The Role of Toll-Like Receptors in Hematopoietic Malignancies

Monlish, Darlene; Bhatt, Sima T.; Schuettpelz, Laura G.

doi:10.3389/fimmu.2016.00390

Cited by 91 publications

(92 citation statements)

References 109 publications

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“…For example, we identify a network centered around the TNKS pathway that is involved in micro-RNA mediated transcriptional regulation that may be involved in ALL risk (58–63), and we uncover a gene subnetwork containing UNC93B1 and other genes that plays an important role in innate and adaptive immunity (64–66) (Supplementary Figure S2 and Supplementary Tables S6–S7). An open question in the literature is whether genes associated with ALL in GWA studies (such as CEBPE , IKZF1 , ARID5B , etc.)…”

Section: Discussionmentioning

confidence: 99%

Novel Gene and Network Associations Found for Acute Lymphoblastic Leukemia Using Case–Control and Family-Based Studies in Multiethnic Populations

Nakka

Archer

et al. 2017

Cancer Epidemiology, Biomarkers &Amp; Prevention

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Background Acute lymphoblastic leukemia (ALL) is the most common childhood cancer, suggesting that germline variants influence ALL risk. Although multiple genome-wide association (GWA) studies have identified variants predisposing children to ALL, it remains unclear whether genetic heterogeneity affects ALL susceptibility and how interactions within and among genes containing ALL-associated variants influence ALL risk. Methods Here we jointly analyze two published datasets of case-control GWA summary statistics along with germline data from ALL case-parent trios. We use the gene-level association method PEGASUS to identify genes with multiple variants associated with ALL. We then use PEGASUS gene scores as input to the network analysis algorithm HotNet2 to characterize the genomic architecture of ALL. Results Using PEGASUS, we confirm associations previously observed at genes such as ARID5B, IKZF1, CDKN2A/2B, and PIP4K2A, and we identify novel candidate gene associations. Using HotNet2, we uncover significant gene subnetworks that may underlie inherited ALL risk: a subnetwork involved in B-cell differentiation containing the ALL-associated gene CEBPE; and a subnetwork of homeobox genes including MEIS1. Conclusions Gene and network analysis uncovers loci associated with ALL that are missed by GWA studies such as MEIS1. Further, ALL-associated loci do not appear to interact directly with each other to influence ALL risk, and instead appear to influence leukemogenesis through multiple, complex pathways. Impact We present a new pipeline for post-hoc analysis of association studies that yields new insight into the etiology of ALL, and can be applied in future studies to shed light on the genomic underpinnings of cancer.

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Section: Discussionmentioning

confidence: 99%

Novel Gene and Network Associations Found for Acute Lymphoblastic Leukemia Using Case–Control and Family-Based Studies in Multiethnic Populations

Nakka

Archer

et al. 2017

Cancer Epidemiology, Biomarkers &Amp; Prevention

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“…Our results thus enable identifying candidate targets in cell-cycle therapeutics in childhood cancer. The majority of the hub genes of the grey60 module have key roles in innate immune recognition and activation and comprise Toll-like receptors (TLR1 and TLR6) that are potential therapeutic targets in onco-hematology 49 . Hematopoietic malignancies promote unique immune evasion pathways and genes taking part in the innate immune system appear to be logical innate immune targets.…”

Section: Scientific Reports |mentioning

confidence: 99%

Depicting the genetic architecture of pediatric cancers through an integrative gene network approach

Savary

Kim

Lespagnol³

et al. 2020

Sci Rep

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the genetic etiology of childhood cancers still remains largely unknown. it is therefore essential to develop novel strategies to unravel the spectrum of pediatric cancer genes. Statistical network modeling techniques have emerged as powerful methodologies for enabling the inference of genedisease relationship and have been performed on adult but not pediatric cancers. We performed a deep multi-layer understanding of pan-cancer transcriptome data selected from the treehouse Childhood Cancer Initiative through a co-expression network analysis. We identified six modules strongly associated with pediatric tumor histotypes that were functionally linked to developmental processes. topological analyses highlighted that pediatric cancer predisposition genes and potential therapeutic targets were central regulators of cancer-histotype specific modules. A module was related to multiple pediatric malignancies with functions involved in DnA repair and cell cycle regulation. this canonical oncogenic module gathered most of the childhood cancer predisposition genes and clinically actionable genes. in pediatric acute leukemias, the driver genes were co-expressed in a module related to epigenetic and post-transcriptional processes, suggesting a critical role of these pathways in the progression of hematologic malignancies. this integrative pan-cancer study provides a thorough characterization of pediatric tumor-associated modules and paves the way for investigating novel candidate genes involved in childhood tumorigenesis.Cancer remains the leading cause of death by disease in children of less than fourteen years of age 1 . Improving the management of pediatric cancer is essential and will benefit from more accurate diagnosis, new personalized treatment and development of specific and less damaging therapies. To face these challenges, it is necessary to unravel the complete genetic repertoire of pediatric malignancies. Recent studies have improved the understanding of the genetics of childhood cancer, but have mainly focused on depicting the germline and somatic mutational landscape of these diseases [2][3][4] .Several evidences demonstrated that the biology and genetics of pediatric cancers set them apart from adult tumors 4,5 . Childhood cancers have a 14-times lower mutation rate compared to adult tumors and mostly arise from mutations in few driver genes. Somatic alterations mostly target a handful of major genes such as CDKN2A, NOTCH1, NRAS, KRAS or TP53, and pathways disrupted by driver alterations are either common to cancer (e.g. cell cycle) or specific to pediatric cancer histotypes 4 . More than half of the driver genes are restricted to one cancer histotype and 83% of them are not shared between hematologic and solid tumors. This indicates that certain genes and pathways are exclusively dysregulated in a single type of childhood cancer. reconstructed 100 times with the same parameters on a random selection of the initial samples. The robustness was measured as the number of times a gene was assigned to the observed m...

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“…Сотни SNPs (single nucleotide polymorphisms) были идентифицированы в генах TLRs, но связь с функцией не была раскрыта в подавляющем большинстве. Существует множество работ, описывающих ассоциацию полиморфных маркеров в генах TLRs и с инфекционными заболеваниями, и с образованием опухолей [7,39]. К TLR2-подсемейству относятся TLR2, TLR1 и TLR6, которые имеют высокую степень гомологии, следует отметить, что гены TLR1 и TLR6 образуют кластер с геном TLR10 в районе 4p14.…”

Section: ассоциация полиморфизмов в генах Tlrs с раз витием опухолевоunclassified

The Role of Innate Immunity Factors in Tumorigenesis Process

Свитич¹,

Филина²,

Давыдова³

et al. 2018

Med. immunol.

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Резюме. Одной из важнейших теорий канцерогенеза является теория о полиэтиологичности опухолеобразования. Большое место в этой теории отводится роли воспалительного компонента, который реализуется посредством факторов врожденного иммунитета.К факторам врожденного иммунитета, участвующим в опухолеобразовании, относятся TLRs, хемокины и их рецепторы. Активация TLRs может приводить как к снижению прогрессии онкологического процесса, так и, наоборот, к усилению. Известно, что TLR3, TLR5, TLR7, TLR9 обладают наибольшим противоопухолевым эффектом через DCs-опосредованную активацию Тh1, активацию макрофагов М1-типа и ингибирование Treg. Стимуляция TLR4 и TLR2 обладает опухоль-активирующим эффектом, путем гиперактивации MyD88 и выработки IL-6 и TNFα, однако механизмы до конца не изучены. Помимо TLRs, большое влияние на развитие онкологического процесса оказывают хемокины и их рецепторы. Показано, что CCL2, CCL4, CCL17, CCL22 и CXCL12, выделяемые клетками микроокружения опухоли, активно влияют на хемотаксис опухолевых клеток. Также известно, что CXCR4 и CCR7, экспрессируемые опухолевыми клетками, активируются хемокинами, что ведет к метастазированию. Также показаны ассоциации некоторых полиморфизмов генов TLRs, хемокинов и их рецепторов с развитием опухолевого процесса. Таким образом, на основании литературных данных, можно сделать заключение о том, что TLR и хемокины имеют большое значение при онкогенезе. Дальнейшее изучение влияния факторов врожденного иммунитета на онкогенез имеет больше значение для обоснования новых подходов терапии рака, а также потенциал для создания вакцин против рака.Abstract. The theory of polyetiological tumorigenesis is one of the most important theories of carcinogenesis. A great place in this theory is given to the role of inflammatory component, which is implemented via the Svitich O.A., PhD, MD (Medicine), Corresponding Member,

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The Role of Toll-Like Receptors in Hematopoietic Malignancies

Cited by 91 publications

References 109 publications

Novel Gene and Network Associations Found for Acute Lymphoblastic Leukemia Using Case–Control and Family-Based Studies in Multiethnic Populations

Novel Gene and Network Associations Found for Acute Lymphoblastic Leukemia Using Case–Control and Family-Based Studies in Multiethnic Populations

Depicting the genetic architecture of pediatric cancers through an integrative gene network approach

The Role of Innate Immunity Factors in Tumorigenesis Process

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