MYC Translocations In Multiple Myeloma Involve Recruitment Of Enhancer Elements Resulting In Over- Expression and Decreased Overall Survival
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1 in partnership with MYC Translocations In Multiple Myeloma Involve Recruitment Of Enhancer Elements Resulting In Over- Expression and Decreased Overall Survival Brian A Walker Centre for Myeloma Research, Division of Molecular Pathology, The Institute of Cancer Research, London, United Kingdom UK Myeloma Forum 19 th March 2014 Making the discoveries that defeat cancer
2 Translocations In Myeloma 2 Primary events: IGH translocations t(4;14) t(6;14) t(11;14) t(14;16) t(14;20) Secondary events: IGH translocations t(8;14) Morgan, Walker & Davies Nat Rev Cancer :335
3 Oncogene Over-expression 3 Chr.14 Chr.4
4 Genetic Prognostic Markers in Myeloma Translocations t(4;14) t(14;16) t(14;20) vs months 32.9 vs months 16.9 vs months t(11;14) t(6;14) Adverse vs Neutral 51.6 vs months Not reached vs months 25.8 vs months
5 Translocation Detection in Myeloma 5 FISH in patient samples in the 2000 s IGH breakapart Fusion Probe No translocation Fusion Probe t(4;14) Breakapart probes for IGH@ followed by dual fusion probes for the partner chromosomes Cook et al. J Mol Diagn :459 The Next-Generation Sequencing (NGS) Approach Capture the regions in the Ig loci where the breakpoints occur and identify the partner chromosome by sequencing it
6 Targeted Capture Methodology 6 Capture sequences using baits designed against 14q232 Fragmented DNA containing normal and translocated hybrid fragments Sequence captured fragments using paired-end reads Align sequences to genome and identify fragments with sequences from different chromosomes Chr. 14 Chr. 4
7 Targeted Capture of IGH/K/L and MYC Samples Targeted Capture using SureSelect (Agilent) Selection of translocated samples defined by FISH 11x t(4;14) 3x t(6;14) 11x t(11;14) 9x t(14;16) 2x t(14;20) 10x non-translocated 4x unknown partner translocations 50x HRD Run over 2 lanes on HiSeq with 76 bp paired end reads Median depth of 289x
8 Translocation Breakpoint Summary 8
9 Secondary Translocations Involving MYC 9 Secondary translocations at 8q24 are present in ~15% of presentation myeloma patients (Walker et al., 2010; Avet-Loiseau et al. 2001) MYC is the oncogene of interest on 8q24 MYC has been shown to be activated in the transition from MGUS to MM implicating it in disease progression (Chng et al., 2011) Myeloma cells have a dependency on MYC for survival as shown by shrna and small molecule inhibitors (Holien et al., 2012) Activation of MYC in the Vk*MYC transgeneic mouse model results in myeloma (Chesi et al., 2008) t(8;14) MYC-IGH translocation accounts for ~25% of MYC rearrangements (Avet- Loiseau et al., 2001)
10 MYC capture 10 Fabris et al., GCC 2003 ~2.5 Mb of DNA tiled around MYC to capture rearrangements
11 Targeted Capture Methodology 11 Capture sequences using baits designed against 8q24 Fragmented DNA containing normal and translocated hybrid fragments Sequence captured fragments using paired-end reads Align sequences to genome and identify fragments with sequences from different chromosomes Chr. 8 Chr. 14
12 Incidence of MYC breakpoints in cytogenetic groups 12 Translocation Assayed With 8q24 Breakpoint P-value (%) (%) t(4;14) 13 (12.5) 0 (0) t(6;14) 8 (7.7) 1 (4.3) NS t(11;14) 28 (26.9) 6 (26.1) NS t(14;16) 17 (16.3) 11 (47.8) <0.001 t(14;20) 6 (5.8) 1 (4.3) NS HRD 31 (29.8) 3 (13) Other* 1 (0.9) 1 (4.3) NS TOTAL Depletion Enrichment Depletion
13 MYC Breakpoint Locations 13 19% 15% 12% 51.5%
14 MYC Partner Loci 14 Ig loci 34.8% - MYC over-expression through Ig enhancer (H>L>K)
15 Non-Ig MYC Partner Loci 15 Non-Ig loci 65.2% -?? Partners include: FAM46C KRAS LRRTM4 TOB2 CCND1 FOXO3 CHST15 XBP1
16 Non-Ig MYC Partner Loci 16 Non-Ig loci 65.2% -?? Partners include: FAM46C KRAS LRRTM4 TOB2 CCND1 FOXO3 CHST15 XBP1 Involved in plasma cell or myeloma development Do these genes also have active enhancers?
17 Identification of Super-Enhancers in MM1s Myeloma Cells 17 BRD4 and MED1 ChIP-seq to identify super-enhancer elements in MM1s cells
18 Super-Enhancers are Recruited to MYC 18
19 19 Enrichment for Super-Enhancers Surrounding Breakpoints Super-enhancers are known to be tissue-specific Therefore, if MYC is recruiting super-enhancers there should be enrichment of these elements surrounding the breakpoints in B cells. Compare breakpoint locations in myeloma to super-enhancers present in: 1 Mb - MM1.s (myeloma cell line) - CD19 (B cells) P= P= K562 (CML cell line) P= CD3 (T cell) P= skeletal muscle myoblast P= Significant enrichment for myeloma-specific super-enhancers near breakpoints (Super-enhancer data taken from Hnisz et al., Cell 2013)
20 MYC Translocations Result in Over-Expression and Decreased Survival Patients with expression and survival data from MRC Myeloma IX
21 A Unifying Method of MYC Dysregulation 21 MYC rearrangements in B-cell lymphoma identify partners including: IGH, IGK, IGL BCL6, PAX5, IKAROS (Bertrand et al., 2007) B-cell lineage Partners: IG loci B-cell Lymphoma Specific: BCL6, PAX5, IKAROS Myeloma Specific: CCND1, XBP1, KRAS, FAM46C, CHST15 MYC recruits active enhancers from highly expressed genes, which are specific to the cell type.
22 Oncogene Over-expression Chr.14 Enhancer IGH 22 Chr.14 Enhancer IGH MYC Chr.22 Enhancer XBP1 MYC
23 Conclusions Translocations at 8q can be detected using a capture method followed by massively parallel sequencing. 23 Breakpoints can be detected in 24% of presentation myeloma samples. Ig loci account for 35% of 8q24 partners, the remainder being non-ig partners. The non-ig partners include genes involved in B cell biology and myelomagenesis (such as XBP1, CHST15, FAM46C, KRAS, CCND1) There is significant enrichment for myeloma-specific super-enhancers around partner gene breakpoints MYC is more highly expressed in samples with a breakpoint Patients with a 8q24 breakpoint have a poorer PFS and OS Patients with MYC translocations may benefit from BRD inhibitors such as JQ1, which disrupt super-enhancers
24 Acknowledgements 24 Centre for Myeloma Research, The Institute of Cancer Research, London Gareth Morgan Faith Davies Chris Wardell Lorenzo Melchor Annamaria Brioli David Johnson Martin Kaiser Dil Begum Nasrin Dahir Paula Proszek Fabio Mirabella Alex Murison Ping Wu Charlotte Pawlyn Eileen Boyle Ni Li Wessex Regional Genetics Laboratory, Salisbury District Hospital, Salisbury Fiona Ross and her team
This is a repository copy of APOBEC family mutational signatures are associated with poor prognosis translocations in multiple myeloma.
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