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ADAR1 Promotes Malignant Progenitor Reprogramming in Chronic Myeloid Leukemia

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ADAR1 promotes malignant progenitor reprogramming in chronic myeloid leukemia Qingfei Jianga,b,c, Leslie A. Crewsa,b,c, Christian L. Barrettd, Hye-Jung Chune, Angela C. Courta,b,c, Jane M. Isquitha,b,c,f, Maria A. Zipetoa,b,c,g, Daniel J. Goffa,b,c, Mark Mindenh, Anil Sadarangania,b,c, Jessica M. Rusertc,i, Kim-Hien T. Daoj, Sheldon R. Morrisa,b, Lawrence S. B. Goldsteinc,i,k, Marco A. Marrae, Kelly A. Frazerd, and Catriona H. M. Jamiesona,b,c,1 aStem Cell Program, Department of Medicine, bMoores Cancer Center, dDivision of Genome Information Sciences, Department of Pediatrics, iDepartment of Cellular and Molecular Medicine, and kHoward Hughes Medical Institute, University of California at San Diego, La Jolla, CA 92093; eCanada’s Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC, Canada V5Z 1L3; fDepartment of Animal Science, California Polytechnic State University, San Luis Obispo, CA 93405; gDepartment of Health Sciences, University of Milano-Bicocca, 20052 Milan, Italy; hPrincess Margaret Hospital, Toronto, ON, Canada M5T 2M9; jCenter for Hematologic Malignancies, Oregon Health and Science University Knight Cancer Institute, Portland, OR 97239; and cSanford Consortium for Regenerative Medicine, La Jolla, CA 92037 Edited* by Irving L. Weissman, Stanford University, Stanford, CA, and approved November 30, 2012 (received for review July 30, 2012) The molecular etiology of human progenitor reprogramming into ADAR2 are active in embryonic cell types (18), and ADAR3 self-renewing leukemia stem cells (LSC) has remained elusive. Al- may play a nonenzymatic regulatory role in RNA editing activity though DNA sequencing has uncovered spliceosome gene muta- (22). ADAR enzymes regulate fetal and adult hematopoietic stem tions that promote alternative splicing and portend leukemic cell (HSC) maintenance and stem cell responses to inflammation transformation, isoform diversity also may be generated by RNA (23–26). ADAR-mediated adenosine-to-inosine (A-to-I) RNA editing mediated by adenosine deaminase acting on RNA (ADAR) editing in an Alu sequence containing dsRNA hairpin structures enzymes that regulate stem cell maintenance. In this study, whole- (14, 20) can generate alternative donor or acceptor splice sites transcriptome sequencing of normal, chronic phase, and serially (27, 28), alter RNA structure (21), modulate regulatory RNAs transplantable blast crisis chronic myeloid leukemia (CML) progen- and gene silencing activities (29), and introduce codon sequence itors revealed increased IFN-γ pathway gene expression in concert alterations (29). Interestingly, ADAR deregulation has been im- with BCR-ABL amplification, enhanced expression of the IFN-re- plicated in a variety of malignant cell types (30, 31). However, the sponsive ADAR1 p150 isoform, and a propensity for increased functional effects of RNA editing in leukemia have not been adenosine-to-inosine RNA editing during CML progression. Lenti- elucidated. Here we examined the role of ADAR1-mediated RNA editing in malignant reprogramming of myeloid progenitors viral overexpression experiments demonstrate that ADAR1 p150 into LSC that drive BC transformation in CML. promotes expression of the myeloid transcription factor PU.1 and Whole-transcriptome sequencing coupled with quantitative induces malignant reprogramming of myeloid progenitors. More- RT-PCR (qRT-PCR) analysis demonstrated increased IFN-re- over, enforced ADAR1 p150 expression was associated with produc- sponsive ADAR1 expression in LSC from primary BC CML pa- β tion of a misspliced form of GSK3 implicated in LSC self-renewal. tient samples as compared with CP CML and normal cord blood Finally, functional serial transplantation and shRNA studies dem- progenitors. This increase coincided with enhanced expression of MEDICAL SCIENCES onstrate that ADAR1 knockdown impaired in vivo self-renewal inflammatory pathway genes during the progression from CP to capacity of blast crisis CML progenitors. Together these data pro- BC. Moreover, ADAR1 p150 mRNA expression correlated with vide a compelling rationale for developing ADAR1-based LSC de- BCR-ABL amplification and increased A-to-I editing with dif- tection and eradication strategies. ferential expression of ADAR target genes in BC CML. Lentiviral ADAR1 p150 expression induced PU.1 expression that promotes lthough advanced malignancies are diverse in phenotype, expansion of myeloid progenitors and was associated with pro- Athey often exhibit stem-cell properties including enhanced duction of a misspliced form of glycogen synthase kinase (GSK)- survival, differentiation, quiescence, and self-renewal potential 3β that has been implicated in LSC self-renewal (7). Lentiviral ADAR1 knockdown also reduced BC LSC self-renewal capacity (1, 2). Early insights into the molecular pathogenesis of cancer − − − − stemmed from the discovery of the Philadelphia chromosome in RAG2 / γc / mice. These data shed light on the contribution + (Ph ) and its constitutively active BCR-ABL1 tyrosine kinase in of ADAR1-mediated RNA editing to malignant progenitor chronic myeloid leukemia (CML) (3–5). Tyrosine kinase inhibitor reprogramming driving leukemic progression. (TKI) therapy targeting BCR-ABL1 suppresses CML during the chronic phase (CP) of the disease in most patients able to tolerate Results long-term therapy (6). Although the CP stage of CML often can Inflammatory Mediator-Driven RNA Editing Portends Blastic Trans- be controlled for long periods of time with standard TKI thera- formation. To investigate the mechanisms driving malignant pies, subsequent genetic and epigenetic alterations promote pro- reprogramming of myeloid progenitors into LSC, we performed genitor expansion and the generation of self-renewing leukemia whole-transcriptome sequencing (RNA-seq) on FACS-purified + + − stem cells (LSC) that fuel disease progression and blast crisis (BC) CD34 CD38 Lin progenitor cells isolated from primary CML transformation along with TKI resistance (7, 8). Furthermore, TKI discontinuation usually results in CML resurgence, suggesting – that quiescent progenitors persist despite therapy (9 12). Author contributions: Q.J., M.A.M., K.A.F., and C.H.M.J. designed research; Q.J., C.L.B., Mutations in spliceosome genes and alternative splicing of H.-J.C., A.C.C., J.M.I., M.A.Z., D.J.G., A.S., and J.M.R. performed research; M.M., A.S., K.-H.T.D., coding and noncoding RNAs are emerging as important drivers L.S.B.G., M.A.M., and K.A.F. contributed new reagents/analytic tools; Q.J., L.A.C., C.L.B., of transcriptomic diversity that fuel leukemic progression and H.-J.C., A.C.C., J.M.I., M.A.Z., D.J.G., S.R.M., and C.H.M.J. analyzed data; and Q.J., L.A.C., therapeutic resistance (7, 8, 13). Moreover, previous studies re- and C.H.M.J. wrote the paper. veal extensive RNA editing in the human transcriptome (14–17), The authors declare no conflict of interest. primarily in primate-specific Alu sequences (18–20), which pro- *This Direct Submission article had a prearranged editor. motes splice isoform diversity. RNA editing activity is mediated Freely available online through the PNAS open access option. by the adenosine deaminase acting on dsRNA (ADAR) family of 1To whom correspondence should be addressed. E-mail: [email protected]. editases (21), which includes ADAR1 (also known as ADAR), This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. ADAR2 (ADARB1), and ADAR3 (ADARB2). ADAR1 and 1073/pnas.1213021110/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1213021110 PNAS | January 15, 2013 | vol. 110 | no. 3 | 1041–1046 Downloaded by guest on September 29, 2021 Imatinib- A FGF SIGNALING G treated PATHWAY(N) NATURAL PROTEOGLYCAN KILLER 3.00 SYNDECAN-MEDIATED ROLE OF MEF2D CELL MEDIATED 2.00 SIGNALING IN CYTOTOXICITY(K) 1.00 EVENTS(N) T-CELL 0.00 APOPTOSIS(B) -1.00 PDGFR-BETA BCELL T CELL -2.00 CP-13 CP-05 CP-01 BC-17 BC-06 BC-02 CP-12 CP-04 CP-19 BC-05 BC-08 BC-09 CP-02 CB-03 BC-07 CB-02 CP-06 BC-25 SIGNALING BCELL ACTIVATION(P) CB-01 FAM107B NECTIN ACTIVATION(P) -3.00 PATHWAY(N) RECEPTOR CD70 ADHESION THROMBOXANE RPS6KA2 A2 SIGNALING DCTN4 PATHWAY(N) FARP1 SPHINGOSINE RECEPTOR PATHWAY(K) RAP1GAP2 1-PHOSPHATE SIGNALING(N) SERINC5 S1P1 NRP1 PATHWAY(N) (S1P) KIF1C PATHWAY(N) CPM TRAIL NLRC5 SIGNALING T CELL ZCCHC7 EVENTS SIGNALING LARGE RECEPTOR MXRA7 REGULATION OF PATHWAY(N) MEDIATED BY SIGNALING NEK11 PTP1B(N) NUCLEAR STAT1 PATHWAY(K) TSPAN13 SMAD2/3 TNF RECEPTOR MGAT4A SIGNALING(N) CDK9 SIGNALING IL12RB1 BCR SIGNALING PLASMA GLYPICAN 1 C4orf34 P38 MAPKPATHWAY(N) PATHWAY(N) AGPS MEMBRANE NETWORK(N) TMEM154 ESTROGEN SIGNALING OLFML2A PATHWAY(N) GLYPICAN VCAN RECEPTOR PATHWAY(N) TCR SIGNALING ANXA2 SIGNALING(N) FBXW7 REGULATION OF CLASS I PI3K IN LY96 NAIVE CD4+ T RBM47 REGULATION OF P38-ALPHA SIGNALING GALNT3 AND EVENTS(N) CELLS(N) PTPN14 CYTOPLASMIC TRIM38 AND P38-BETA(N) IL1-MEDIATED HDAC5 SIGNALING FLNB NUCLEAR TCR SIGNALING CMTM8 BMP RECEPTOR EVENTS(N) SMAD2/3 IN CLMN SIGNALING(N) ARHGAP25 SIGNALING(N) NAIVE CD8+ T CUEDC1 TGF-BETA BC Increased in CML CELLS(N) SLC27A1 RECEPTOR TCR LAPTM5 γ ALOX5 IFN- SIGNALING(N) SIGNALING(R) SLC35E3 SPATS2L IL6-MEDIATED PATHWAY(N) RNASET2 MS4A7 SIGNALING CD58 EVENTS(N) RAB31 FDR 4.0E-05 0.01 IL12-MEDIATED PLCD3 SIGNALING MEF2A CDS2 EVENTS(N) LRRFIP1 PIK3IP1 NCUBE1 ICOSLG MEF2D ADAR1 mRNA Expression ANXA6 BC HCK *P<0.05 VIL2 2 FGD6 p150 r =0.63, P=0.058 RNF125 20 **P<0.05 50 TPM4 2 S100A16 p110 r =0.42, P=0.162 FRMD4B MYO5C GUCY1A3 40 ABCA1 15 PKM2 SSBP2 SNX2 30 KIAA2018 PROM1 10 RUNX2 DUSP3 20 ANPEP TIMP2 SH3BP2 ARHGAP26 5 MAML2 10 SMAD1 TCF7L2 SVIL ADAR1 mRNA Expression PLCB1 0 0 COQ10B ATF3 d 0.0 0.5 1.0 1.5 2.0 2.5 IRGQ Ratio of p150 to p110 mRNA Levels mRNA Ratio of p150 to p110 CP SESN1 RNF11 BCR-ABL mRNA Expression CLEC2B CML CML BC RHOC Cord Bloo RIPK2 NSUN7 RASGEF1B CNST A-to-I Editing Changes in CML BC v.
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  • G Protein-Coupled Receptors

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    S.P.H. Alexander et al. The Concise Guide to PHARMACOLOGY 2015/16: G protein-coupled receptors. British Journal of Pharmacology (2015) 172, 5744–5869 THE CONCISE GUIDE TO PHARMACOLOGY 2015/16: G protein-coupled receptors Stephen PH Alexander1, Anthony P Davenport2, Eamonn Kelly3, Neil Marrion3, John A Peters4, Helen E Benson5, Elena Faccenda5, Adam J Pawson5, Joanna L Sharman5, Christopher Southan5, Jamie A Davies5 and CGTP Collaborators 1School of Biomedical Sciences, University of Nottingham Medical School, Nottingham, NG7 2UH, UK, 2Clinical Pharmacology Unit, University of Cambridge, Cambridge, CB2 0QQ, UK, 3School of Physiology and Pharmacology, University of Bristol, Bristol, BS8 1TD, UK, 4Neuroscience Division, Medical Education Institute, Ninewells Hospital and Medical School, University of Dundee, Dundee, DD1 9SY, UK, 5Centre for Integrative Physiology, University of Edinburgh, Edinburgh, EH8 9XD, UK Abstract The Concise Guide to PHARMACOLOGY 2015/16 provides concise overviews of the key properties of over 1750 human drug targets with their pharmacology, plus links to an open access knowledgebase of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. The full contents can be found at http://onlinelibrary.wiley.com/doi/ 10.1111/bph.13348/full. G protein-coupled receptors are one of the eight major pharmacological targets into which the Guide is divided, with the others being: ligand-gated ion channels, voltage-gated ion channels, other ion channels, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading.
  • Genetic Alterations of Protein Tyrosine Phosphatases in Human Cancers

    Genetic Alterations of Protein Tyrosine Phosphatases in Human Cancers

    Oncogene (2015) 34, 3885–3894 © 2015 Macmillan Publishers Limited All rights reserved 0950-9232/15 www.nature.com/onc REVIEW Genetic alterations of protein tyrosine phosphatases in human cancers S Zhao1,2,3, D Sedwick3,4 and Z Wang2,3 Protein tyrosine phosphatases (PTPs) are enzymes that remove phosphate from tyrosine residues in proteins. Recent whole-exome sequencing of human cancer genomes reveals that many PTPs are frequently mutated in a variety of cancers. Among these mutated PTPs, PTP receptor T (PTPRT) appears to be the most frequently mutated PTP in human cancers. Beside PTPN11, which functions as an oncogene in leukemia, genetic and functional studies indicate that most of mutant PTPs are tumor suppressor genes. Identification of the substrates and corresponding kinases of the mutant PTPs may provide novel therapeutic targets for cancers harboring these mutant PTPs. Oncogene (2015) 34, 3885–3894; doi:10.1038/onc.2014.326; published online 29 September 2014 INTRODUCTION tyrosine/threonine-specific phosphatases. (4) Class IV PTPs include Protein tyrosine phosphorylation has a critical role in virtually all four Drosophila Eya homologs (Eya1, Eya2, Eya3 and Eya4), which human cellular processes that are involved in oncogenesis.1 can dephosphorylate both tyrosine and serine residues. Protein tyrosine phosphorylation is coordinately regulated by protein tyrosine kinases (PTKs) and protein tyrosine phosphatases 1 THE THREE-DIMENSIONAL STRUCTURE AND CATALYTIC (PTPs). Although PTKs add phosphate to tyrosine residues in MECHANISM OF PTPS proteins, PTPs remove it. Many PTKs are well-documented oncogenes.1 Recent cancer genomic studies provided compelling The three-dimensional structures of the catalytic domains of evidence that many PTPs function as tumor suppressor genes, classical PTPs (RPTPs and non-RPTPs) are extremely well because a majority of PTP mutations that have been identified in conserved.5 Even the catalytic domain structures of the dual- human cancers are loss-of-function mutations.