Multiple myeloma (MM) represents the continued proliferation of a terminal differentiated B cell. MM cells share the properties of normal plasma cells such as high protein production and hardiness but differ in that MM cells continue to proliferate and express c-Myc despite their terminal differentiated state. The proliferative program of MM is coordinated by transcription factors and chromatin-associated factors. Transcription factors such as MYC, NFGB, MAF and XBP1 are linked to disease pathogenesis, tissue specificity, and drug resistance. Several of these factors are overexpressed in MM through aberrant linkage of the immunoglobulin promoter to the TF gene. Furthermore, sequence analysis of the MM genome revealed that amongst the genes mutated or deleted in MM, there is over-representation of chromatin regulatory factors. The centrality of histone methylation in MM was firmly established by the discovery that a lysine methyltransferase (MMSET) is rearranged and activated in poor prognosis t(4;14)-associated MM. Additional research from our group and others found that MM proliferation is dependent on the bromodomain and extra-terminal (BET) domain family of proteins (BRD2, BRD3 and BRD4) and their ability to support the transcriptional program of c-MYC. Together these findings create our central hypothesis that aberrant gene regulation underlies the biology of MM, and that these anomalies can be therapeutically targeted. Building on our mutual interest in chromatin biology, we have undertaken a collaborative program to study and target BRD4 and MMSET in MM. Hypotheses: Aberrant overexpression of Myc in a differentiated plasma cell remains a central paradox of and driver of MM. Transcriptional signaling, which underlies the pathogenesis of MM, requires the co-activator function of BET bromodomains. Direct inhibition of BET bromodomains alone and in combination comprises a powerful therapeutic strategy in MM. The MMSET lysine methyltransferase, which is found in complex with BRD4, stimulates myeloma pathogenesis through global changes in histone modification and gene expression. The oncogenic activity of MMSET is closely linked to its histone methylation activity and MMSET and BRD4 represent compelling molecular targets for development of new MM therapies. We will pursue following Specific Aims:
Aim 1. To characterize the role of BET bromodomains in epigenetic bookmarking of the Myc and E2F transcriptional programs.
Aim 2. To study domains of MMSET amenable for therapeutic targeting, guided by crystallographic structures, and develop MMSET inhibitors as chemical probes and lead therapeutics.
Aim 3. To translate BET and MMSET inhibitors to therapeutic use in patients with MM.

Public Health Relevance

Based on MM genetics and detailed biological studies in our laboratories, we propose to develop first-in-class inhibitors of BET bromodomains and the MMSET lysine methyltransferase. Chemical probes emerging from this research will be openly distributed to academic laboratories world-wide. Investigational therapeutics will emanate from these efforts, with clinical translation evident within the time-frame of the SPORE award.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
5P50CA100707-12
Application #
8764976
Study Section
Special Emphasis Panel (ZCA1-RPRB-0)
Project Start
Project End
Budget Start
2014-09-01
Budget End
2015-08-31
Support Year
12
Fiscal Year
2014
Total Cost
$243,569
Indirect Cost
$94,856
Name
Dana-Farber Cancer Institute
Department
Type
DUNS #
076580745
City
Boston
State
MA
Country
United States
Zip Code
02215
Ye, Shuai; Lawlor, Matthew A; Rivera-Reyes, Adrian et al. (2018) YAP1-Mediated Suppression of USP31 Enhances NF?B Activity to Promote Sarcomagenesis. Cancer Res 78:2705-2720
Hunter, Zachary R; Xu, Lian; Tsakmaklis, Nickolas et al. (2018) Insights into the genomic landscape of MYD88 wild-type Waldenström macroglobulinemia. Blood Adv 2:2937-2946
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
Bolli, Niccolò; Maura, Francesco; Minvielle, Stephane et al. (2018) Genomic patterns of progression in smoldering multiple myeloma. Nat Commun 9:3363
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
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
Xu, Yan; Deng, Shuhui; Mao, Xuehan et al. (2018) Tolerance, Kinetics, and Depth of Response for Subcutaneous Versus Intravenous Administration of Bortezomib Combination in Chinese Patients With Newly Diagnosed Multiple Myeloma. Clin Lymphoma Myeloma Leuk 18:422-430
Michallet, M; Chapuis-Cellier, C; Dejoie, T et al. (2018) Heavy+light chain monitoring correlates with clinical outcome in multiple myeloma patients. Leukemia 32:376-382
Ray, A; Das, D S; Song, Y et al. (2018) Combination of a novel HDAC6 inhibitor ACY-241 and anti-PD-L1 antibody enhances anti-tumor immunity and cytotoxicity in multiple myeloma. Leukemia 32:843-846

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