Principal Investigator, Wellcome Trust Beit Fellow
Research themes:Myeloma and normal lymphoid biology
Description of research
Multiple Myeloma is a haematological cancer characterized by the expansion of a clonal population of malignant plasma cells that results in organ damage. The pathophysiology is complex and commonly results in pancytopenia, painful bone disease, and renal failure. Although recent improvements have been made in the treatment with the introduction of immunomodulatory drugs and proteasome inhibitors, the disease is still considered incurable and has a median survival of around 4-5 years.
Our long-term aim is to understand the interplay between the myriad pathways involved in the pathogenesis of Multiple Myeloma so that these can be targeted for therapeutic benefit. The initial focus of our research is the role of aberrant RNA processing in Multiple Myeloma biology, based on findings from an initial sequencing of the Multiple Myeloma genome (Chapman et al. Nature 471:467-72). Indeed, emerging data imply that dysregulation of RNA processing is an important mechanism in cancer pathogenesis in general and may represent an “Achilles’ Heel” that can be targeted therapeutically. We are investigating not only the molecular mechanisms involved, but also the affected RNA targets, as these will identify nodes of intersection with known pathways as well as novel pathways in Myeloma biology.
This global understanding of RNA targets and its integration into our understanding of the key pathways will provide a strong platform for an expansion of our interests into other areas with significant translational impact. These will include: a molecular classification of the disease, based on mutational data; therapeutic choice based on the underlying genetics of the disease (personalized medicine); and screening and development of small molecules to target the vulnerable nodes in the key pathways of the disease.
Drawing on a wide experience in both molecular biology and bioinformatics, as well as extensive local expertise, we are applying a multidisciplinary approach, involving a number of cutting edge techniques. These will include molecular, cellular, genetic, structural, and genomic approaches and our work benefits from established local and international collaborations.
Keywords: RNA binding Post-transcriptional processing Lymphoid biology
Clinical conditions: Multiple Myeloma
Methodologies: RNA immunoprecipitation techniques Genetic approaches Human Myeloma Cell Lines Structural/functional protein studies RNA sequencing
Prof. Alan Warren, Laboratory of Molecular Biology
Dr. Peter Campbell, Wellcome Trust Sanger Institute
Dr. Brian Huntly, Cambridge Institute for Medical Research
Dr. Jernej Ule, Laboratory of Molecular Biology
Prof. Charlie Boone, University of Toronto
Chapman M, Warren EH, and Wu CJ. Applications of next generation sequencing to blood and marrow transplantation. Biol Blood Marrow Transplant. 2012 Jan;18(1 Suppl):S151-60.
Chapman MA, Lawrence MS, Keats JJ, Cibulskis K, Sougnez C, Schinzel AC, Harview CL, Brunet J, Ahmann GJ, Adli M, Anderson KC, Ardlie KG, Auclair D, Baker A, Bergsagel PL, Bernstein BL, Drier Y, Fonseca R, Gabriel SB, Hofmeister CC, Jagannath S, Jakubowiak AJ, Krishnan A, Levy J, Liefeld T, Lonial S, Mahan S, Mfuko B, Monti S, Perkins LM, Onofrio R, Pugh TJ, Rajkumar SV, Ramos AH, Siegel DS, Sivachenko A, Trudel S, Vij R, Voet D, Winckler W, Zimmerman T, Carpten J, Trent J, Hahn WC, Garraway LA, Meyerson M, Lander ES, Getz G, Golub TR. Initial genome sequencing and analysis of multiple myeloma. Nature 2011 Mar 24;471(7339):467-72.
Göttgens B, Ferreira R, Sanchez M, Ishibashi S, Li J, Spensberger D, Lefevre P, Ottersbach K, Chapman M, Kinston S, Knezevic K, Hoogenkamp M, Follows G, Bonifer C, Amaya E, Green A. Cis-regulatory remodeling of the SCL locus during vertebrate evolution. Mol Cell Biol. 2010 Dec;30(24):5741-5.
Delabesse E, Ogilvy S, Chapman MA, Piltz SG, Gottgens B, Green AR. Transcriptional regulation of the SCL locus: identification of an enhancer that targets the primitive erythroid lineage in vivo. Mol Cell Biol. 2005 Jun;25(12):5215-25.
Donaldson IJ, Chapman M, Göttgens B. TFBS cluster: a resource for the characterization of transcriptional regulatory networks. Bioinformatics. 2005 Jul 1;21(13):3058-9.
Donaldson IJ, Chapman M, Kinston S, Landry JR, Knezevic K, Piltz S, Buckley N, Green AR, Göttgens B. Genome-wide identification of cis-regulatory sequences controlling blood and endothelial development. Hum Mol Genet. 2005 Mar 1;14(5):595-601.
Chapman MA and Green AR. Transcription factors in hematopoietic differentiation and leukemia Chapter 5: Textbook of Malignant Hematology. Laurent Degos, David C. Linch, Bob Lowenberg (editors)
Bruce AW, Donaldson IJ, Wood IC, Yerbury SA, Sadowski MI, Chapman M, Göttgens B, Buckley NJ. Genome-wide analysis of repressor element 1 silencing transcription factor/neuron-restrictive silencing factor (REST/NRSF) target genes. Proc Natl Acad Sci U S A. 2004 Jul 13;101(28):10458-63.
Chapman MA, Donaldson IJ, Gilbert J, Grafham D, Rogers J, Green AR, Göttgens B. Analysis of multiple genomic sequence alignments: a web resource, online tools, and lessons learned from analysis of mammalian SCL loci. Genome Res. 2004 Feb;14(2):313-8.
Brudno M, Chapman MA, Göttgens B, Batzoglou S, Morgenstern B. Fast and sensitive multiple alignment of large genomic sequences. BMC Bioinformatics. 2003 Dec 23;4:66.
Chapman MA, Charchar FJ, Kinston S, Bird CP, Grafham D, Rogers J, Grützner F, Graves JA, Green AR, Göttgens B. Comparative and functional analyses of LYL1 loci establish marsupial sequences as a model for phylogenetic footprinting. Genomics. 2003 Mar;81(3):249-59.
Göttgens B, Barton LM, Chapman MA, Sinclair AM, Knudsen B, Grafham D, Gilbert JG, Rogers J, Bentley DR, Green AR. Transcriptional regulation of the stem cell leukemia gene (SCL) – comparative analysis of five vertebrate SCL loci. Genome Res. 2002 May;12(5):749-59.