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Article ; Online: Chromatin Remodelers Are Regulators of the Tumor Immune Microenvironment.

Chaudhri, Apoorvi / Lizee, Gregory / Hwu, Patrick / Rai, Kunal

2024 Volume 84, Issue 7, Page(s) 965–976

Abstract: Immune checkpoint inhibitors show remarkable responses in a wide range of cancers, yet patients develop adaptive resistance. This necessitates the identification of alternate therapies that synergize with immunotherapies. Epigenetic modifiers are potent ... ...

Abstract	Immune checkpoint inhibitors show remarkable responses in a wide range of cancers, yet patients develop adaptive resistance. This necessitates the identification of alternate therapies that synergize with immunotherapies. Epigenetic modifiers are potent mediators of tumor-intrinsic mechanisms and have been shown to regulate immune response genes, making them prime targets for therapeutic combinations with immune checkpoint inhibitors. Some success has been observed in early clinical studies that combined immunotherapy with agents targeting DNA methylation and histone modification; however, less is known about chromatin remodeler-targeted therapies. Here, we provide a discussion on the regulation of tumor immunogenicity by the chromatin remodeling SWI/SNF complex through multiple mechanisms associated with immunotherapy response that broadly include IFN signaling, DNA damage, mismatch repair, regulation of oncogenic programs, and polycomb-repressive complex antagonism. Context-dependent targeting of SWI/SNF subunits can elicit opportunities for synthetic lethality and reduce T-cell exhaustion. In summary, alongside the significance of SWI/SNF subunits in predicting immunotherapy outcomes, their ability to modulate the tumor immune landscape offers opportunities for therapeutic intervention.
MeSH term(s)	Humans ; Chromatin ; Transcription Factors/metabolism ; Chromosomal Proteins, Non-Histone/genetics ; Immune Checkpoint Inhibitors/pharmacology ; Immune Checkpoint Inhibitors/therapeutic use ; Neoplasms/genetics ; Neoplasms/therapy ; Chromatin Assembly and Disassembly ; Tumor Microenvironment
Chemical Substances	Chromatin ; Transcription Factors ; Chromosomal Proteins, Non-Histone ; Immune Checkpoint Inhibitors
Language	English
Publishing date	2024-01-24
Publishing country	United States
Document type	Journal Article
ZDB-ID	1432-1
ISSN	1538-7445 ; 0008-5472
ISSN (online)	1538-7445
ISSN	0008-5472
DOI	10.1158/0008-5472.CAN-23-2244
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Article ; Online: Personalized Cancer Therapy: YES1 Is the New Kid on the Block.

Rai, Kunal

Cancer research

2019 Volume 79, Issue 22, Page(s) 5702–5703

Abstract: The key bottleneck for the continued success of precision medicine in cancer lies in identifying more targetable genes and associated efficacious clinically usable inhibitors. In this issue ... ...

Abstract	The key bottleneck for the continued success of precision medicine in cancer lies in identifying more targetable genes and associated efficacious clinically usable inhibitors. In this issue of
MeSH term(s)	Cell Line, Tumor ; Gene Amplification ; Genes, src ; Oncogenes ; Proto-Oncogene Proteins c-yes
Chemical Substances	Proto-Oncogene Proteins c-yes (EC 2.7.10.2)
Language	English
Publishing date	2019-11-26
Publishing country	United States
Document type	Journal Article ; Comment
ZDB-ID	1432-1
ISSN	1538-7445 ; 0008-5472
ISSN (online)	1538-7445
ISSN	0008-5472
DOI	10.1158/0008-5472.CAN-19-2995
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Article: Demystifying extrachromosomal DNA circles: Categories, biogenesis, and cancer therapeutics.

Wu, Manrong / Rai, Kunal

Computational and structural biotechnology journal

2022 Volume 20, Page(s) 6011–6022

Abstract: Since the advent of sequencing technologies in the 1990s, researchers have focused on the association between aberrations in chromosomal DNA and disease. However, not all forms of the DNA are linear and chromosomal. Extrachromosomal circular DNAs ( ... ...

Abstract	Since the advent of sequencing technologies in the 1990s, researchers have focused on the association between aberrations in chromosomal DNA and disease. However, not all forms of the DNA are linear and chromosomal. Extrachromosomal circular DNAs (eccDNAs) are double-stranded, closed-circled DNA constructs free from the chromosome that reside in the nuclei. Although widely overlooked, the eccDNAs have recently gained attention for their potential roles in physiological response, intratumoral heterogeneity and cancer therapeutics. In this review, we summarize the history, classifications, biogenesis, and highlight recent progresses on the emerging topic of eccDNAs and comment on their potential application as biomarkers in clinical settings.
Language	English
Publishing date	2022-10-26
Publishing country	Netherlands
Document type	Journal Article ; Review
ZDB-ID	2694435-2
ISSN	2001-0370
ISSN	2001-0370
DOI	10.1016/j.csbj.2022.10.033
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Article ; Online: Machine Learning in Epigenomics: Insights into Cancer Biology and Medicine.

Arslan, Emre / Schulz, Jonathan / Rai, Kunal

Biochimica et biophysica acta. Reviews on cancer

2021 Volume 1876, Issue 2, Page(s) 188588

Abstract: The recent deluge of genome-wide technologies for the mapping of the epigenome and resulting data in cancer samples has provided the opportunity for gaining insights into and understanding the roles of epigenetic processes in cancer. However, the ... ...

Abstract	The recent deluge of genome-wide technologies for the mapping of the epigenome and resulting data in cancer samples has provided the opportunity for gaining insights into and understanding the roles of epigenetic processes in cancer. However, the complexity, high-dimensionality, sparsity, and noise associated with these data pose challenges for extensive integrative analyses. Machine Learning (ML) algorithms are particularly suited for epigenomic data analyses due to their flexibility and ability to learn underlying hidden structures. We will discuss four overlapping but distinct major categories under ML: dimensionality reduction, unsupervised methods, supervised methods, and deep learning (DL). We review the preferred use cases of these algorithms in analyses of cancer epigenomics data with the hope to provide an overview of how ML approaches can be used to explore fundamental questions on the roles of epigenome in cancer biology and medicine.
MeSH term(s)	Biology/methods ; Epigenomics/methods ; Humans ; Machine Learning/standards ; Medicine/methods
Language	English
Publishing date	2021-07-07
Publishing country	Netherlands
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S. ; Review
ZDB-ID	2918802-7
ISSN	1879-2561 ; 0304-419X
ISSN (online)	1879-2561
ISSN	0304-419X
DOI	10.1016/j.bbcan.2021.188588
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Article: Loss of histone acetylation and H3K4 methylation promotes melanocytic malignant transformation.

Raman, Ayush T / Rai, Kunal

Molecular & cellular oncology

2018 Volume 5, Issue 3, Page(s) e1359229

Abstract: Epigenetic mechanisms play essential roles in biological processes such as cell maintenance, differentiation, proliferation and apoptosis. A recent report from our laboratory showed that the loss of histone acetylation and H3K4 (Histone H3 Lysine 4) ... ...

Abstract	Epigenetic mechanisms play essential roles in biological processes such as cell maintenance, differentiation, proliferation and apoptosis. A recent report from our laboratory showed that the loss of histone acetylation and H3K4 (Histone H3 Lysine 4) methylation in the proximal regions of cancer regulatory genes promote tumorigenesis.
Language	English
Publishing date	2018-02-26
Publishing country	United States
Document type	Journal Article
ISSN	2372-3556
ISSN	2372-3556
DOI	10.1080/23723556.2017.1359229
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Article ; Online: Sirtuin 2 inhibition modulates chromatin landscapes genome-wide to induce senescence in ATRX-deficient malignant glioma.

Malgulwar, Prit Benny / Danussi, Carla / Dharmaiah, Sharvari / Johnson, William / Singh, Anand / Rai, Kunal / Rao, Arvind / Huse, Jason T

Neuro-oncology

2023 Volume 26, Issue 1, Page(s) 55–67

Abstract: Background: Functional inactivation of ATRX characterizes large subgroups of malignant gliomas in adults and children. ATRX deficiency in glioma induces widespread chromatin remodeling, driving transcriptional shifts and oncogenic phenotypes. Effective ... ...

Abstract	Background: Functional inactivation of ATRX characterizes large subgroups of malignant gliomas in adults and children. ATRX deficiency in glioma induces widespread chromatin remodeling, driving transcriptional shifts and oncogenic phenotypes. Effective strategies to therapeutically target these broad epigenomic sequelae remain undeveloped. Methods: We utilized integrated multiomics and the Broad Institute Connectivity Map (CMAP) to identify drug candidates that could potentially revert ATRX-deficient transcriptional changes. We then employed disease-relevant experimental models to evaluate functional phenotypes, coupling these studies with epigenomic profiling to elucidate molecular mechanism(s). Results: CMAP analysis and transcriptional/epigenomic profiling implicated the Class III HDAC Sirtuin2 (SIRT2) as a central mediator of ATRX-deficient cellular phenotypes and a driver of unfavorable prognosis in ATRX-deficient glioma. SIRT2 inhibitors reverted Atrx-deficient transcriptional signatures in murine neuroepithelial progenitor cells (mNPCs), impaired cell migration in Atrx/ATRX-deficient mNPCs and human glioma stem cells (GSCs), and increased expression of senescence markers in glioma models. Moreover, SIRT2 inhibition impaired growth and increased senescence in ATRX-deficient GSCs in vivo. These effects were accompanied by genome-wide shifts in enhancer-associated H3K27ac and H4K16ac marks, with the latter in particular demonstrating compelling transcriptional links to SIRT2-dependent phenotypic reversals. Motif analysis of these data identified the transcription factor KLF16 as a mediator of phenotype reversal in Atrx-deficient cells upon SIRT2 inhibition. Conclusions: Our findings indicate that SIRT2 inhibition selectively targets ATRX-deficient gliomas for senescence through global chromatin remodeling, while demonstrating more broadly a viable approach to combat complex epigenetic rewiring in cancer.
MeSH term(s)	Adult ; Child ; Humans ; Animals ; Mice ; Chromatin ; Sirtuin 2/genetics ; Sirtuin 2/metabolism ; Glioma/pathology ; X-linked Nuclear Protein/genetics ; Kruppel-Like Transcription Factors/genetics
Chemical Substances	Chromatin ; Sirtuin 2 (EC 3.5.1.-) ; X-linked Nuclear Protein (EC 3.6.4.12) ; ATRX protein, human (EC 3.6.4.12) ; KLF16 protein, human ; Kruppel-Like Transcription Factors
Language	English
Publishing date	2023-08-25
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	2028601-6
ISSN	1523-5866 ; 1522-8517
ISSN (online)	1523-5866
ISSN	1522-8517
DOI	10.1093/neuonc/noad155
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Article: H3K9me3-mediated repression of KLF6: Discovering a novel tumor suppressor in liposarcoma using a systematic epigenomic approach.

Keung, Emily Z / Rai, Kunal

Molecular & cellular oncology

2015 Volume 3, Issue 3, Page(s) e1093691

Abstract: The pathogenesis of well-differentiated and dedifferentiated liposarcoma is poorly understood. We recently reported Kruppel-like factor 6 (KLF6) as a histone H3 lysine 9 trimethyl (H3K9me3)-regulated and differentially expressed transcription factor ... ...

Abstract	The pathogenesis of well-differentiated and dedifferentiated liposarcoma is poorly understood. We recently reported Kruppel-like factor 6 (KLF6) as a histone H3 lysine 9 trimethyl (H3K9me3)-regulated and differentially expressed transcription factor serving a previously unappreciated tumor suppressor role in liposarcoma. Mechanistically, KLF6 may drive adipocytic differentiation through increased expression of known regulators of adipogenesis.
Language	English
Publishing date	2015-10-29
Publishing country	United States
Document type	Journal Article
ISSN	2372-3556
ISSN	2372-3556
DOI	10.1080/23723556.2015.1093691
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Article: Clinical Benefit from Docetaxel +/- Ramucirumab Is Not Associated with Mutation Status in Metastatic Non-Small-Cell Lung Cancer Patients Who Progressed on Platinum Doublets and Immunotherapy.

Cancers

2024 Volume 16, Issue 5

Abstract: Docetaxel +/- ramucirumab remains the standard-of-care therapy for patients with metastatic non-small-cell lung cancer (NSCLC) after progression on platinum doublets and immune checkpoint inhibitors (ICIs). The aim of our study was to investigate whether ...

Abstract	Docetaxel +/- ramucirumab remains the standard-of-care therapy for patients with metastatic non-small-cell lung cancer (NSCLC) after progression on platinum doublets and immune checkpoint inhibitors (ICIs). The aim of our study was to investigate whether the cancer gene mutation status was associated with clinical benefits from docetaxel +/- ramucirumab. We also investigated whether platinum/taxane-based regimens offered a better clinical benefit in this patient population. A total of 454 patients were analyzed (docetaxel +/- ramucirumab n=381; platinum/taxane-based regimens n=73). Progression-free survival (PFS) and overall survival (OS) were compared among different subpopulations with different cancer gene mutations and between patients who received docetaxel +/- ramucirumab versus platinum/taxane-based regimens. Among patients who received docetaxel +/- ramucirumab, the top mutated cancer genes included TP53 (n=167), KRAS (n=127), EGFR (n=65), STK11 (n=32), ERBB2 (HER2) (n=26), etc. None of these cancer gene mutations or PD-L1 expression was associated with PFS or OS. Platinum/taxane-based regimens were associated with a significantly longer mQS (13.00 m, 95% Cl: 11.20-14.80 m versus 8.40 m, 95% Cl: 7.12-9.68 m, LogRank P=0.019) than docetaxel +/- ramcirumab. Key prognostic factors including age, histology, and performance status were not different between these two groups. In conclusion, in patients with metastatic NSCLC who have progressed on platinum doublets and ICIs, the clinical benefit from docetaxel +/- ramucirumab is not associated with the cancer gene mutation status. Platinum/taxane-based regimens may offer a superior clinical benefit over docetaxel +/- ramucirumab in this patient population.
Language	English
Publishing date	2024-02-26
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers16050935
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Article ; Online: Tsyn-Seq: a T-cell Synapse-Based Antigen Identification Platform.

Cancer immunology research

2024 Volume 12, Issue 5, Page(s) 530–543

Abstract: Tools for genome-wide rapid identification of peptide-major histocompatibility complex targets of T-cell receptors (TCR) are not yet universally available. We present a new antigen screening method, the T-synapse (Tsyn) reporter system, which includes ... ...

Abstract	Tools for genome-wide rapid identification of peptide-major histocompatibility complex targets of T-cell receptors (TCR) are not yet universally available. We present a new antigen screening method, the T-synapse (Tsyn) reporter system, which includes antigen-presenting cells (APC) with a Fas-inducible NF-κB reporter and T cells with a nuclear factor of activated T cells (NFAT) reporter. To functionally screen for target antigens from a cDNA library, productively interacting T cell-APC aggregates were detected by dual-reporter activity and enriched by flow sorting followed by antigen identification quantified by deep sequencing (Tsyn-seq). When applied to a previously characterized TCR specific for the E7 antigen derived from human papillomavirus type 16 (HPV16), Tsyn-seq successfully enriched the correct cognate antigen from a cDNA library derived from an HPV16-positive cervical cancer cell line. Tsyn-seq provides a method for rapidly identifying antigens recognized by TCRs of interest from a tumor cDNA library. See related Spotlight by Makani and Joglekar, p. 515.
MeSH term(s)	Humans ; Receptors, Antigen, T-Cell/immunology ; Receptors, Antigen, T-Cell/genetics ; T-Lymphocytes/immunology ; High-Throughput Nucleotide Sequencing ; Papillomavirus E7 Proteins/immunology ; Papillomavirus E7 Proteins/genetics ; Gene Library ; Antigen-Presenting Cells/immunology ; NFATC Transcription Factors/metabolism ; NFATC Transcription Factors/immunology ; Cell Line, Tumor ; NF-kappa B/metabolism ; Immunological Synapses/immunology ; Human papillomavirus 16/immunology ; Human papillomavirus 16/genetics ; Female
Chemical Substances	Receptors, Antigen, T-Cell ; Papillomavirus E7 Proteins ; NFATC Transcription Factors ; oncogene protein E7, Human papillomavirus type 16 ; NF-kappa B
Language	English
Publishing date	2024-02-16
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	2732489-8
ISSN	2326-6074 ; 2326-6066
ISSN (online)	2326-6074
ISSN	2326-6066
DOI	10.1158/2326-6066.CIR-23-0467
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Article ; Online: Single-cell chromatin accessibility profiling of acute myeloid leukemia reveals heterogeneous lineage composition upon therapy-resistance.

Fan, Huihui / Wang, Feng / Zeng, Andy / Murison, Alex / Tomczak, Katarzyna / Hao, Dapeng / Jelloul, Fatima Zahra / Wang, Bofei / Barrodia, Praveen / Liang, Shaoheng / Chen, Ken / Wang, Linghua / Zhao, Zhongming / Rai, Kunal / Jain, Abhinav K / Dick, John / Daver, Naval / Futreal, Andy / Abbas, Hussein A

Communications biology

2023 Volume 6, Issue 1, Page(s) 765

Abstract: Acute myeloid leukemia (AML) is a heterogeneous disease characterized by high rate of therapy resistance. Since the cell of origin can impact response to therapy, it is crucial to understand the lineage composition of AML cells at time of therapy ... ...

Abstract	Acute myeloid leukemia (AML) is a heterogeneous disease characterized by high rate of therapy resistance. Since the cell of origin can impact response to therapy, it is crucial to understand the lineage composition of AML cells at time of therapy resistance. Here we leverage single-cell chromatin accessibility profiling of 22 AML bone marrow aspirates from eight patients at time of therapy resistance and following subsequent therapy to characterize their lineage landscape. Our findings reveal a complex lineage architecture of therapy-resistant AML cells that are primed for stem and progenitor lineages and spanning quiescent, activated and late stem cell/progenitor states. Remarkably, therapy-resistant AML cells are also composed of cells primed for differentiated myeloid, erythroid and even lymphoid lineages. The heterogeneous lineage composition persists following subsequent therapy, with early progenitor-driven features marking unfavorable prognosis in The Cancer Genome Atlas AML cohort. Pseudotime analysis further confirms the vast degree of heterogeneity driven by the dynamic changes in chromatin accessibility. Our findings suggest that therapy-resistant AML cells are characterized not only by stem and progenitor states, but also by a continuum of differentiated cellular lineages. The heterogeneity in lineages likely contributes to their therapy resistance by harboring different degrees of lineage-specific susceptibilities to therapy.
MeSH term(s)	Humans ; Chromatin/genetics ; Leukemia, Myeloid, Acute/drug therapy ; Leukemia, Myeloid, Acute/genetics ; Cell Differentiation ; Cell Division ; Cell Lineage/genetics
Chemical Substances	Chromatin
Language	English
Publishing date	2023-07-21
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ISSN	2399-3642
ISSN (online)	2399-3642
DOI	10.1038/s42003-023-05120-6
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