MBNL1 regulates essential alternative RNA splicing patterns in MLL-rearranged leukemia.

Alternative Splicing Animals Antineoplastic Agents / pharmacology Apoptosis / drug effects Bone Marrow Transplantation Cell Line, Tumor DNA-Binding Proteins / genetics Datasets as Topic Gene Expression Regulation, Neoplastic Gene Knockdown Techniques Gene Rearrangement Histone-Lysine N-Methyltransferase / genetics Humans Introns / genetics Leukemia / drug therapy Mice Mice, Knockout Myeloid-Lymphoid Leukemia Protein / genetics Oncogene Proteins, Fusion / genetics Primary Cell Culture RNA, Small Interfering / metabolism RNA-Binding Proteins / antagonists & inhibitors RNA-Seq Transplantation Chimera Xenograft Model Antitumor Assays

Journal

Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555

Informations de publication

Date de publication:
12 05 2020
Historique:
received: 27 01 2019
accepted: 25 03 2020
entrez: 14 5 2020
pubmed: 14 5 2020
medline: 1 9 2020
Statut: epublish

Résumé

Despite growing awareness of the biologic features underlying MLL-rearranged leukemia, targeted therapies for this leukemia have remained elusive and clinical outcomes remain dismal. MBNL1, a protein involved in alternative splicing, is consistently overexpressed in MLL-rearranged leukemias. We found that MBNL1 loss significantly impairs propagation of murine and human MLL-rearranged leukemia in vitro and in vivo. Through transcriptomic profiling of our experimental systems, we show that in leukemic cells, MBNL1 regulates alternative splicing (predominantly intron exclusion) of several genes including those essential for MLL-rearranged leukemogenesis, such as DOT1L and SETD1A. We finally show that selective leukemic cell death is achievable with a small molecule inhibitor of MBNL1. These findings provide the basis for a new therapeutic target in MLL-rearranged leukemia and act as further validation of a burgeoning paradigm in targeted therapy, namely the disruption of cancer-specific splicing programs through the targeting of selectively essential RNA binding proteins.

Identifiants

DOI: 10.1038/s41467-020-15733-8 PMID: 32398749 PMC: PMC7217953
pubmed: 32398749
doi: 10.1038/s41467-020-15733-8
pii: 10.1038/s41467-020-15733-8
pmc: PMC7217953
doi:

Substances chimiques

Antineoplastic Agents 0
DNA-Binding Proteins 0
MBNL1 protein, human 0
MLL-AF9 fusion protein, human 0
Mbnl1 protein, mouse 0
Oncogene Proteins, Fusion 0
RNA, Small Interfering 0
RNA-Binding Proteins 0
Myeloid-Lymphoid Leukemia Protein 149025-06-9
DOT1L protein, human EC 2.1.1.-
Histone-Lysine N-Methyltransferase EC 2.1.1.43
Setd1A protein, human EC 2.1.1.43

Types de publication

Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

2369

Subventions

Organisme : NCI NIH HHS
ID : R01 CA226802
Pays : United States
Organisme : NCI NIH HHS
ID : R50 CA211404
Pays : United States
Organisme : NIH HHS
ID : S10 OD023410
Pays : United States
Organisme : NHLBI NIH HHS
ID : L40 HL143713
Pays : United States

Commentaires et corrections

Type : ErratumIn

Références

Ziemin-van der Poel, S. et al. Identification of a gene, MLL, that spans the breakpoint in 11q23 translocations associated with human leukemias. Proc. Natl Acad. Sci. USA 88, 10735–10739 (1991).
pubmed: 1720549 doi: 10.1073/pnas.88.23.10735 pmcid: 53005
Chen, C. S. et al. The chromosome 4q21 gene (AF-4/FEL) is widely expressed in normal tissues and shows breakpoint diversity in t(4;11)(q21;q23) acute leukemia. Blood 82, 1080–1085 (1993).
pubmed: 8353274 doi: 10.1182/blood.V82.4.1080.bloodjournal8241080
Chen, W. et al. Malignant transformation initiated by Mll-AF9: gene dosage and critical target cells. Cancer Cell 13, 432–440 (2008).
pubmed: 18455126 pmcid: 2430522 doi: 10.1016/j.ccr.2008.03.005
Ross, M. E. et al. Gene expression profiling of pediatric acute myelogenous leukemia. Blood 104, 3679–3687 (2004).
pubmed: 15226186 doi: 10.1182/blood-2004-03-1154
Armstrong, S. A. et al. MLL translocations specify a distinct gene expression profile that distinguishes a unique leukemia. Nat. Genet. 30, 41–47 (2002).
pubmed: 11731795 doi: 10.1038/ng765
Stam, R. W. et al. Gene expression profiling-based dissection of MLL translocated and MLL germline acute lymphoblastic leukemia in infants. Blood 115, 2835–2844 (2010).
pubmed: 20032505 doi: 10.1182/blood-2009-07-233049
Ho, T. H. et al. Muscleblind proteins regulate alternative splicing. EMBO J. 23, 3103–3112 (2004).
pubmed: 15257297 pmcid: 514918 doi: 10.1038/sj.emboj.7600300
Terenzi, F. & Ladd, A. N. Conserved developmental alternative splicing of muscleblind-like (MBNL) transcripts regulates MBNL localization and activity. RNA Biol. 7, 43–55 (2010).
pubmed: 20009516 doi: 10.4161/rna.7.1.10401
Wang, E. T. C. et al. regulation of pre-mRNA splicing and mRNA localization by muscleblind proteins. Cell 150, 710–724 (2012).
pubmed: 22901804 pmcid: 3428802 doi: 10.1016/j.cell.2012.06.041
Batra, R. et al. Loss of MBNL leads to disruption of developmentally regulated alternative polyadenylation in RNA-mediated disease. Mol. Cell 56, 311–322 (2014).
pubmed: 25263597 pmcid: 4224598 doi: 10.1016/j.molcel.2014.08.027
Masuda, A. et al. CUGBP1 and MBNL1 preferentially bind to 3’ UTRs and facilitate mRNA decay. Sci. Rep. 2, 209 (2012).
pubmed: 22355723 pmcid: 3250574 doi: 10.1038/srep00209
Konieczny, P., Stepniak-Konieczna, E. & Sobczak, K. MBNL proteins and their target RNAs, interaction and splicing regulation. Nucleic Acids Res. 42, 10873–10887 (2014).
pubmed: 25183524 pmcid: 4176163 doi: 10.1093/nar/gku767
Han, H. et al. MBNL proteins repress ES-cell-specific alternative splicing and reprogramming. Nature 498, 241–245 (2013).
pubmed: 23739326 pmcid: 3933998 doi: 10.1038/nature12270
Cheng, A. W. et al. Muscleblind-like 1 (Mbnl1) regulates pre-mRNA alternative splicing during terminal erythropoiesis. Blood 124, 598–610 (2014).
pubmed: 24869935 pmcid: 4110662 doi: 10.1182/blood-2013-12-542209
Adamia, S. et al. A genome-wide aberrant RNA splicing in patients with acute myeloid leukemia identifies novel potential disease markers and therapeutic targets. Clin. Cancer Res. 20, 1135–1145 (2014).
pubmed: 24284058 doi: 10.1158/1078-0432.CCR-13-0956
Adamia, S. et al. NOTCH2 and FLT3 gene mis-splicings are common events in patients with acute myeloid leukemia (AML): new potential targets in AML. Blood 123, 2816–2825 (2014).
pubmed: 24574459 pmcid: 4007608 doi: 10.1182/blood-2013-02-481507
Mohamed, A. M. et al. How mRNA is misspliced in acute myelogenous leukemia (AML). Oncotarget 5, 9534–9545 (2014).
Mohamed, A. M. et al. Oncogene- and drug resistance-associated alternative exon usage in acute myeloid leukemia (AML). Oncotarget 7, 2889–2909 (2016).
pubmed: 26284582 doi: 10.18632/oncotarget.3898
Sun, L. et al. Expression of aberrantly spliced oncogenic ikaros isoforms in childhood acute lymphoblastic leukemia. J. Clin. Oncol. 17, 3753–3766 (1999).
pubmed: 10577847 doi: 10.1200/JCO.1999.17.12.3753
Wilkinson, A. C. et al. RUNX1 is a key target in t(4;11) leukemias that contributes to gene activation through an AF4-MLL complex interaction. Cell Rep. 3, 116–127 (2013).
pubmed: 23352661 pmcid: 3607232 doi: 10.1016/j.celrep.2012.12.016
Zangrando, A., Dell’orto, M. C., Te Kronnie, G. & Basso, G. MLL rearrangements in pediatric acute lymphoblastic and myeloblastic leukemias: MLL specific and lineage specific signatures. BMC Med Genomics 2, 36 (2009).
pubmed: 19549311 pmcid: 2709660 doi: 10.1186/1755-8794-2-36
Mullighan, C. G. et al. Pediatric acute myeloid leukemia with NPM1 mutations is characterized by a gene expression profile with dysregulated HOX gene expression distinct from MLL-rearranged leukemias. Leukemia 21, 2000–2009 (2007).
pubmed: 17597811 doi: 10.1038/sj.leu.2404808
Tyner, J. W. et al. Functional genomic landscape of acute myeloid leukaemia. Nature 562, 526–531 (2018).
pubmed: 30333627 pmcid: 6280667 doi: 10.1038/s41586-018-0623-z
Liu, Y. et al. The genomic landscape of pediatric and young adult T-lineage acute lymphoblastic leukemia. Nat. Genet. 49, 1211–1218 (2017).
pubmed: 28671688 pmcid: 5535770
Zhang, J. et al. Deregulation of DUX4 and ERG in acute lymphoblastic leukemia. Nat. Genet. 48, 1481–1489 (2016).
pubmed: 27776115 pmcid: 5144107 doi: 10.1038/ng.3691
Andersson, A. K. et al. The landscape of somatic mutations in infant MLL-rearranged acute lymphoblastic leukemias. Nat. Genet. 47, 330–337 (2015).
pubmed: 25730765 pmcid: 4553269 doi: 10.1038/ng.3230
Faber, Z. J. et al. The genomic landscape of core-binding factor acute myeloid leukemias. Nat. Genet. 48, 1551–1556 (2016).
pubmed: 27798625 pmcid: 5508996 doi: 10.1038/ng.3709
de Rooij, J. D. et al. Pediatric non-Down syndrome acute megakaryoblastic leukemia is characterized by distinct genomic subsets with varying outcomes. Nat. Genet. 49, 451–456 (2017).
pubmed: 28112737 pmcid: 5687824 doi: 10.1038/ng.3772
Lin, S. et al. Instructive role of MLL-fusion proteins revealed by a model of t(4;11) Pro-B acute lymphoblastic leukemia. Cancer Cell 30, 737–749 (2016).
pubmed: 27846391 doi: 10.1016/j.ccell.2016.10.008
Prange, K. et al. MLL-AF9 and MLL-AF4 oncofusion proteins bind a distinct enhancer repertoire and target the RUNX1 program in 11q23 acute myeloid leukemia. Oncogene 36, 3346–3356 (2017).
pubmed: 28114278 pmcid: 5474565 doi: 10.1038/onc.2016.488
Numata, A. et al. The basic helix-loop-helix transcription factor SHARP1 is an oncogenic driver in MLL-AF6 acute myelogenous leukemia. Nat. Commun. 9, 1–16 (2018).
doi: 10.1038/s41467-018-03854-0
Geng, H. et al. Integrative epigenomic analysis identifies biomarkers and therapeutic targets in adult B-acute lymphoblastic leukemia. Cancer Discov. 2, 1004–1023 (2012).
pubmed: 23107779 pmcid: 3516186 doi: 10.1158/2159-8290.CD-12-0208
Guenther, M. G. et al. Aberrant chromatin at genes encoding stem cell regulators in human mixed-lineage leukemia. Genes Dev. 22, 3403–3408 (2008).
pubmed: 19141473 pmcid: 2607073 doi: 10.1101/gad.1741408
Zhao, X. et al. Downregulation of RUNX1/CBFbeta by MLL fusion proteins enhances hematopoietic stem cell self-renewal. Blood 123, 1729–1738 (2014).
pubmed: 24449215 pmcid: 4067497 doi: 10.1182/blood-2013-03-489575
Zuber, J. et al. An integrated approach to dissecting oncogene addiction implicates a Myb-coordinated self-renewal program as essential for leukemia maintenance. Genes Dev. 25, 1628–1640 (2011).
pubmed: 21828272 pmcid: 3182026 doi: 10.1101/gad.17269211
Wei, J. et al. Microenvironment determines lineage fate in a human model of MLL-AF9 leukemia. Cancer Cell 13, 483–495 (2008).
pubmed: 18538732 pmcid: 2486365 doi: 10.1016/j.ccr.2008.04.020
Childs-Disney, J. L. et al. Induction and reversal of myotonic dystrophy type 1 pre-mRNA splicing defects by small molecules. Nat Commun 4, 2044, (2013).
Kanadia, R. N. et al. A muscleblind knockout model for myotonic dystrophy. Science 302, 1978–1980 (2003).
pubmed: 14671308 doi: 10.1126/science.1088583
Du, H. et al. Aberrant alternative splicing and extracellular matrix gene expression in mouse models of myotonic dystrophy. Nat. Struct. Mol. Biol. 17, 187–193 (2010).
pubmed: 20098426 pmcid: 2852634 doi: 10.1038/nsmb.1720
Lin, X. et al. Failure of MBNL1-dependent post-natal splicing transitions in myotonic dystrophy. Hum. Mol. Genet. 15, 2087–2097 (2006).
pubmed: 16717059 doi: 10.1093/hmg/ddl132
Venables, J. P. et al. MBNL1 and RBFOX2 cooperate to establish a splicing programme involved in pluripotent stem cell differentiation. Nat. Commun. 4, 1–10 (2013).
doi: 10.1038/ncomms3480
Du, J. et al. RNA toxicity and missplicing in the common eye disease fuchs endothelial corneal dystrophy. J. Biol. Chem. 290, 5979–5990 (2015).
pubmed: 25593321 pmcid: 4358235 doi: 10.1074/jbc.M114.621607
Gates, D. P., Coonrod, L. A. & Berglund, J. A. Autoregulated splicing of muscleblind-like 1 (MBNL1) Pre-mRNA. J. Biol. Chem. 286, 34224–34233 (2011).
pubmed: 21832083 pmcid: 3190765 doi: 10.1074/jbc.M111.236547
Lavallee, V.-P. et al. The transcriptomic landscape and directed chemical interrogation of MLL-rearranged acute myeloid leukemias. Nat. Genet. 47, 1030–1037 (2015).
pubmed: 26237430 doi: 10.1038/ng.3371
Fang, J. et al. TRAF6 Mediates Basal Activation of NF-kappaB Necessary for Hematopoietic Stem Cell Homeostasis. Cell Rep 22, 1250–1262 (2018)
Muench, D. E. et al. SKI controls MDS-associated chronic TGF-beta signaling, aberrant splicing, and stem cell fitness. Blood 132, e24–e34, (2018).
Hoshii, T. et al. A Non-catalytic function of SETD1A regulates cyclin K and the DNA damage response. Cell 172, 1007–1021 (2018).
pubmed: 29474905 pmcid: 6052445 doi: 10.1016/j.cell.2018.01.032
Deshpande, A. J. et al. Leukemic transformation by the MLL-AF6 fusion oncogene requires the H3K79 methyltransferase Dot1l. Blood 121, 2533–2541 (2013).
pubmed: 23361907 pmcid: 3612861 doi: 10.1182/blood-2012-11-465120
Bernt, K. M. et al. MLL-rearranged leukemia is dependent on aberrant H3K79 methylation by DOT1L. Cancer Cell 20, 66–78 (2011).
pubmed: 21741597 pmcid: 3329803 doi: 10.1016/j.ccr.2011.06.010
Winters, A. C. & Bernt, K. M. MLL-rearranged leukemias— an update on science and clinical approaches. Front. Pediatrics 5, 1–21 (2017).
doi: 10.3389/fped.2017.00004
Subramanian, A. et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc. Natl Acad. Sci. USA 102, 15545–15550 (2005).
pubmed: 16199517 pmcid: 1239896
Faber, J. et al. HOXA9 is required for survival in human MLL-rearranged acute leukemias. Blood 113, 2375–2385 (2009).
pubmed: 19056693 pmcid: 2656267 doi: 10.1182/blood-2007-09-113597
Wang, Z. et al. GSK-3 promotes conditional association of CREB and its coactivators with MEIS1 to facilitate HOX-mediated transcription and oncogenesis. Cancer Cell 17, 597–608 (2010).
pubmed: 20541704 pmcid: 2919232 doi: 10.1016/j.ccr.2010.04.024
Wang, Z. et al. Glycogen synthase kinase 3 in MLL leukaemia maintenance and targeted therapy. Nature 455, 1205–1209 (2008).
pubmed: 18806775 pmcid: 4084721 doi: 10.1038/nature07284
Miller, J. W. et al. Recruitment of human muscleblind proteins to (CUG)(n) expansions associated with myotonic dystrophy. EMBO J. 19, 4439–4448 (2000).
pubmed: 10970838 pmcid: 302046 doi: 10.1093/emboj/19.17.4439
Starkova, J. et al. HOX gene expression in phenotypic and genotypic subgroups and low HOXA gene expression as an adverse prognostic factor in pediatric ALL. Pediatr. Blood Cancer 55, 1072–1082 (2010).
pubmed: 20672366 doi: 10.1002/pbc.22749
Trentin, L. et al. Two independent gene signatures in pediatric t(4;11) acute lymphoblastic leukemia patients. Eur. J. Haematol. 83, 406–419 (2009).
pubmed: 19558506 doi: 10.1111/j.1600-0609.2009.01305.x
Chen, L. et al. Transcriptional diversity during lineage commitment of human blood progenitors. Science 345, 1251033 (2014).
pubmed: 25258084 pmcid: 4254742 doi: 10.1126/science.1251033
Lee, K. Y. et al. Compound loss of muscleblind-like function in myotonic dystrophy. EMBO Mol. Med. 5, 1887–1900 (2013).
pubmed: 24293317 pmcid: 3914532 doi: 10.1002/emmm.201303275
Wang, E. et al. Targeting an RNA-binding protein network in acute myeloid leukemia. Cancer Cell 35, 369–384 e367 (2019).
pubmed: 30799057 pmcid: 6424627 doi: 10.1016/j.ccell.2019.01.010
Dobin, A. et al. STAR: ultrafast universal RNA-seq aligner. Bioinformatics 29, 15–21 (2013).
pubmed: 23104886
Heinz, S. et al. Simple combinations of lineage-determining transcription factors prime cis-regulatory elements required for macrophage and B cell identities. Mol. Cell 38, 576–589 (2010).
pubmed: 20513432 pmcid: 2898526
Ray, D. et al. A compendium of RNA-binding motifs for decoding gene regulation. Nature 499, 172–177 (2013).
pubmed: 23846655 pmcid: 3929597 doi: 10.1038/nature12311
Chen, J., Bardes, E. E., Aronow, B. J. & Jegga, A. G. ToppGene Suite for gene list enrichment analysis and candidate gene prioritization. Nucleic Acids Res. 37, W305–311 (2009).
pubmed: 19465376 pmcid: 2703978 doi: 10.1093/nar/gkp427

Auteurs

Svetlana S Itskovich (SS)

Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45229, USA.

Arun Gurunathan (A)

Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45229, USA.
ORCID: 0000-0003-3332-7395

Jason Clark (J)

Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45229, USA.
ORCID: 0000-0001-7812-4685

Matthew Burwinkel (M)

Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45229, USA.

Mark Wunderlich (M)

Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45229, USA.

Mikaela R Berger (MR)

College of Medicine, University of Cincinnati School of Medicine, Cincinnati, OH, 45267, USA.

Aishwarya Kulkarni (A)

Department of Electrical Engineering and Computer Science, University of Cincinnati, Cincinnati, OH, 45221, USA.
Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45229, USA.

Kashish Chetal (K)

Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45229, USA.

Meenakshi Venkatasubramanian (M)

Department of Electrical Engineering and Computer Science, University of Cincinnati, Cincinnati, OH, 45221, USA.
Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45229, USA.

Nathan Salomonis (N)

Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45229, USA.
Department of Pediatrics, University of Cincinnati School of Medicine, Cincinnati, OH, 45229, USA.
ORCID: 0000-0001-9689-2469

Ashish R Kumar (AR)

Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45229, USA.
Department of Pediatrics, University of Cincinnati School of Medicine, Cincinnati, OH, 45229, USA.
ORCID: 0000-0002-8306-8419

Lynn H Lee (LH)

Department of Pediatrics, University of Cincinnati School of Medicine, Cincinnati, OH, 45229, USA. lynn.lee@cchmc.org.
Division of Oncology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45229, USA. lynn.lee@cchmc.org.
ORCID: 0000-0002-2898-6196

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Classifications MeSH

questionsmedicales.fr › Phénomènes génétiques › Régulation de l'expression des gènes › Maturation post-transcriptionnelle des ARN › Épissage des ARN › Épissage alternatif › MBNL1 regulates essential alternative RNA...
questionsmedicales.fr › Eucaryotes › Animaux › MBNL1 regulates essential alternative RNA...
questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Utilisations thérapeutiques › Antinéoplasiques › MBNL1 regulates essential alternative RNA...
questionsmedicales.fr › Phénomènes physiologiques cellulaires › Mort cellulaire › Mort cellulaire régulée › Apoptose › MBNL1 regulates essential alternative RNA...
questionsmedicales.fr › Procédures de chirurgie opératoire › Transplantation › Transplantation de tissu › Transplantation de moelle osseuse › MBNL1 regulates essential alternative RNA...
questionsmedicales.fr › Cellules › Cellules cultivées › Cellules cancéreuses en culture › Lignée cellulaire tumorale › MBNL1 regulates essential alternative RNA...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines de liaison à l'ADN › MBNL1 regulates essential alternative RNA...
questionsmedicales.fr › Environnement et santé publique › Santé publique › Méthodes épidémiologiques › Collecte de données › Jeux de données comme sujet › MBNL1 regulates essential alternative RNA...
questionsmedicales.fr › Phénomènes génétiques › Régulation de l'expression des gènes › Régulation de l'expression des gènes tumoraux › MBNL1 regulates essential alternative RNA...
questionsmedicales.fr › Techniques d'investigation › Techniques génétiques › Ciblage de gène › Techniques de knock-down de gènes › MBNL1 regulates essential alternative RNA...
questionsmedicales.fr › Phénomènes génétiques › Réarrangement des gènes › MBNL1 regulates essential alternative RNA...
questionsmedicales.fr › Enzymes et coenzymes › Enzymes › Transferases › One-carbon group transferases › Methyltransferases › Protein Methyltransferases › Histone méthyltransférases › Histone-lysine N-methyltransferase › MBNL1 regulates essential alternative RNA...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › MBNL1 regulates essential alternative RNA...
questionsmedicales.fr › Phénomènes génétiques › Structures génétiques › Génome › Composants de génome › Gènes › Composants de gène › Introns › MBNL1 regulates essential alternative RNA...
questionsmedicales.fr › Tumeurs › Tumeurs par type histologique › Leucémies › MBNL1 regulates essential alternative RNA...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › MBNL1 regulates essential alternative RNA...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Souris transgéniques › Souris knockout › MBNL1 regulates essential alternative RNA...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Facteurs de transcription › Protéine de la leucémie myéloïde-lymphoïde › MBNL1 regulates essential alternative RNA...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines tumorales › Protéines oncogènes › Protéines de fusion oncogènes › MBNL1 regulates essential alternative RNA...
questionsmedicales.fr › Techniques d'investigation › Techniques in vitro › Techniques de culture › Techniques de culture cellulaire › Culture de cellules primaires › MBNL1 regulates essential alternative RNA...
questionsmedicales.fr › Acides nucléiques, nucléotides et nucléosides › Acides nucléiques › ARN › ARN non traduit › Petit ARN non traduit › Petit ARN interférent › MBNL1 regulates essential alternative RNA...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Nucléoprotéines › Protéines de liaison à l'ARN › MBNL1 regulates essential alternative RNA...
questionsmedicales.fr › Techniques d'investigation › Techniques génétiques › Analyse de séquence › Analyse de séquence d'ARN › RNA-Seq › MBNL1 regulates essential alternative RNA...
questionsmedicales.fr › Stades d'organismes › Chimère › Chimère obtenue par transplantation › MBNL1 regulates essential alternative RNA...
questionsmedicales.fr › Techniques d'investigation › Transplantation tumorale › Tests d'activité antitumorale sur modèle de xénogreffe › MBNL1 regulates essential alternative RNA...