Demo Faculty

162 articles

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Feb 2021 • Molecular Cell

Systematic characterization of mutations altering protein degradation in human cancers

Collin Tokheim, Xiaoqing Wang, Richard T Timms, Boning Zhang, Elijah L Mena, Binbin Wang, Cynthia Chen, Jun Ge, Jun Chu, Wubing Zhang, Stephen J Elledge, Myles Brown, X Shirley Liu

The ubiquitin-proteasome system (UPS) is the primary route for selective protein degradation in human cells. The UPS is an attractive target for novel cancer therapies, but the precise UPS genes and substrates important for cancer growth are incompletely understood. Leveraging multi-omics data across more than 9,000 human tumors and 33 cancer types, we found that over 19% of all cancer driver genes affect UPS function. We implicate transcription factors as important substrates and show that c-Myc stability is modulated by CUL3. Moreover, we developed a deep learning model (deepDegron) to identify mutations that result in degron loss and experimentally validated the prediction that gain-of-function truncating mutations in GATA3 and PPM1D result in increased protein stability. Last, we identified UPS driver genes associated with prognosis and the tumor microenvironment. This study demonstrates the …

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Jan 2021 • Frontiers in Immunology

Natural Barcodes for Longitudinal Single Cell Tracking of Leukemic and Immune Cell Dynamics

Livius Penter, Satyen H Gohil, Catherine J Wu

Blood malignancies provide unique opportunities for longitudinal tracking of disease evolution following therapeutic bottlenecks and for the monitoring of changes in anti-tumor immunity. The expanding development of multi-modal single-cell sequencing technologies affords newer platforms to elucidate the mechanisms underlying these processes at unprecedented resolution. Furthermore, the identification of molecular events that can serve as in-vivo barcodes now facilitate the tracking of the trajectories of malignant and of immune cell populations over time within primary human samples, as these permit unambiguous identification of the clonal lineage of cell populations within heterogeneous phenotypes. Here, we provide an overview of the potential for chromosomal copy number changes, somatic nuclear and mitochondrial DNA mutations, single nucleotide polymorphisms, and T and B cell receptor sequences …

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Jan 2021 • bioRxiv

Machine learning modeling of protein-intrinsic features predicts tractability of targeted protein degradation

Wubing Zhang, Shourya S Roy Burman, Jiaye Chen, Katherine A Donovan, Yang Cao, Boning Zhang, Zexian Zeng, Yi Zhang, Dian Li, Eric S Fischer, Collin Tokheim, Xiaole Shirley Liu

Targeted protein degradation (TPD) has rapidly emerged as a therapeutic modality to eliminate previously undruggable proteins by repurposing the cell9s endogenous protein degradation machinery. However, the susceptibility of proteins for targeting by TPD approaches, termed "degradability", is largely unknown. Recent systematic studies to map the degradable kinome have shown differences in degradation between kinases with similar drug-target engagement, suggesting yet unknown factors influencing degradability. We therefore developed a machine learning model, MAPD (Model-based Analysis of Protein Degradability), to predict degradability from protein features that encompass post-translational modifications, protein stability, protein expression and protein-protein interactions. MAPD shows accurate performance in predicting kinases that are degradable by TPD compounds (auPRC=0.759) and is likely generalizable to independent non-kinase proteins. We found five features with statistical significance to achieve optimal prediction, with ubiquitination potential being the most predictive. By structural modeling, we found that E2-accessible ubiquitination sites, but not lysine residues in general, are particularly associated with kinase degradability. Finally, we extended MAPD predictions to the entire proteome to find 964 disease-causing proteins, including 278 cancer genes, that may be tractable to TPD drug development.

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Jan 2021 • Cancer Discovery

Longitudinal single-cell dynamics of chromatin accessibility and mitochondrial mutations in chronic lymphocytic leukemia mirror disease history

Livius Penter, Satyen H Gohil, Caleb Lareau, Leif S Ludwig, Erin M Parry, Teddy Huang, Shuqiang Li, Wandi Zhang, Dimitri Livitz, Ignaty Leshchiner, Laxmi Parida, Gad Getz, Laura Z Rassenti, Thomas J Kipps, Jennifer R Brown, Matthew S Davids, Donna S Neuberg, Kenneth J Livak, Vijay G Sankaran, Catherine J Wu

While cancers evolve during disease progression and in response to therapy, temporal dynamics remain difficult to study in humans due to the lack of consistent barcodes marking individual clones in vivo. We employ mitochondrial single-cell assay for transposase-accessible chromatin with sequencing to profile 163,279 cells from 9 patients with chronic lymphocytic leukemia (CLL) collected across disease course and utilize mitochondrial DNA (mtDNA) mutations as natural genetic markers of cancer clones. We observe stable propagation of mtDNA mutations over years in the absence of strong selective pressure indicating clonal persistence, but dramatic changes following tight bottlenecks including disease transformation and relapse post-therapy, paralleled by acquisition of copy number variants, changes in chromatin accessibility and gene expression. Furthermore, we link CLL subclones to distinct chromatin …

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Jan 2021 • Clinical Cancer Research

Network for biomarker immunoprofiling for cancer immunotherapy: Cancer Immune Monitoring and Analysis Centers and Cancer Immunologic Data Commons (CIMAC-CIDC)

Helen X Chen, Minkyung Song, Holden T Maecker, Sacha Gnjatic, David Patton, J Jack Lee, Stacey J Adam, Radim Moravec, X Shirley Liu, Ethan Cerami, James Lindsay, F Stephen Hodi, Catherine Wu, Ignacio I Wistuba, Gheath Al-Atrash, Chantale Bernatchez, Sean C Bendall, Stephen M Hewitt, Elad Sharon, Howard Streicher, Rebecca A Enos, Melissa D Bowman, Valerie M Tatard-Leitman, Beatriz Sanchez-Espiridion, Srinika Ranasinghe, Mina Pichavant, Diane M Del Valle, Joyce Yu, Sylvie Janssens, Jenny Peterson-Klaus, Cathy Rowe, Gerold Bongers, Robert R Jenq, Chia-Chi Chang, Jeffrey S Abrams, Margaret Mooney, James H Doroshow, Lyndsay N Harris, Magdalena Thurin

Immunoprofiling to identify biomarkers and integration with clinical trials outcome are critical to improve immunotherapy approaches for cancer patients. However, the translational potential of individual studies is often limited by small sample size of trials and the complexity of immuno-oncology biomarkers. Variability in assays further limits comparison and interpretation of data across studies and laboratories. To enable a systematic approach to biomarker identification and correlation with clinical outcome across trials, the Cancer Immune Monitoring and Analysis Centers and Cancer Immunologic Data Commons (CIMAC-CIDC) Network was established through support of the Cancer MoonshotSM Initiative of the National Cancer Institute and the Partnership for Accelerating Cancer Therapies (PACT) with industry partners via the Foundation for the National Institutes of Health. The CIMAC-CIDC Network is composed …

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Jan 2021 • Cancer Cell

Integrin αvβ6–TGFβ–SOX4 Pathway Drives Immune Evasion in Triple-Negative Breast Cancer

Archis Bagati, Sushil Kumar, Peng Jiang, Jason Pyrdol, Angela E Zou, Anze Godicelj, Nathan D Mathewson, Adam NR Cartwright, Paloma Cejas, Myles Brown, Anita Giobbie-Hurder, Deborah Dillon, Judith Agudo, Elizabeth A Mittendorf, X Shirley Liu, Kai W Wucherpfennig

Cancer immunotherapy shows limited efficacy against many solid tumors that originate from epithelial tissues, including triple-negative breast cancer (TNBC). We identify the SOX4 transcription factor as an important resistance mechanism to T cell-mediated cytotoxicity for TNBC cells. Mechanistic studies demonstrate that inactivation of SOX4 in tumor cells increases the expression of genes in a number of innate and adaptive immune pathways important for protective tumor immunity. Expression of SOX4 is regulated by the integrin αvβ6 receptor on the surface of tumor cells, which activates TGFβ from a latent precursor. An integrin αvβ6/8-blocking monoclonal antibody (mAb) inhibits SOX4 expression and sensitizes TNBC cells to cytotoxic T cells. This integrin mAb induces a substantial survival benefit in highly metastatic murine TNBC models poorly responsive to PD-1 blockade. Targeting of the integrin αvβ6-TGFβ …

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Jan 2021 • Cancer Discovery

CARM1 Inhibition Enables Immunotherapy of Resistant Tumors by Dual Action on Tumor cells and T cells

Sushil Kumar, Zexian Zeng, Archis Bagati, Rong En Tay, Lionel A Sanz, Stella R Hartono, Yoshinaga Ito, Fieda Abderazzaq, Elodie Hatchi, Peng Jiang, Adam NR Cartwright, Olamide Olawoyin, Nathan D Mathewson, Jason W Pyrdol, Mamie Z Li, John G Doench, Matthew A Booker, Michael Y Tolstorukov, Stephen J Elledge, Frederic Chedin, X Shirley Liu, Kai W Wucherpfennig

A number of cancer drugs activate innate immune pathways in tumor cells but unfortunately also compromise anti-tumor immune function. We discovered that inhibition of Carm1, an epigenetic enzyme and co-transcriptional activator, elicited beneficial anti-tumor activity in both cytotoxic T cells and tumor cells. In T cells, Carm1 inactivation substantially enhanced their anti-tumor function and preserved memory-like populations required for sustained anti-tumor immunity. In tumor cells, Carm1 inactivation induced a potent type 1 interferon response that sensitized resistant tumors to cytotoxic T cells. Substantially increased numbers of dendritic cells, CD8 T cells and NK cells were present in Carm1-deficient tumors, and infiltrating CD8 T cells expressed low levels of exhaustion markers. Targeting of Carm1 with a small molecule elicited potent anti-tumor immunity and sensitized resistant tumors to checkpoint blockade …

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Jan 2021 • bioRxiv

Machine learning modeling of protein-intrinsic features predicts tractability of targeted protein degradation

Wubing Zhang, Shourya S Roy Burman, Jiaye Chen, Katherine A Donovan, Yang Cao, Boning Zhang, Zexian Zeng, Yi Zhang, Dian Li, Eric S Fischer, Collin Tokheim, Xiaole Shirley Liu

Targeted protein degradation (TPD) has rapidly emerged as a therapeutic modality to eliminate previously undruggable proteins by repurposing the cell9s endogenous protein degradation machinery. However, the susceptibility of proteins for targeting by TPD approaches, termed "degradability", is largely unknown. Recent systematic studies to map the degradable kinome have shown differences in degradation between kinases with similar drug-target engagement, suggesting yet unknown factors influencing degradability. We therefore developed a machine learning model, MAPD (Model-based Analysis of Protein Degradability), to predict degradability from protein features that encompass post-translational modifications, protein stability, protein expression and protein-protein interactions. MAPD shows accurate performance in predicting kinases that are degradable by TPD compounds (auPRC=0.759) and is likely generalizable to independent non-kinase proteins. We found five features with statistical significance to achieve optimal prediction, with ubiquitination potential being the most predictive. By structural modeling, we found that E2-accessible ubiquitination sites, but not lysine residues in general, are particularly associated with kinase degradability. Finally, we extended MAPD predictions to the entire proteome to find 964 disease-causing proteins, including 278 cancer genes, that may be tractable to TPD drug development.

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Jan 2021 • bioRxiv

Leveraging epigenomes and three-dimensional genome organization for interpreting regulatory variation

Brittany Anne Baur, Junha Shin, Jacob Schreiber, Shilu Zhang, Yi Zhang, Mohith Manjunath, Jun S Song, William Stafford Noble, Sushmita Roy

Understanding the impact of regulatory variants on complex phenotypes is a significant challenge because the genes and pathways that are targeted by such variants are typically unknown. Furthermore, a regulatory variant might influence a particular gene9s expression in a cell type or tissue-specific manner. Cell-type specific long-range regulatory interactions that occur between a distal regulatory sequence and a gene offers a powerful framework for understanding the impact of regulatory variants on complex phenotypes. However, high-resolution maps of such long-range interactions are available only for a handful of model cell lines. To address this challenge, we have developed L-HiC-Reg, a Random Forests based regression method to predict high-resolution contact counts in new cell lines, and a network-based framework to identify candidate cell line-specific gene networks targeted by a set of variants from a Genome-wide association study (GWAS). We applied our approach to predict interactions in 55 Roadmap Epigenome Consortium cell lines, which we used to interpret regulatory SNPs in the NHGRI GWAS catalogue. Using our approach, we performed an in-depth characterization of fifteen different phenotypes including Schizophrenia, Coronary Artery Disease (CAD) and Crohn9s disease. In CAD, we found differentially wired subnetworks consisting of known as well as novel gene targets of regulatory SNPs. Taken together, our compendium of interactions and associated network-based analysis pipeline offers a powerful resource to leverage long-range regulatory interactions to examine the context-specific impact of regulatory …

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Jan 2021 • Cancer Discovery

CARM1 Inhibition Enables Immunotherapy of Resistant Tumors by Dual Action on Tumor cells and T cells

Sushil Kumar, Zexian Zeng, Archis Bagati, Rong En Tay, Lionel A Sanz, Stella R Hartono, Yoshinaga Ito, Fieda Abderazzaq, Elodie Hatchi, Peng Jiang, Adam NR Cartwright, Olamide Olawoyin, Nathan D Mathewson, Jason W Pyrdol, Mamie Z Li, John G Doench, Matthew A Booker, Michael Y Tolstorukov, Stephen J Elledge, Frederic Chedin, X Shirley Liu, Kai W Wucherpfennig

A number of cancer drugs activate innate immune pathways in tumor cells but unfortunately also compromise anti-tumor immune function. We discovered that inhibition of Carm1, an epigenetic enzyme and co-transcriptional activator, elicited beneficial anti-tumor activity in both cytotoxic T cells and tumor cells. In T cells, Carm1 inactivation substantially enhanced their anti-tumor function and preserved memory-like populations required for sustained anti-tumor immunity. In tumor cells, Carm1 inactivation induced a potent type 1 interferon response that sensitized resistant tumors to cytotoxic T cells. Substantially increased numbers of dendritic cells, CD8 T cells and NK cells were present in Carm1-deficient tumors, and infiltrating CD8 T cells expressed low levels of exhaustion markers. Targeting of Carm1 with a small molecule elicited potent anti-tumor immunity and sensitized resistant tumors to checkpoint blockade …

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Jan 2021 • bioRxiv

Leveraging epigenomes and three-dimensional genome organization for interpreting regulatory variation

Brittany Anne Baur, Junha Shin, Jacob Schreiber, Shilu Zhang, Yi Zhang, Mohith Manjunath, Jun S Song, William Stafford Noble, Sushmita Roy

Understanding the impact of regulatory variants on complex phenotypes is a significant challenge because the genes and pathways that are targeted by such variants are typically unknown. Furthermore, a regulatory variant might influence a particular gene9s expression in a cell type or tissue-specific manner. Cell-type specific long-range regulatory interactions that occur between a distal regulatory sequence and a gene offers a powerful framework for understanding the impact of regulatory variants on complex phenotypes. However, high-resolution maps of such long-range interactions are available only for a handful of model cell lines. To address this challenge, we have developed L-HiC-Reg, a Random Forests based regression method to predict high-resolution contact counts in new cell lines, and a network-based framework to identify candidate cell line-specific gene networks targeted by a set of variants from a Genome-wide association study (GWAS). We applied our approach to predict interactions in 55 Roadmap Epigenome Consortium cell lines, which we used to interpret regulatory SNPs in the NHGRI GWAS catalogue. Using our approach, we performed an in-depth characterization of fifteen different phenotypes including Schizophrenia, Coronary Artery Disease (CAD) and Crohn9s disease. In CAD, we found differentially wired subnetworks consisting of known as well as novel gene targets of regulatory SNPs. Taken together, our compendium of interactions and associated network-based analysis pipeline offers a powerful resource to leverage long-range regulatory interactions to examine the context-specific impact of regulatory …

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Jan 2021 • Cancer Discovery

Longitudinal single-cell dynamics of chromatin accessibility and mitochondrial mutations in chronic lymphocytic leukemia mirror disease history

Livius Penter, Satyen H Gohil, Caleb Lareau, Leif S Ludwig, Erin M Parry, Teddy Huang, Shuqiang Li, Wandi Zhang, Dimitri Livitz, Ignaty Leshchiner, Laxmi Parida, Gad Getz, Laura Z Rassenti, Thomas J Kipps, Jennifer R Brown, Matthew S Davids, Donna S Neuberg, Kenneth J Livak, Vijay G Sankaran, Catherine J Wu

While cancers evolve during disease progression and in response to therapy, temporal dynamics remain difficult to study in humans due to the lack of consistent barcodes marking individual clones in vivo. We employ mitochondrial single-cell assay for transposase-accessible chromatin with sequencing to profile 163,279 cells from 9 patients with chronic lymphocytic leukemia (CLL) collected across disease course and utilize mitochondrial DNA (mtDNA) mutations as natural genetic markers of cancer clones. We observe stable propagation of mtDNA mutations over years in the absence of strong selective pressure indicating clonal persistence, but dramatic changes following tight bottlenecks including disease transformation and relapse post-therapy, paralleled by acquisition of copy number variants, changes in chromatin accessibility and gene expression. Furthermore, we link CLL subclones to distinct chromatin …

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Jan 2021 • Cancer Discovery

Therapeutically increasing MHC-I expression potentiates immune checkpoint blockade

Shengqing Stan Gu, Wubing Zhang, Xiaoqing Wang, Peng Jiang, Nicole Traugh, Ziyi Li, Clifford Meyer, Blair Stewig, Yingtian Xie, Xia Bu, Michael P Manos, Alba Font-Tello, Evisa Gjini, Ana Lako, Klothilda Lim, Jake Conway, Alok K Tewari, Zexian Zeng, Avinash Das Sahu, Collin Tokheim, Jason L Weirather, Jingxin Fu, Yi Zhang, Benjamin Kroger, Jin Hua Liang, Paloma Cejas, Gordon J Freeman, Scott Rodig, Henry W Long, Benjamin E Gewurz, F Stephen Hodi, Myles Brown, X Shirley Liu

Immune checkpoint blockade (ICB) therapy revolutionized cancer treatment, but many patients with impaired MHC-I expression remain refractory. Here, we combined FACS-based genome-wide CRISPR screens with a data-mining approach to identify drugs that can upregulate MHC-I without inducing PD-L1. CRISPR screening identified TRAF3, a suppressor of the NFκB pathway, as a negative regulator of MHC-I but not PD-L1. The Traf3-knockout gene expression signature is associated with better survival in ICB-naïve patients with cancer and better ICB response. We then screened for drugs with similar transcriptional effects as this signature and identified Second Mitochondria-derived Activator of Caspase (SMAC) mimetics. We experimentally validated that the SMAC mimetic birinapant upregulates MHC-I, sensitizes cancer cells to T cell–dependent killing, and adds to ICB efficacy. Our findings provide …

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Jan 2021 • bioRxiv

MYC drives aggressive prostate cancer by disrupting transcriptional pause release at androgen receptor targets

Xintao Qiu, Nadia Boufaied, Tarek Hallal, Avery Feit, Anna de Polo, Adrienne M Luoma, Janie Larocque, Giorgia Zadra, Yingtian Xie, Shengqing Gu, Qin Tang, Yi Zhang, Sudeepa Syamala, Ji-Heui Seo, Connor Bell, Edward O’Connor, Yang Liu, Edward M Schaeffer, R Jeffrey Karnes, Sheila Weinmann, Elai Davicioni, Paloma Cejas, Leigh Ellis, Massimo Loda, Kai W Wucherpfennig, Mark M Pomerantz, Daniel E Spratt, Eva Corey, Matthew L Freedman, X Shirley Liu, Myles Brown, Henry W Long, David P Labbé

c-MYC (MYC) is a major driver of prostate cancer tumorigenesis and progression. Although MYC is overexpressed in both early and metastatic disease and associated with poor survival, its impact on prostate transcriptional reprogramming remains elusive. We demonstrate that MYC overexpression significantly diminishes the androgen receptor (AR) transcriptional program (the set of genes directly targeted by the AR protein) in luminal prostate cells without altering AR expression. Importantly, analyses of clinical specimens revealed that concurrent low AR and high MYC transcriptional programs accelerate prostate cancer progression toward a metastatic, castration-resistant disease. Data integration of single-cell transcriptomics together with ChIP-seq revealed an increased RNA polymerase II (Pol II) promoter-proximal pausing at AR-dependent genes following MYC overexpression without an accompanying deactivation of AR-bound enhancers. Altogether, our findings suggest that MYC overexpression antagonizes the canonical AR transcriptional program and contributes to prostate tumor initiation and progression by disrupting transcriptional pause release at AR-regulated genes.

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Dec 2020 • Genome Biology

Clonal tracing reveals diverse patterns of response to immune checkpoint blockade

Shengqing Stan Gu, Xiaoqing Wang, Xihao Hu, Peng Jiang, Ziyi Li, Nicole Traugh, Xia Bu, Qin Tang, Chenfei Wang, Zexian Zeng, Jingxin Fu, Cliff Meyer, Yi Zhang, Paloma Cejas, Klothilda Lim, Jin Wang, Wubing Zhang, Collin Tokheim, Avinash Das Sahu, Xiaofang Xing, Benjamin Kroger, Zhangyi Ouyang, Henry Long, Gordon J Freeman, Myles Brown, X Shirley Liu

Immune checkpoint blockade (ICB) therapy has improved patient survival in a variety of cancers, but only a minority of cancer patients respond. Multiple studies have sought to identify general biomarkers of ICB response, but elucidating the molecular and cellular drivers of resistance for individual tumors remains challenging. We sought to determine whether a tumor with defined genetic background exhibits a stereotypic or heterogeneous response to ICB treatment. We establish a unique mouse system that utilizes clonal tracing and mathematical modeling to monitor the growth of each cancer clone, as well as the bulk tumor, in response to ICB. We find that tumors derived from the same clonal populations showed heterogeneous ICB response and diverse response patterns. Primary response is associated with higher immune infiltration and leads to enrichment of pre-existing ICB-resistant cancer clones. We further …

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Dec 2020 • Optics Express

A perceptual eyebox for near-eye displays

Steven A Cholewiak, Zeynep Başgöze, Ozan Cakmakci, David M Hoffman, Emily A Cooper

In near-eye display systems that support three-dimensional (3D) augmented and virtual reality, a central factor in determining the user experience is the size of the eyebox. The eyebox refers to a volume where the eye receives an acceptable view of the image with respect to a set of criteria and thresholds. The size and location of this volume are primarily driven by optical architecture choices in which designers trade-off a number of constraints, such as field of view, image quality, and product design. It is thus important to clearly quantify how design decisions affect the properties of the eyebox. Recent work has started evaluating the eyebox in 3D based purely on optical criteria. However, such analyses do not incorporate perceptual criteria that determine visual quality, which are particularly important for binocular 3D systems. To address this limitation, we introduce the framework of a perceptual eyebox. The …

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Dec 2020 • Genome biology

Lisa: inferring transcriptional regulators through integrative modeling of public chromatin accessibility and ChIP-seq data

Qian Qin, Jingyu Fan, Rongbin Zheng, Changxin Wan, Shenglin Mei, Qiu Wu, Hanfei Sun, Myles Brown, Jing Zhang, Clifford A Meyer, X Shirley Liu

We developed Lisa (http://lisa.cistrome.org/) to predict the transcriptional regulators (TRs) of differentially expressed or co-expressed gene sets. Based on the input gene sets, Lisa first uses histone mark ChIP-seq and chromatin accessibility profiles to construct a chromatin model related to the regulation of these genes. Using TR ChIP-seq peaks or imputed TR binding sites, Lisa probes the chromatin models using in silico deletion to find the most relevant TRs. Applied to gene sets derived from targeted TF perturbation experiments, Lisa boosted the performance of imputed TR cistromes and outperformed alternative methods in identifying the perturbed TRs.

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Nov 2020 • Blood 136, 34-35, 2020

Local and Systemic Effects of Immune Checkpoint Blockade on Relapsed Myeloid Malignancies Following Allogeneic Hematopoietic Stem Cell Transplantation

Livius Penter, Yi Zhang, Alexandra Savell, Srinika Ranasinghe, Teddy Huang, Nicoletta Cieri, Satyen H Gohil, Wandi Zhang, Shuqiang Li, Robert Zeiser, Haesook T Kim, Kenneth J Livak, Jerome Ritz, Donna S Neuberg, Robert J Soiffer, X Shirley Liu, Matthew S Davids, Pavan Bachireddy, Catherine J Wu

Relapse after allogeneic hematopoietic stem cell transplantation (HSCT) remains an unmet medical need. The ETCTN 9204 study evaluated in 71 study subjects if immune checkpoint blockade with anti-CTLA-4 (Ipilimumab (Ipi), n = 43) or anti-PD-1 (Nivolumab (Nivo), n = 28) antibodies could stimulate graft-versus-leukemia (GvL) responses in this setting. We focused mainly on patients (pts) with relapsed AML/MDS, which constituted the majority of pts (n = 38; 54%). Ipi induced both long-term complete remissions (CR; n = 3) and transient CRs (TR; n = 3), while Nivo did not generate any CRs, but 4 patients demonstrated partial remissions (PR). To define the molecular features associated with response to Ipi, we performed bulk transcriptomic analyses of formalin-fixed paraffin-embedded biopsies of sites of AML/MDS involvement (n = 35) collected before and after Ipi treatment from 13 pts. Our analysis of …

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Nov 2020 • Blood

Clonally Expanded Bone Marrow T Cells Show Effector Differentiation and Rarely Recognize Disease-Associated Antigens in Multiple Myeloma

Carlotta Welters, Meng-Tung Hsu, Christian Alexander Stein, Livius Penter, María Fernanda Lammoglia Cobo, Kerstin Dietze, Eric Blanc, Dieter Beule, Lars Bullinger, Julian Strobel, Holger Hackstein, Armin Gerbitz, Klaus Dornmair, Thomas Blankenstein, Leo Hansmann

Multiple myeloma is a malignancy of monoclonal plasma cells accumulating in the bone marrow. The critical influence of tumor-infiltrating T cells on disease control and therapeutic responses has been shown in a variety of malignancies, however, the role of multiple myeloma bone marrow-infiltrating T cells is incompletely understood. Although it has been shown that multiple myeloma neo-antigen-specific T cells can be expanded in vitro, little is known about functions and specificities of clonally expanded multiple myeloma-infiltrating bone marrow T cells.Here we asked at the single cell level whether clonally expanded T cells i) were detectable in multiple myeloma bone marrow and peripheral blood, ii) showed characteristic immune phenotypes, and iii) recognized antigens selectively presented on multiple myeloma cells.A total of 6,744 single bone marrow T cells from 13 treatment-naïve patients were index …

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Nov 2020 • Clinical Cancer Research

Inhibition of MAN2A1 Enhances the Immune Response to Anti–PD-L1 in Human Tumors

Sailing Shi, Shengqing Gu, Tong Han, Wubing Zhang, Lei Huang, Ziyi Li, Deng Pan, Jingxin Fu, Jun Ge, Myles Brown, Peng Zhang, Peng Jiang, Kai W Wucherpfennig, X Shirley Liu

Purpose:Immune checkpoint blockade has shown remarkable efficacy, but in only a minority of patients with cancer, suggesting the need to develop additional treatment strategies. Aberrant glycosylation in tumors, resulting from the dysregulated expression of key enzymes in glycan biosynthesis, modulates the immune response. However, the role of glycan biosynthesis enzymes in antitumor immunity is poorly understood. We aimed to study the immunomodulatory effects of these enzymes.Experimental Design:We integrated transcriptional profiles of treatment-naïve human tumors and functional CRISPR screens to identify glycometabolism genes with immunomodulatory effects. We further validated our findings using in vitro coculture and in vivo syngeneic tumor growth assays.Results:We identified MAN2A1, encoding an enzyme in N-glycan maturation, as a key immunomodulatory gene. Analyses of public …

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Nov 2020 • Blood

Safety and Efficacy of Decitabine Plus Ipilimumab in Relapsed or Refractory MDS/AML in the Post-BMT or Transplant Naïve Settings

Jacqueline S Garcia, Yael Flamand, Benjamin K Tomlinson, Michael Keng, Lourdes M Mendez, Samer Khaled, Asad Bashey, Andrew M Brunner, Alexandra Savell, Donna Neuberg, Ilene Galinsky, Marlise R Luskin, David P Steensma, Martha Wadleigh, Eric S Winer, David E Avigan, Nicole Cullen, Scott Rodig, Livius Penter, R Coleman Lindsley, Stephanie Andrews, Matthew S Davids, Catherine J Wu, Richard M Stone, Daniel J DeAngelo, Robert J Soiffer

Background: CTLA-4 blockade with ipilimumab (IPI) has modest activity in hematologic malignancies relapsed post allogeneic hematopoietic cell transplantation (allo-HCT) (Davids M, NEJM). Adding decitabine (DAC) to IPI may increase efficacy of this approach in myelodysplastic syndromes (MDS)/acute myeloid leukemia (AML), and we further asked the extent to which alloreactivity contributed to this activity. Here, we present safety (Table 1) and clinical activity (Figure 1) from a phase I, multicenter, investigator-initiated study (CTEP 10026) of DAC plus IPI in pts with R/R MDS/AML with (Arm A) and without (Arm B) prior HCT.Methods: Pts ≥ 18 y with R/R MDS (≥ 5% blasts), R/R AML or untreated secondary AML were eligible. Prior HMA was permitted but trial was later amended to exclude those with disease progression on HMA therapy within 12 weeks of study entry. Pts post allo-HCT (Arm A) were required to …

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