Sandeep S. Dave's research while affiliated with Institute of Genomic Medicine and other places
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Publications (226)
Mantle cell lymphoma (MCL) is a rare and aggressive form of B-cell non-Hodgkin lymphoma (NHL). Approximately 40%–50% of MCL patients carry inactivating mutations in the gene ataxia telangiectasia mutated (ATM), a core component of the cell's DNA damage response system. MCL cells with mutations in ATM are known to have increased chromosomal imbalanc...
Epstein-Barr virus (EBV) is one of the most common viruses associated with multiple malignancies including hematopoietic, epithelial, and mesenchymal neoplasms. EBV is linked to B- and T-cell lymphomas, ranging from indolent to highly aggressive neoplasms. EBV-positive follicular lymphoma (FL) is not well characterized due to its low prevalence. In...
While survival has improved for Burkitt lymphoma patients, potential differences in outcome between pediatric and adult patients remain unclear. In both age groups, survival remains poor at relapse. Therefore, we conducted a comparative study in a large pediatric cohort, including 191 cases and 97 samples from adults. While TP53 and CCND3 mutation...
3074
Background: While NGS applications of DNAseq and RNAseq have proven to be powerful tools for genomic discovery, NGS remains underutilized in the clinic. We hypothesized that the clinical translation of NGS would be greatly improved by addressing two critical issues: first, having a single assay for both DNA and RNA sequencing, and second, incl...
We herein present an overview of the upcoming 5th edition of the World Health Organization Classification of Haematolymphoid Tumours focussing on lymphoid neoplasms. Myeloid and histiocytic neoplasms will be presented in a separate accompanying article. Besides listing the entities of the classification, we highlight and explain changes from the re...
SETD2 is the sole histone methyltransferase responsible for H3K36me3, with roles in splicing, transcription initiation, and DNA damage response. Homozygous disruption of SETD2 yields a tumor suppressor effect in various cancers. However, SETD2 mutation is typically heterozygous in diffuse large B-cell lymphomas. Here we show that heterozygous Setd2...
Importance
Ticagrelor inhibits platelet function, prevents myocardial infarction, and causes bleeding. A comprehensive analysis of the on- and off-target platelet effects of ticagrelor that underlie its clinical effects is lacking.
Objective
To test the hypothesis that platelet transcripts that change in response to ticagrelor exposure are associa...
INTRODUCTION
Diffuse large B-cell lymphoma (DLBCL) represents several distinct clinical pathologic entities recently identified by molecular profiling. Treatment with anti-CD19 chimeric antigen receptor (CAR) T-cell therapies is now standard for many patients with relapsed/refractory (R/R) disease. Although antigen loss of CD19 represents a known c...
Background: Enhancer of zeste homolog 2 (EZH2) is an epigenetic regulator implicated as a genetic driver in multiple lymphoma types. Approximately 20% of patients with follicular lymphoma (FL) present with activating, gain-of-function (GoF) EZH2 mutations. The results of a phase 2 clinical trial of the first-in-class oral EZH2 inhibitor tazemetosta...
Introduction
Blood cancers are collectively common and strikingly heterogeneous diseases both clinically and molecularly. According to the WHO taxonomy, there are over 100 distinct myeloid and lymphoid neoplasms. Genomic profiling of blood cancers has been applied in a somewhat ad hoc fashion using diverse sequencing approaches including the use of...
Introduction: Primary mediastinal large B-cell lymphoma (PMBL) is a rare non-Hodgkin lymphoma subtype that occurs predominantly in young adults, with an overall favorable prognosis. The cell of origin is presumed to be thymic medullary B-cells and the gene expression profile of PMBL is similar to classic Hodgkin lymphoma. Recent studies have begun...
Introduction
ALK-negative anaplastic large cell lymphoma (ALK- ALCL) is an uncommon type of T-cell non-Hodgkin lymphoma (T-NHL) with worse prognosis compared to ALK-positive (ALK+) ALCLs. Most published studies on the genomics of T-NHL have focused on peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS), and previous studies of ALCL descr...
Aspirin has known effects beyond inhibiting platelet cyclooxygenase‐1 (COX1) that have been incompletely characterized. Transcriptomics can comprehensively characterize the on‐ and off‐target effects of medications. We used a systems pharmacogenomics approach of aspirin exposure in volunteers coupled with serial platelet function and purified plate...
Metabolic dysfunctions enabling increased nucleotide biosynthesis are necessary for supporting malignant proliferation. Our investigations indicate that upregulation of fatty acid synthase (FASN) and de novo lipogenesis, commonly observed in many cancers, are associated with nucleotide metabolic dysfunction in lymphoma. The results from our experim...
A comprehensive constellation of somatic nonsilent mutations and copy-number (CN) variations in ocular adnexa marginal zone lymphoma (OAMZL) is unknown. By utilizing whole-exome sequencing in 69 tumors, we define the genetic landscape of OAMZL. Mutations and CN changes in CABIN1 (30%), RHOA (26%), TBL1XR1 (22%), and CREBBP (17%) and inactivation of...
Aspirin has known effects beyond inhibiting platelet cyclooxygenase-1 (COX1) that have been incompletely characterized. Transcriptomics can comprehensively characterize the on- and off-target effects of medications. We used a systems pharmacogenomics approach of aspirin exposure in volunteers coupled with serial platelet function and purified plate...
Significance
Epstein–Barr virus (EBV) infects virtually every human by adulthood with limited symptoms. However, in the context of immune suppression, EBV can cause lymphomas. EBV-associated lymphomas have poor prognoses and limited treatment options, highlighting a need to better understand EBV-mediated tumorigenesis. One common feature of viral r...
This chapter describes the clinical, pathological, and genetic characteristics of enteropathy‐associated T‐cell lymphoma (EATL), monomorphic epitheliotropic intestinal T‐cell lymphoma, and refractory celiac disease (RCD), a rare lymphoproliferative disorder that is a precursor to a subset of EATLs. It discusses current and emerging treatment option...
Significant differences have been observed in the incidence, age of onset, and clinical outcomes of diffuse large B-cell lymphoma (DLBCL) by race in the United States. However, it remains unclear what factors underlie these differences and whether genomic differences contribute to these disparities. We examined differences in baseline clinical char...
INTRODUCTION:
Canine Lymphoma (CL) is the most commonly diagnosed malignancy in the domestic dog, with estimates reaching 80,000 new cases per year in the United States. Understanding of genetic factors involved in development and progression of canine B-Cell Lymphoma (cBCL), the most common of the two major subtypes of CL, can help guide efforts t...
Background:
Significant racial differences have been observed in the incidence and clinical outcomes of diffuse large B-cell lymphoma (DLBCL) in the United States, but to the authors' knowledge it remains unclear whether genomic differences contribute to these disparities.
Methods:
To understand the influences of genetic ancestry on tumor genomi...
Non-Hodgkin lymphomas (NHLs) are a diverse group of entities, both clinically and molecularly. Here, we review the evolution of classification schemes in B-cell lymphoma, noting the now standard WHO classification system that is based on immune cell-of-origin and molecular phenotypes. We review how lymphomas arise throughout the B-cell development...
Lymphoma incidence in sub-Saharan Africa (SSA) is increasing due to HIV and population aging. Diffuse Large B-cell lymphoma (DLBCL), the most common lymphoma in SSA and worldwide, is highly associated with HIV, but molecular studies of HIV-associated DLBCL are scarce globally. We describe profiling of DLBCL from Malawi, aiming to elucidate tumor bi...
Introduction: FASN catalyzes de novo fatty acid (FA) biosynthesis, which is an oncogenic function observed in many cancers, including NHL. HIF1a inducible FASN activity is responsible for overcoming negative hypoxic influence and upregulation of glucose metabolism as observed during premalignant transformation. FASN catalytic activity is also depen...
Follicular Lymphoma (FL) is the most common indolent lymphoma derived from light zone germinal center B cells and characterized by a t(14;18) translocation resulting in upregulation of BCL2 in over 80% of cases. This translocation alone is not sufficient for tumorogenesis, and must be combined with additional genetic mutations to transform B cells....
Burkitt lymphoma (BL) is an aggressive, MYC-driven lymphoma comprising 3 distinct clinical subtypes: sporadic BLs that occur worldwide, endemic BLs that occur predominantly in sub-Saharan Africa, and immunodeficiency-associated BLs that occur primarily in the setting of HIV. In this study, we comprehensively delineated the genomic basis of BL throu...
In large B‐cell lymphoma (LBCL) MYC translocation and MYC/BCL2 or MYC/BCL6 double hit (DH) is associated with poor prognosis and there is an unmet need for novel treatment targets in this patient group. Treatments targeting the PD‐L1/PD‐1 pathway are still poorly elucidated in LBCL. PD‐L1 expression might predict response to treatment targeting the...
TET2 is a well-established tumor suppressor in the context of myeloid malignancies, but its role in lymphoma development has been less clear. In this issue of Cancer Discovery, Dominguez and colleagues report that TET2 function is critical for germinal center exit and plasma cell differentiation, and its deficiency can lead to B-cell lymphoma pheno...
Introduction: Plasmablastic lymphoma (PL) is an aggressive variant of lymphoma, with strong association with HIV. Despite significant improvements in the survival of other lymphomas, PL has a short overall survival (14 months). The association with Epstein-Barr virus (EBV) infection and MYC chromosomal translocations are defining features of PL. Ho...
Background: Ocular adnexa lymphomas (OAL) consist of a heterogeneous group of tumors that can arise in the lacrimal gland, orbit, conjunctiva and eyelid. More than 95% of these lymphomas are of B-cell origin and extranodal marginal zone lymphoma (EMZL) of mucosa-associated lymphoid tissue is the most common subtype of OAL, accounting for 55-85% of...
Introduction:
Diffuse large B cell lymphoma (DLBCL) is a clinically heterogeneous disease. While roughly half of the patients respond well to standard R-CHOP therapy, the majority of the remainder succumb to their disease. While many targeted therapies have been developed in DLBCL, resistance to single agents develops almost invariably. While drug...
Introduction: In large B-cell lymphoma (LBCL) MYC translocation and MYC/BCL2 or BCL6 double hit (DH) is associated with poor prognosis and there is an unmet need for novel treatment targets in this patient group. Treatment targeting the PD-L1/PD-1 pathway has been successfully introduced in Hodgkin lymphoma and solid cancers but are still poorly el...
Introduction. Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoid malignancy with a diverse genomic appearance. To date, the coding genomes of almost 2000 DLBCLs have been recognized, and the translation of this genetic information into clinical practice is awaited.
Here, we have investigated translocations and protein expression of t...
Cancer results from the accumulation of genetic mutations in a susceptible cell of origin. We and others have also shown that injury promotes sarcoma development, but how injury cooperates with genetic mutations at the earliest stages of tumor formation is not known. Here, we utilized dual recombinase technology to dissect the complex interplay of...
Primary effusion lymphoma (PEL) is caused by Kaposi's sarcoma-associated herpesvirus. Our understanding of PEL is poor and therefore treatment strategies are lacking. To address this need, we conducted genome-wide CRISPR/Cas9 knockout screens in eight PEL cell lines. Integration with data from unrelated cancers identifies 210 genes as PEL-specific...
Immunofluorescent imaging analysis of AQP3 signal.
HuH7 cells infected with P. berghei were stained for AQP3 (red) and DAPI (white). Nuclei of P. berghei were pseudo-colored blue. Scale bar 10 μm. AQP3 staining is only found in P. berghei infected hepatocytes and localizes exclusively to the PVM.
(TIF)
siRNAs used for depletion of aquaporin genes expressed in hepatocytes and primers used for qRT-PCR.
Product names are for Dharmacon (scramble and SR-B1) or Qiagen (all AQP siRNAs).
(PDF)
siRNA depletion of aquaporin transcripts.
(A) Cell viability of HuH7 cells treated with multiple (2) siRNAs targeting AQP3 and SR-BI and infected with P. berghei. Non-targeting scrambled siRNAs were used as a negative control. Transfection of hepatocytes with siRNAs did not affect cell viability. (B) Parasite load and (C) cell viability of HuH7 cel...
HuH7 gene set enrichment analysis.
Gene sets that have been found to be statistically significant for (A) early, (B) mid, and (C) late P. berghei-infected HuH7 hepatocytes.
(TIF)
Parasite load, cell viability, and relative mRNA expression of targeted genes in HuH7 cells treated with individual siRNAs and infected with P. berghei.
(PDF)
Within the liver a single Plasmodium parasite transforms into thousands of blood-infective forms to cause malaria. Here, we use RNA-sequencing to identify host genes that are upregulated upon Plasmodium berghei infection of hepatocytes with the hypothesis that host pathways are hijacked to benefit parasite development. We found that expression of a...
Differential expression of hepatocytes infected with P. berghei.
(XLSX)
Generation of mutant AQP3 cell lines.
(A) Parasite load measured in wildtype HuH7 cells and AQP3mut1-4 cell lines 48 hpi. All mutant cell lines had significant reduction in parasite load, averaging 80% reduction (One-Way ANOVA, Dunnett’s multiple comparison; n = 3 independent experiments). ****P < 0.0001. (B) Amplification of AQP3 mRNA from cDNA ge...
3D confocal image of P. berghei infected hepatocyte.
(MP4)
Synthesis of auphen.
(A) 1H NMR of [AuCl2(phen)]Cl (Auphen) in DMSO-d6 (400 MHz). (B) 13C NMR of [AuCl2(phen)]Cl (Auphen) in DMSO-d6 (100 MHz).
(TIF)
Gene set enrichment using GSEA for each cell and time point.
(XLSX)
Auphen inhibits parasite load in multiple hepatoma cell lines and is effective at inhibition of P. berghei parasite load up to 24 hpi.
(A) Parasite load of HepG2 cells infected with luciferase-expressing P. berghei and treated with 0.05–20 μM auphen at time of infection (circles) or 24 hpi (squares). EC50 = 0.62 ± 0.09 when auphen is added at 0 hpi...
Gating strategy for GFP-expressing P. berghei infected hepatocytes.
(A) Uninfected HepG2 cells and cells sorted (B) 4, (C) 24, and (D) 48 hours post P. berghei infection. Sytox Blue was used as a live/dead cell indicator.
(TIF)
List of gRNAs used for generating AQP3mut cell lineusing the CRISPR/Cas9 genome editing.
(PDF)
Purpose of review:
We review the genetic foundations of different rare lymphomas to examine their shared origins. These data indicate the potential application of genomics to improve the diagnosis and treatment of these rare diseases.
Recent findings:
Next generation sequencing technologies have provided an important window into the genetic unde...
A family of transcription factors known as E proteins, and their antagonists, Id proteins, regulate T cell differentiation at critical developmental checkpoints. Id proteins promote the differentiation of conventional αβ T cells and suppress the expansion of innate-like αβ T cells known as invariant natural killer T (iNKT) cells. However, it remain...
Genetically engineered mouse models (GEMMs) that employ site-specific recombinase (SSR) technology are important tools for cancer research, and recently the CRISPR/Cas9 system has been increasingly utilized to model cancer in mice. Here, we used CRISPR/Cas9 to generate two primary mouse models of sarcoma, undifferentiated pleomorphic sarcoma (UPS)...
Epstein-Barr virus (EBV) is a common human herpesvirus that establishes latency in B cells. While EBV infection is asymptomatic for most individuals, immune-suppressed individuals are at significantly higher risk of a form of EBV latent infection in which infected B cells are reactivated, grow unchecked, and generate lymphomas. This form of latency...
Id proteins have been shown to promote the differentiation of conventional αβ and γδT cells, and to suppress the expansion of invariant Natural Killer T (iNKT) cells and innate-like γδNKT within their respective cell lineages. However, it remains to be determined whether Id proteins regulate lineage specification in developing T cells that give ris...
Graphical Abstract Highlights d Exome sequencing in 1,001 DLBCL patients comprehensively identifies 150 driver genes d Unbiased CRISPR screen in DLBCL cell lines identifies essential oncogenes d Integrative analysis connects genomics, CRISPR hits, and clinical outcome d A genomic risk model of survival outperforms existing risk-assessment methods
The adult high-grade B-cell lymphomas sharing molecular features with Burkitt lymphoma (BL) are highly aggressive lymphomas with poor clinical outcome. High-resolution structural and functional genomic analysis of adult Burkitt lymphoma (BL) and high-grade B-cell lymphoma with BL gene signature (adult-molecularly defined BL [mBL]) revealed the MYC-...
Genetically engineered mouse models that employ site-specific recombinase technology are important tools for cancer research but can be costly and time-consuming. The CRISPR-Cas9 system has been adapted to generate autochthonous tumours in mice, but how these tumours compare to tumours generated by conventional recombinase technology remains to be...
