Diffuse Large B-cell Lymphoma (DLBCL) represents the most common form of B-cell non-Hodgkin Lymphoma (B-NHL), accounting for ~30% of de-novo diagnoses and also arising as a frequent clinical evolution of Follicular Lymphoma (FL). Despite remarkable progress in the treatment of this disease, a significant fraction of DLBCL remains incurable, underscoring the need to identify molecular mechanisms that are responsible for disease development and that can be targeted therapeutically. By integrating whole exome sequencing and high-resolution single nucleotide polymorphism array analysis, we have identified recurrent inactivating mutations and deletions of CREBBP (CBP) and, more rarely, EP300 (p300) in a large fraction of DLBCL patients, including 40% of those diagnosed de novo and ~50% of those derived from transformation of FL (Pasqualucci et al., Nature 2011; Pasqualucci et al., Cell Reports 2014). CBP and p300 are two highly related histone and non-histone acetyltransferases (HATs) and are involved in multiple signaling pathways by modulating the activity of several proteins, such as the oncoprotein BCL6, which is typically inactivated by acetylation, and the tumor suppressor p53, which instead requires acetylation for its function. Defects in CBP and p300 may therefore play a central role in promoting the development and maintenance of lymphoma cells. Following on these findings, the general objective of this proposal is to elucidate the normal and pathologic role of CBP and p300 in B cells, to establish pre-clinical models for their therapeutic targeting, and to test the activity of the novel HDAC inhibitor Mocetinostat in a phase II clinical trial. The following Specific Aims will be pursued: 1). Identify the full complement of genetic and epigenetic lesions affecting CBP/p300 in DLBCL, as a pre-requisite to design an optimal stratification strategy for the clinical trials proposed in Specific Aim 4. 2). Identify biomarkers of CBP/p300 activity (and loss thereof) by defining the set of genes that are bound by CBP and whose expression is modulated by CBP/p300 inactivation in GC B cells. 3). Elucidate the role of CBP inactivation in normal B cell development and transformation, by constructing mutant mice in which CBP is conditionally inactivated in GC B cells and which could be used as preclinical models for therapeutic testing. 4). Investigate whether pharmacologic inhibition of specific deacetylases in DLBCL patients with CBP/p300 inactivation predicts improved clinical efficacy of deacetylase inhibitors, either alone or in combination with other drugs.

Public Health Relevance

Diffuse large B cell lymphoma is an aggressive disease that requires multi-regimen treatment and remains incurable in approximately 30% of the patients. The results of this project will contribute to the understanding of the pathogenesis of diffuse large B cell lymphoma and identify new targets for the treatment of these malignancies. The validity of these targets will be tested in a clinical trial using a novel drug, and has the potential of improving therapeutic responses in this aggressive disease.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Special Emphasis Panel (ZCA1)
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Sloan-Kettering Institute for Cancer Research
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Lu, Xiaoqing; Fernando, Tharu M; Lossos, Chen et al. (2018) PRMT5 interacts with the BCL6 oncoprotein and is required for germinal center formation and lymphoma cell survival. Blood 132:2026-2039
Kaittanis, Charalambos; Andreou, Chrysafis; Hieronymus, Haley et al. (2018) Prostate-specific membrane antigen cleavage of vitamin B9 stimulates oncogenic signaling through metabotropic glutamate receptors. J Exp Med 215:159-175
Liu, Yuxuan; Mondello, Patrizia; Erazo, Tatiana et al. (2018) NOXA genetic amplification or pharmacologic induction primes lymphoma cells to BCL2 inhibitor-induced cell death. Proc Natl Acad Sci U S A 115:12034-12039
Intlekofer, Andrew M; Joffe, Erel; Batlevi, Connie L et al. (2018) Integrated DNA/RNA targeted genomic profiling of diffuse large B-cell lymphoma using a clinical assay. Blood Cancer J 8:60
Avanzi, Mauro P; Yeku, Oladapo; Li, Xinghuo et al. (2018) Engineered Tumor-Targeted T Cells Mediate Enhanced Anti-Tumor Efficacy Both Directly and through Activation of the Endogenous Immune System. Cell Rep 23:2130-2141
Pasqualucci, Laura; Dalla-Favera, Riccardo (2018) Genetics of diffuse large B-cell lymphoma. Blood 131:2307-2319
Joshi, Suhasini; Wang, Tai; Araujo, ThaĆ­s L S et al. (2018) Adapting to stress - chaperome networks in cancer. Nat Rev Cancer 18:562-575
Kishinevsky, Sarah; Wang, Tai; Rodina, Anna et al. (2018) HSP90-incorporating chaperome networks as biosensor for disease-related pathways in patient-specific midbrain dopamine neurons. Nat Commun 9:4345
Rafiq, Sarwish; Yeku, Oladapo O; Jackson, Hollie J et al. (2018) Targeted delivery of a PD-1-blocking scFv by CAR-T cells enhances anti-tumor efficacy in vivo. Nat Biotechnol 36:847-856
Guo, A; Lu, P; Lee, J et al. (2017) HSP90 stabilizes B-cell receptor kinases in a multi-client interactome: PU-H71 induces CLL apoptosis in a cytoprotective microenvironment. Oncogene 36:3441-3449

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