A5102939509- Protein Degradation and Inhibitors
- Histone Deacetylase Inhibitors Research
- Epigenetics and DNA Methylation
- Cancer-related gene regulation
- Multiple Myeloma Research and Treatments
- Peptidase Inhibition and Analysis
- Ubiquitin and proteasome pathways
- Acute Lymphoblastic Leukemia research
- RNA modifications and cancer
- CAR-T cell therapy research
- Chronic Myeloid Leukemia Treatments
- Cholangiocarcinoma and Gallbladder Cancer Studies
- Acute Myeloid Leukemia Research
- Immune Cell Function and Interaction
- Galectins and Cancer Biology
- Immune cells in cancer
- Cutaneous lymphoproliferative disorders research
- Lymphoma Diagnosis and Treatment
- T-cell and Retrovirus Studies
- Protease and Inhibitor Mechanisms
- Cancer-related Molecular Pathways
- Click Chemistry and Applications
- Genomics and Chromatin Dynamics
- Chronic Lymphocytic Leukemia Research
- Genetic factors in colorectal cancer
Dana-Farber Cancer Institute
2015-2024
Harvard University
2014-2024
Broad Institute
2007-2023
Novartis (United States)
2020-2021
Brigham and Women's Hospital
2008-2020
Boston Children's Hospital
2018
Dana-Farber Brigham Cancer Center
2008-2017
Universidade de São Paulo
2014
Dana-Farber/Harvard Cancer Center
2013
Loyola University Chicago
2013
The hydroxamic acid (HAA) analogue pan-histone deacetylase (HDAC) inhibitors (HDIs) LAQ824 and LBH589 have been shown to induce acetylation inhibit the ATP binding chaperone function of heat shock protein (HSP) 90. This promotes polyubiquitylation degradation pro-growth pro-survival client proteins Bcr-Abl, mutant FLT-3, c-Raf, AKT in human leukemia cells. HDAC6 is a member class IIB HDACs. It predominantly cytosolic, microtubule-associated α-tubulin that also known promote aggresome...
Restoration of anti-tumor immunity by blocking PD-L1 signaling through the use antibodies has proven to be beneficial in cancer therapy. Here, we show that BET bromodomain inhibition suppresses expression and limits tumor progression ovarian cancer. CD274 (encoding PD-L1) is a direct target BRD4-mediated gene transcription. In mouse models, treatment with inhibitor JQ1 significantly reduced on cells tumor-associated dendritic macrophages, which correlated an increase activity cytotoxic T...
The efficacy of proteasome inhibition for myeloma is limited by therapeutic resistance, which may be mediated activation the autophagy pathway as an alternative mechanism protein degradation. Preclinical studies demonstrate that with hydroxychloroquine augments antimyeloma inhibitor bortezomib. We conducted a phase I trial combining bortezomib and relapsed or refractory myeloma. enrolled 25 patients, including 11 (44%) to prior No protocol-defined dose-limiting toxicities occurred, we...
A small set of core transcription factors (TFs) dominates control the gene expression program in embryonic stem cells and other well-studied cellular models. These TFs collectively regulate their own expression, thus forming an interconnected auto-regulatory loop that can be considered transcriptional regulatory circuitry (CRC) for cell type. There is limited knowledge TFs, models circuitry, most types. We recently discovered genes encoding known CRCs are driven by super-enhancers, which...
AbstractFoxp3+ T-regulatory cells (Tregs) are key to immune homeostasis such that their diminished numbers or function can cause autoimmunity and allograft rejection. Foxp3+ Tregs express multiple histone/protein deacetylases (HDACs) regulate chromatin remodeling, gene expression, protein function. Pan-HDAC inhibitors developed for oncologic applications enhance Treg production suppression but have limited nononcologic utility given broad actions various side effects. We show, using...
Synovial sarcoma tumours contain a characteristic fusion protein, SS18-SSX, which drives disease development. Targeting oncogenic proteins presents an attractive therapeutic opportunity. However, SS18-SSX has proven intractable for intervention. Using domain-focused CRISPR screen we identified the bromodomain of BRD9 as critical functional dependency in synovial sarcoma. is component containing BAF complexes cells; and integration into these cell growth. Moreover co-localize extensively on...
NUT midline carcinoma (NMC) is a lethal pediatric tumor defined by the presence of BRD-NUT fusion proteins that arrest differentiation. Here we explore mechanisms underlying ability BRD4-NUT to prevent squamous In both gain-of and loss-of-expression assays, find expression associated with globally decreased histone acetylation transcriptional repression. Bulk chromatin can be restored treatment NMC cells deacetylase inhibitors (HDACi), engaging program differentiation arrested growth in...
Amplification of MYC is one the most common genetic alterations in lung cancer, contributing to a myriad phenotypes associated with growth, invasion, and drug resistance. Murine genetics has established both centrality somatic Kras as well dependency mutant tumors on function. Unfortunately, drug-like small-molecule inhibitors KRAS have yet be realized. The recent discovery, hematologic malignancies, that bromodomain extra-terminal (BET) inhibition impairs expression transcriptional function...
Multiple myeloma (MM) has proven clinically susceptible to modulation of pathways protein homeostasis. Blockade proteasomal degradation polyubiquitinated misfolded proteins by the proteasome inhibitor bortezomib (BTZ) achieves responses and prolongs survival in MM, but long-term treatment with BTZ leads drug-resistant relapse most patients. In a proof-of-concept study, we previously demonstrated that blocking aggresomal breakdown histone deacetylase 6 (HDAC6) tubacin enhances BTZ-induced...
The release of paused RNA polymerase II into productive elongation is highly regulated, especially at genes that affect human development and disease. To exert control over this rate-limiting step, we designed sequence-specific synthetic transcription factors (Syn-TEFs). These molecules are composed programmable DNA-binding ligands flexibly tethered to a small molecule engages the machinery. By limiting activity targeted loci, Syn-TEFs convert constituent modules from broad-spectrum...
Abstract As a master regulator of chromatin function, the lysine methyltransferase EZH2 orchestrates transcriptional silencing developmental gene networks. Overexpression is commonly observed in human epithelial cancers, such as non–small cell lung carcinoma (NSCLC), yet definitive demonstration malignant transformation by deregulated remains elusive. Here, we demonstrate causal role overexpression NSCLC with new genetically engineered mouse models adenocarcinoma. Deregulated silences normal...
Merkel cell carcinoma (MCC) frequently contains integrated copies of polyomavirus DNA that express a truncated form Large T antigen (LT) and an intact Small (ST). While LT binds RB inactivates its tumor suppressor function, it is less clear how ST contributes to MCC tumorigenesis. Here we show specifically the MYC homolog MYCL (L-MYC) recruits 15-component EP400 histone acetyltransferase chromatin remodeling complex. We performed large-scale immunoprecipitation for identified...
Tyrosine kinase inhibitors (TKI) have revolutionized chronic myelogenous leukemia (CML) management. Disease eradication, however, is hampered by innate resistance of leukemia-initiating cells (LIC) to TKI-induced killing, which also provides the basis for subsequent emergence TKI-resistant mutants. We report that EZH2, catalytic subunit Polycomb Repressive Complex 2 (PRC2), overexpressed in CML LICs and required colony formation survival cell-cycle progression cell lines. A critical role...
Chimeric antigen receptor (CAR) T cells have induced remarkable antitumor responses in B cell malignancies. Some patients do not respond because of deficiencies that hamper the expansion, persistence, and effector function these cells. We used longitudinal immune profiling to identify phenotypic pharmacodynamic changes CD19-directed CAR with chronic lymphocytic leukemia (CLL). expression maintenance was also investigated this can affect response durability. failure accompanied by preexisting...
N1-Hydroxy-N8-ferrocenyloctanediamide, JAHA (7), an organometallic analogue of SAHA containing a ferrocenyl group as phenyl bioisostere, displays nanomolar inhibition class I HDACs, excellent selectivity over IIa and anticancer action in intact cells (IC50 = 2.4 μM, MCF7 cell line). Molecular docking studies 7 HDAC8 (a,b) suggested that the moiety can overlap with aryl cap should display similar HDAC inhibition, which was borne out vitro assay values against (μM, SD parentheses): SAHA, 1.41...