Multiple Myeloma (MM) Is a complex disease driven by numerous genetic and epigenetic alterations. Our compretiensive oncogenomic analysis indicates the presence of many tightly recurrent and tightly focal amplifications/deletions in the MM genome. Indeed, integrated oncogenomic analyses of human MM have identified candidates resident within regions of amplification/deletions predicted to be involved in MM pathogenesis and progression. Using the clinical and genomic information from patient samples, our goals are to identify novel molecular lesions with clinical prognostic and therapeutic correlation. Our preliminary oncogenomic studies have confirmed our ability to perform large-scale high-throughput genomic profiling on myeloma cells from patient bone marrow (BM) samples. We hypothesize that the biological behavior and clinical outcome in MM is dependent on molecular determinants, which are also attractive therapeutic targets. In this Project we will: characterize the spectrum of genomic lesions associated with pathogenesis and progression of monoclonal gammopathy of undetermined significance (MGUS)/Smoldering MM (SMM) to active MM (Sp Aim 1);identify genomic alterations in 1,000 newly diagnosed uniformly treated patients correlating with clinical outcome (Sp Aim 2);and determine whether mechanisms modifying transcriptome are associated with clinical outcome (Sp Aim 3). This project will provide a better understanding of the impact of copy number and gene expression alterations and their functional consequences on MM initiation and progression, as well as identify novel targets for therapeutic intervention.

Public Health Relevance

This project will identify genomic markers of progression of MGUS/SMM to myeloma and highlight alteration in copy number and gene expression predictive of prognosis in uniformly treated patients. This will also identify novel targets for validation and therapeutic application.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA155258-04
Application #
8733612
Study Section
Special Emphasis Panel (ZCA1-RPRB-J)
Project Start
Project End
Budget Start
2014-09-01
Budget End
2015-08-31
Support Year
4
Fiscal Year
2014
Total Cost
$155,746
Indirect Cost
$40,148
Name
Dana-Farber Cancer Institute
Department
Type
DUNS #
076580745
City
Boston
State
MA
Country
United States
Zip Code
02215
Bae, J; Hideshima, T; Zhang, G L et al. (2018) Identification and characterization of HLA-A24-specific XBP1, CD138 (Syndecan-1) and CS1 (SLAMF7) peptides inducing antigens-specific memory cytotoxic T lymphocytes targeting multiple myeloma. Leukemia 32:752-764
O'Donnell, Elizabeth K; Laubach, Jacob P; Yee, Andrew J et al. (2018) A phase 2 study of modified lenalidomide, bortezomib and dexamethasone in transplant-ineligible multiple myeloma. Br J Haematol 182:222-230
Guo, Guangwu; Raje, Noopur S; Seifer, Charles et al. (2018) Genomic discovery and clonal tracking in multiple myeloma by cell-free DNA sequencing. Leukemia 32:1838-1841
Szalat, R; Samur, M K; Fulciniti, M et al. (2018) Nucleotide excision repair is a potential therapeutic target in multiple myeloma. Leukemia 32:111-119
Nair, Shiny; Sng, Joel; Boddupalli, Chandra Sekhar et al. (2018) Antigen-mediated regulation in monoclonal gammopathies and myeloma. JCI Insight 3:
Gullà, A; Hideshima, T; Bianchi, G et al. (2018) Protein arginine methyltransferase 5 has prognostic relevance and is a druggable target in multiple myeloma. Leukemia 32:996-1002
Mazzotti, Céline; Buisson, Laure; Maheo, Sabrina et al. (2018) Myeloma MRD by deep sequencing from circulating tumor DNA does not correlate with results obtained in the bone marrow. Blood Adv 2:2811-2813
Miannay, Bertrand; Minvielle, Stéphane; Magrangeas, Florence et al. (2018) Constraints on signaling network logic reveal functional subgraphs on Multiple Myeloma OMIC data. BMC Syst Biol 12:32
Samur, Mehmet Kemal; Minvielle, Stephane; Gulla, Annamaria et al. (2018) Long intergenic non-coding RNAs have an independent impact on survival in multiple myeloma. Leukemia 32:2626-2635
Singh, Irtisha; Lee, Shih-Han; Sperling, Adam S et al. (2018) Widespread intronic polyadenylation diversifies immune cell transcriptomes. Nat Commun 9:1716

Showing the most recent 10 out of 218 publications