2 Double-Deficient Mice. PLoS ONE. 2015;10:e0137797. doi: 10.1371/journal.pone.0137797. PubMed DOI PMC

Daigle S.R., Olhava E.J., Therkelsen C.A., Majer C.R., Sneeringer C.J., Song J., Johnston L.D., Scott M.P., Smith J.J., Xiao Y., et al. Selective killing of mixed lineage leukemia cells by a potent small-molecule DOT1L inhibitor. Cancer Cell. 2011;20:53–65. doi: 10.1016/j.ccr.2011.06.009. PubMed DOI PMC

Dawson M.A., Prinjha R.K., Dittmann A., Giotopoulos G., Bantscheff M., Chan W.-I., Robson S.C., Chung C., Hopf C., Savitski M.M., et al. Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia. Nature. 2011;478:529–533. doi: 10.1038/nature10509. PubMed DOI PMC

Borkin D., He S., Miao H., Kempinska K., Pollock J., Chase J., Purohit T., Malik B., Zhao T., Wang J., et al. Pharmacologic Inhibition of the Menin-MLL Interaction Blocks Progression of MLL Leukemia In~Vivo. Cancer Cell. 2015;27:589–602. doi: 10.1016/j.ccell.2015.02.016. PubMed DOI PMC

Aguilar A., Zheng K., Xu T., Xu S., Huang L., Fernandez-Salas E., Liu L., Bernard D., Harvey K.P., Foster C., et al. Structure-Based Discovery of M-89 as a Highly Potent Inhibitor of the Menin-Mixed Lineage Leukemia (Menin-MLL) Protein–Protein Interaction. J. Med. Chem. 2019;62:6015–6034. doi: 10.1021/acs.jmedchem.9b00021. PubMed DOI PMC

Sutherland H.G., Newton K., Brownstein D.G., Holmes M.C., Kress C., Semple C.A., Bickmore W.A. Disruption of Ledgf/Psip1 results in perinatal mortality and homeotic skeletal transformations. Mol. Cell. Biol. 2006;26:7201–7210. doi: 10.1128/MCB.00459-06. PubMed DOI PMC

Zhu X., Lan B., Yi X., He C., Dang L., Zhou X., Lu Y., Sun Y., Liu Z., Bai X., et al. HRP2-DPF3a-BAF complex coordinates histone modification and chromatin remodeling to regulate myogenic gene transcription. Nucleic Acids Res. 2020;48:6563–6582. doi: 10.1093/nar/gkaa441. PubMed DOI PMC

Najít záznam

Citační ukazatele

Pouze přihlášení uživatelé

Možnosti archivace

Nahrávání dat ...