Anatomical Niches Research Articles

DISTRIBUTION OF PDGFR+ CELLS AND INTERSTITIAL CELLS OF CAJAL IN THE HUMAN FETAL GUT

Two types of interstitial cells, interstitial cells of Cajal (ICC) and fibroblast-like cells, recently named platelet-derived growth factors receptor positive (PDGFRa+) cells, are present within the muscular layer of gastrointestinal (GI) tract. ICC and PDGFRa+ cells represent different classes of cells with unique ultrastructure, molecular phenotype and function, and they occupy the same anatomical niches in the GI tract. It is considered that PDGFRa+ cells such as ICC, mediate enteric inhibitory neurotransmission. Platelet-derived growth factors (PDGFs) are major mitogens for many cell types of mesenchymal origin, like fibroblasts and smooth muscle cells, and during embryogenesis, PDGF signaling is important in organogenesis. In the available literature, there is no data on the presence and distribution of PDGFRa immunoreactive cells in the human intestine during fetal period. The aim of this study was to identify PDGFRa immunoreactive cells in the gut of human fetuses, as well as to determine their distribution in relation to smooth muscle cells, ICC and enteric nerve structures. The material consisted of 12 Human Fetuses, gestational age from 10 to 12 weeks. The immunohistochemical test was carried out with the PDGFR-a antibody, ICC were identified using the C-kit antibody, while the muscle structures were demonstrated by the Desmin antibody. During the development of the human intestine, at week 11, PDGFRa immunoreactive cells are present within the circular muscle layer, while they are absent in the myenteric plexus region and in the parts below the serosa. Unlike them, ICC are present only around the inception of the myenteric plexus ganglia. In the fetal period of the human development, PDGFRa immunoreactive cells are present in all parts of the intestines, they are localized within the circular muscle layer and do not coincide with the ICC.

Impact of SARS-CoV-2 on periodontal tissue manifestation

Coronavirus disease 19 (COVID-19) is a recent infectious disease that is rapidly spreading worldwide and targets human angiotensin-converting enzyme 2 receptors. A recent study found that COVID-19 induces immune responses resulting in periodontal manifestation. The purpose of this study was to investigate the impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on periodontal tissue. Periodontal bacteria are implicated in systemic inflammation, bacteremia, and pneumonia. Moreover, it has been shown that 80% of patients with severe COVID-19 had high bacterial load. It has also been reported that the severity of COVID-19 in patients associates with increased levels of inflammatory markers such as interleukin and bacterial invasion. Systemic increase in the inflammatory response reveals the similarity with cytokine storm in COVID-19 patients. These conditions revealed that elevated levels of cytokines detected in locally inflamed gingival tissue through saliva analysis could expand to the systemic circulation, resulting in systemic inflammation and vice versa. It is suggested that there is a possibility of periodontitis due to increased inflammatory responses in host as an impact of SARS-CoV-2 infection. Periodontal impact was seen in COVID-19 patients as localized erythema in margins of gingiva leading to desquamative gingivitis and oral pain. Although COVID-19 might manifest in periodontal tissues, presence of periodontal pathogen could pose a risk of superinfection, and periodontal pocket could be a favorable anatomical niche for the virus, the literature is still lacking to conclude that COVID-19 has an impact on periodontal tissues and more studies are needed.

Atypical, Yet Not Infrequent, Infections with Neisseria Species.

Neisseria species are extremely well-adapted to their mammalian hosts and they display unique phenotypes that account for their ability to thrive within niche-specific conditions. The closely related species N. gonorrhoeae and N. meningitidis are the only two species of the genus recognized as strict human pathogens, causing the sexually transmitted disease gonorrhea and meningitis and sepsis, respectively. Gonococci colonize the mucosal epithelium of the male urethra and female endo/ectocervix, whereas meningococci colonize the mucosal epithelium of the human nasopharynx. The pathophysiological host responses to gonococcal and meningococcal infection are distinct. However, medical evidence dating back to the early 1900s demonstrates that these two species can cross-colonize anatomical niches, with patients often presenting with clinically-indistinguishable infections. The remaining Neisseria species are not commonly associated with disease and are considered as commensals within the normal microbiota of the human and animal nasopharynx. Nonetheless, clinical case reports suggest that they can behave as opportunistic pathogens. In this review, we describe the diversity of the genus Neisseria in the clinical context and raise the attention of microbiologists and clinicians for more cautious approaches in the diagnosis and treatment of the many pathologies these species may cause.

Intestinal neuro-immune interactions: focus on macrophages, mast cells and innate lymphoid cells.

Intestinal homeostasis relies on the reciprocal crosstalk between enteric neurons and immune cells, which together form neuro-immune units that occupy distinct anatomical niches within the gut. Here we will review the recent advances in our understanding of neuro-immune crosstalk within the gut, with focus on macrophages, mast cells and innate lymphoid cells. In particular, we will discuss the role of neuron-immune cell crosstalk in homeostasis, and how aberrant communication may underlie disease in the gastro-intestinal tract.

The Hepatic Central Vein: Structure, Fibrosis, and Role in Liver Biology.

The hepatic central vein is a primary source of Wnt2, Wnt9b, and R-spondin3. These angiocrines activate ß-catenin signaling to regulate hepatic metabolic zonation and perivenous gene expression in mice. Little is known about the central vein ultrastructure. Here, we describe the morphological-functional correlates of the central vein and its draining and branching patterns. Central vein fibrosis occurs in liver disease and is often accompanied by perivenous perisinusoidal fibrosis, which may affect perivenous gene expression. We review the biological properties of perivenous hepatocytes and glutamine synthetase that serve as a biomarker of perivenous hepatocytes. Glutamine synthetase and P4502E1 are indicators of ß-catenin activity in centrilobular liver injury and regeneration. The Wnt/ß-catenin pathway is the master regulator of hepatic metabolic zonation and perivenous gene expression and is modulated by the R-spondin-LGR4/5-ZNRF3/RNF43 module. We examined the structures of the molecules of these pathways and their involvements in liver biology. Central vein-derived Wnts and R-spondin3 participate in the cellular-molecular circuitry of the Wnt/ß-catenin and R-spondin-LGR4/5-ZNRF3/RNF43 module. The transport and secretion of lipidated Wnts in Wnt-producing cells require Wntless protein. Secreted Wnts are carried on exosomes in the extracellular matrix to responder cells. The modes of release of Wnts and R-spondin3 from central veins and their transit in the venular wall toward perivenous hepatocytes are unknown. We hypothesize that central vein fibrosis may impact perivenous gene expression. The proposal that the central vein constitutes an anatomical niche of perivenous stem cells that subserve homeostatic hepatic renewal still needs studies using additional mouse models for validation. Anat Rec, 2019. © 2019 American Association for Anatomy Anat Rec, 303:1747-1767, 2020. © 2019 American Association for Anatomy.

The nonpathogenic commensal Neisseria: friends and foes in infectious disease.

Nonpathogenic commensal Neisseria are rarely considered in the clinical setting despite evidence that they can cause invasive opportunistic infections. In contrast, they may offer protection against pathogenic Neisseria, and such relationships are being actively explored in experimental studies. Recent case reports are presented of invasive infection caused by nonpathogenic Neisseria in patients on novel biologic therapies. On the other hand, Neisseria lactamica, a nonpathogenic commensal, has been shown in human challenge studies to inhibit colonization by Neisseria meningitidis. Experimental mouse models have also explored the inhibitory effects of nonpathogenic Neisseria on Neisseria gonnhoreae infection. Cutting-edge advances in metagenomics and microbiomics are being used to understand the mechanisms underpinning these effects. Clinicians should have increased awareness of nonpathogenic Neisseria. First, as new immunomodulating therapies become licenced, the interactions that maintain balance between commensals and their human hosts may be altered. Second, these bacteria are showing promise in their capacity to exclude pathogenic Neisseria species from their anatomical niches.

Application of Bioengineered Materials in the Surgical Management of Heart Failure.

The epicardial surface of the heart is readily accessible during cardiac surgery and presents an opportunity for therapeutic intervention for cardiac repair and regeneration. As an important anatomic niche for endogenous mechanisms of repair, targeting the epicardium using decellularized extracellular matrix (ECM) bioscaffold therapy may provide the necessary environmental cues to promote functional recovery. Following ischemic injury to the heart caused by myocardial infarction (MI), epicardium derived progenitor cells (EPDCs) become activated and migrate to the site of injury. EPDC differentiation has been shown to contribute to endothelial cell, cardiac fibroblast, cardiomyocyte, and vascular smooth muscle cell populations. Post-MI, it is largely the activation of cardiac fibroblasts and the resultant dysregulation of ECM turnover which leads to maladaptive structural cardiac remodeling and loss of cardiac function. Decellularized ECM bioscaffolds not only provide structural support, but have also been shown to act as a bioactive reservoir for growth factors, cytokines, and matricellular proteins capable of attenuating maladaptive cardiac remodeling. Targeting the epicardium post-MI using decellularized ECM bioscaffold therapy may provide the necessary bioinductive cues to promote differentiation toward a pro-regenerative phenotype and attenuate cardiac fibroblast activation. There is an opportunity to leverage the clinical benefits of this innovative technology with an aim to improve the prognosis of patients suffering from progressive heart failure. An enhanced understanding of the utility of decellularized ECM bioscaffolds in epicardial repair will facilitate their growth and transition into clinical practice. This review will provide a summary of decellularized ECM bioscaffolds being developed for epicardial infarct repair in coronary artery bypass graft (CABG) surgery.

Cystic Fibrosis and Pseudomonas aeruginosa: the Host-Microbe Interface.

In human pathophysiology, the clash between microbial infection and host immunity contributes to multiple diseases. Cystic fibrosis (CF) is a classical example of this phenomenon, wherein a dysfunctional, hyperinflammatory immune response combined with chronic pulmonary infections wreak havoc upon the airway, leading to a disease course of substantial morbidity and shortened life span. Pseudomonas aeruginosa is an opportunistic pathogen that commonly infects the CF lung, promoting an accelerated decline of pulmonary function. Importantly, P. aeruginosa exhibits significant resistance to innate immune effectors and to antibiotics, in part, by expressing specific virulence factors (e.g., antioxidants and exopolysaccharides) and by acquiring adaptive mutations during chronic infection. In an effort to review our current understanding of the host-pathogen interface driving CF pulmonary disease, we discuss (i) the progression of disease within the primitive CF lung, specifically focusing on the role of host versus bacterial factors; (ii) critical, neutrophil-derived innate immune effectors that are implicated in CF pulmonary disease, including reactive oxygen species (ROS) and antimicrobial peptides (e.g., LL-37); (iii) P. aeruginosa virulence factors and adaptive mutations that enable evasion of the host response; and (iv) ongoing work examining the distribution and colocalization of host and bacterial factors within distinct anatomical niches of the CF lung.

The role of the microbiome in scalp hair follicle biology and disease.

The skin surface microbiome and its role in skin diseases have received increasing attention over the past years. Beyond, there is evidence for a continuous exchange with the cutaneous immune system in healthy skin, where hair follicles (HFs) provide unique anatomical niches. Especially, scalp HFs form large tubular invaginations, which extend deeply into the skin and harbour a variety of microorganisms. The distinct immunology of HFs with enhanced immune cell trafficking in superficial compartments in juxtaposition to immune-privileged sites crucial for hair follicle cycling and regeneration makes this organ a highly susceptible structure. Depending on composition and penetration depth, microbiota may cause typical infections, but may also contribute to pro-inflammatory environment in chronic inflammatory scalp diseases. Involvement in hair cycle regulation and immune cell maturation has been postulated. Herein, we review recent insights in hair follicle microbiome, immunology and penetration research and discuss clinical implications for scalp health and disease.

Cholangiocyte pathobiology.

Cholangiocytes, the epithelial cells lining the intrahepatic and extrahepatic bile ducts, are highly specialized cells residing in a complex anatomic niche where they participate in bile production and homeostasis. Cholangiocytes are damaged in a variety of human diseases termed cholangiopathies, often causing advanced liver failure. The regulation of cholangiocyte transport properties is increasingly understood, as is their anatomical and functional heterogeneity along the biliary tract. Furthermore, cholangiocytes are pivotal in liver regeneration, especially when hepatocyte regeneration is compromised. The role of cholangiocytes in innate and adaptive immune responses, a critical subject relevant to immune-mediated cholangiopathies, is also emerging. Finally, reactive ductular cells are present in many cholestatic and other liver diseases. In chronic disease states, this repair response contributes to liver inflammation, fibrosis and carcinogenesis and is a subject of intense investigation. This Review highlights advances in cholangiocyte research, especially their role in development and liver regeneration, their functional and biochemical heterogeneity, their activation and involvement in inflammation and fibrosis and their engagement with the immune system. We aim to focus further attention on cholangiocyte pathobiology and the search for new disease-modifying therapies targeting the cholangiopathies.

Identification and evaluation of the microbiome in the female and male reproductive tracts.

The existence of an extensive microbiome in and on the human body has increasingly dominated the scientific literature during the last decade. A shift from culture-dependent to culture-independent identification of microbes has occurred since the emergence of next-generation sequencing (NGS) techniques, whole genome shotgun and metagenomic sequencing. These sequencing analyses have revealed the presence of a rich diversity of microbes in most exposed surfaces of the human body, such as throughout the reproductive tract. The results of microbiota analyses are influenced by the technical specifications of the applied methods of analyses. Therefore, it is difficult to correctly compare and interpret the results of different studies of the same anatomical niche. The aim of this narrative review is to provide an overview of the currently used techniques and the reported microbiota compositions in the different anatomical parts of the female and male reproductive tracts since the introduction of NGS in 2005. This is crucial to understand and determine the interactions and roles of the different microbes necessary for successful reproduction. A search in Embase, Medline Ovid, Web of science, Cochrane and Google scholar was conducted. The search was limited to English language and studies published between January 2005 and April 2018. Included articles needed to be original microbiome research related to the reproductive tracts. The review provides an extensive up-to-date overview of current microbiome research in the field of human reproductive medicine. The possibility of drawing general conclusions is limited due to diversity in the execution of analytical steps in microbiome research, such as local protocols, sampling methods, primers used, sequencing techniques and bioinformatic pipelines, making it difficult to compare and interpret results of the available studies. Although some microbiota are associated with reproductive success and a good pregnancy outcome, it is still unknown whether a causal link exists. More research is needed to further explore the possible clinical implications and therapeutic interventions. For the field of reproductive medicine, determination of what is a favourable reproductive tract microbiome will provide insight into the mechanisms of both unsuccessful and successful human reproduction. To increase pregnancy chances with live birth and to reduce reproduction-related health costs, future research could focus on postponing treatment or conception in case of the presence of unfavourable microbiota and on the development of therapeutic interventions, such as microbial therapeutics and lifestyle adaptations.

Why microglia kill neurons after neural disorders? The friendly fire hypothesis.

Neuroinflammation plays a fundamental role on the pathophysiology of acute and chronic neural disorders. Microglia activation is a major event following central nervous system inflammation displaying different phenotypes with beneficial and detrimental actions (a Janus face). The reason for this apparent duality is unknown. We have previously shown that following experimental middle cerebral artery occlusion in the rat brain, microglia seem to support and impair adult neurogenesis in the same ischemic striatum. Based on these results, we raised the hypothesis that in the same pathologic environment, gradients of different ligands distributed over different anatomical niches might contribute to both detrimental and beneficial microglial phenotypes. These ligands (“danger signals”) are released by dying cells and bind to microglial receptors in their membranes. Activation of different microglial receptors induces downstream biochemical pathways culminating in a spectrum of microglial phenotypes like M1 and M2 and others. In this paper, we first review the immune functions of microglia and the role of toll-like receptors on the fight against infections. We then briefly revise the dual role of microglia after neural disorders. We then propose a novel hypothesis to explain the Janus face of microglia during the pathophysiology of central nervous system diseases: the “friendly fire hypothesis”. According to this idea “danger signals” or danger associated molecular patterns released by stressed, damaged and/or dying cells during stroke, trauma and other diseases might activate microglial pattern-recognition receptors (i.e., toll like receptors) or other unidentified receptors normally activated by pathogens. This could activate the same genetic and biochemical machinery used by microglia to fight against pathogens even in the absence of infection. According to this notion, microglia may cause bystander neuronal damage with a kind of blind “friendly fire”, fighting against a non-existing infection during non-infectious disorders, like stroke and trauma. The “friendly fire hypothesis” is a novel proposal to explain why microglia may be detrimental and beneficial after acute and chronic neural disorders and may direct future investigations for developing of neuroprotective agents.

Possibility of treatment chronic adenoiditis and otitis media with effusion in children, into account the role of the microbiota of the mucous of the nasopharynx

In recent years, OME in childhood tends to increase. The low efficiency of the currently used traditional methods of conservative therapy and the high rate of relapse of the disease make it necessary to develop new methods of treatment. It is important that there is a connection of development of OME and hypertrophy of the lymphoid tissue of the nasopharynx, which in childhood is considered as a response to the respiratory antigenic virus-bacterial load. The spread of the inflammatory process to the auditory tube with persistence of pathogenic microorganisms in the structure of lymphoid tissue leads to the further development of otitis media effusion; but it is still debatable. All living microorganisms that inhabit a certain anatomical niche (viruses, bacteria, fungi, etc.) are called 'microbiota'. This term includes both commensals and pathogens. 'Microbiome' means the totality of all genes of all microorganisms that inhabit the study area. Thus, the microbiome can be called the collective microbiota genome. Microbiota disorder is a change in the quantitative and qualitative composition of microorganisms, called dysbiosis, and is important in the development of inflammatory pathology. Some drugs (including antibacterial ones) adversely affect indigenous bacteria. Indigenous microbiota develops in abundance in the observed biotope and forms resistance to excessive growth of pathogenic microorganisms. Only NGS sequencing allows to analyze entire mixed bacterial communities ('microbiomes'), which cannot be performed by other diagnostic methods. The use of the NGS sequencing method has proved the important role of microbiota in the development of chronic adenoiditis and OME in children. One of the promising remedies is the inclusion of lysozyme in the treatment regimen. Recent studies indicate the antibacterial and antiviral effects of lysozyme. The use of NGS sequencing made it possible to identify the relationship of the composition of microbiota with the course of chronic adenoiditis and otitis media effusion in children. Inclusion of lysozyme-containing drug Lizobact into therapy promotes colonization of the nasopharynx by indigenous microbiota, while the clinical picture improves.

The Hepatic Central Vein: Anatomical and Molecular Links to Perivenous Liver Biology

The hepatic central vein, the initial branch of the hepatic veins, occupies the central position in the classic liver lobule. The endothelial cells of the vein contain organelles showing secretory modality and are supported by a thin wall containing collagenous matrix and a layer of myofibroblasts. Perivenous hepatocytes differ in ultrastructure from periportal heatocytes and stably express glutamine synthetase serving as a reliable biomarker . Central veins are a primary source of Wnt2, Wnt9b and R-spondin3. These angiocrines participate in the cellular-molecular circuitry of the Wnt/s-catenin and R-spondin-LGR4/5-ZNRF3/RNF43 signaling modules associated with perivenous hepatocytes. These modules regulate hepatic metabolic zonation and perivenous gene expression. The structures of the molecules of these signaling pathways have been elucidated. Expression of glutamine synthetase and cytochrome P4502E1 is indicator of s-catenin activity in liver injury and regeneration . The production, transport and secretion of lipidated Wnts in Wnt-producing cells and their passage in the extracellular matrix to contact responder cells have been described. The modes of Wnts and R-spondin3 release from cental vein endothelial cells and passage in the wall matrix to reach perivenous hepatocytes are unknown. GS + , Axin2 + , Tbx3 + , HNF4a + and CPS - perivenous hepatocytes exhibit stem cell properties, subserving homeostatic hepatocyte renewal. The hepatic central vein constitutes an anatomical niche of perivenous hepatocyte stem cells and provides a molecular link to perivenous hepatic biology.

Induction of Tolerogenic Dendritic Cells by Endogenous Biomolecules: An Update.

The importance of microenvironment on dendritic cell (DC) function and development has been strongly established during the last two decades. Although DCs with general tolerogenic characteristics have been isolated and defined as a particular sub-population, it is predominantly their unequivocal biological plasticity, which allows for unparalleled responsiveness to environmental ques and shaping of their tolerogenic characteristics when interacting with tolerance-inducing biomolecules. Dendritic cells carry receptors for a great number of endogenous factors, which, after ligation, can importantly influence the development of their activation state. For this there is ample evidence merely by observation of DC characteristics isolated from various anatomical niches, e.g., the greater immunosuppressive potential of DCs isolated from intestine compared to conventional blood DCs. Endogenous biomolecules present in these environments most likely play a major role as a determinant of their phenotype and function. In this review, we will concisely summarize in what way various, tolerance-inducing endogenous factors influence DC biology, the development of their particular tolerogenic state and their subsequent actions in context of immune response inhibition and induction of regulatory T cells.

Human Microbiome: Composition and Role in Inflammatory Skin Diseases.

This review focuses on recent evidences about human microbiome composition and functions, exploring the potential implication of its impairment in some diffuse and invalidating inflammatory skin diseases, such as atopic dermatitis, psoriasis, hidradenitis suppurativa and acne. We analysed current scientific literature, focusing on the current evidences about gut and skin microbiome composition and the complex dialogue between microbes and the host. Finally, we examined the consequences of this dialogue for health and skin diseases. This review highlights how human microbes interact with different anatomic niches modifying the state of immune activation, skin barrier status, microbe-host and microbe-microbe interactions. It also shows as most of the factors affecting gut and skin microorganisms' activity have demonstrated to be effective also in modulating chronic inflammatory skin diseases. More and more evidences demonstrate that human microbiome plays a key role in human health and diseases. It is to be expected that these new insights will translate into diagnostic, therapeutic and preventive measures in the context of personalized/precision medicine.

Identification and diversity of Actinomyces species in a clinical microbiology laboratory in the MALDI-TOF MS era

Matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) has emerged as a reliable tool for bacterial identification. This study compared the Bruker MALDI-TOF BioTyper MS (MBT) and 16S rRNA gene sequencing for the identification of Actinomyces and Actinotignum spp. The MBT identified 68/77 (88.3%) of Actinomyces isolates to the genus-level and 44/77 (57.1%) of Actinomyces isolates to the species-level using the manufacturer's identification criteria. The MBT did not yield reliable identification for only 1/77 (1.3%) and generated no identification for 8/77 (10.4%) of the isolates. No misidentifications were found. Discordance at the species level was observed for eight isolates. Overall, the MBT demonstrated good concordance with the 16S rRNA gene sequencing with the exception of the closely related species A. naeslundii, A. viscosus and A. oris. A variety of Actinomyces spp. were isolated from orocervicofacial/dental specimens, but only a limited number of species were isolated from urine or intra-abdominal specimens. This study confirms the utility of MBT in the identification of Actinomyces spp. and describes the diversity and anatomic niche of species in human clinical specimens from various body sites.

Fallopian tube microbiota: evidence beyond DNA.

To determine whether cultivation-dependent and -independent analyses identifying fallopian tube bacteria were associated with visually observable microbial cells in situ using scanning electron microscopy. Fallopian tubes were collected from pre- and postmenopausal women undergoing salpingectomies for benign disease or as prophylaxis. Fresh fallopian tube samples were processed for scanning electron microscopy to characterize fallopian tube ultrastructure. Histopathology was used to exclude fallopian tube abnormalities and for menstrual cycle staging of the endometrium. Scanning electron microscopy revealed observable microbial cells in fallopian tube samples. In the absence of inflammatory pathology, the fallopian tube harbors a visually observable microbial population, which correlates with cultivation-dependent and -independent data, further refuting the sterility of this anatomical niche.

Chronic Niche Inflammation in Endometriosis-Associated Infertility: Current Understanding and Future Therapeutic Strategies.

Endometriosis is an estrogen-dependent inflammatory disease that affects up to 10% of women of reproductive age and accounts for up to 50% of female infertility cases. It has been highly associated with poorer outcomes of assisted reproductive technology (ART), including decreased oocyte retrieval, lower implantation, and pregnancy rates. A better understanding of the pathogenesis of endometriosis-associated infertility is crucial for improving infertility treatment outcomes. Current theories regarding how endometriosis reduces fertility include anatomical distortion, ovulatory dysfunction, and niche inflammation-associated peritoneal or implantation defects. This review will survey the latest evidence on the role of inflammatory niche in the peritoneal cavity, ovaries, and uterus of endometriosis patients. Nonhormone treatment strategies that target these inflammation processes are also included. Furthermore, mesenchymal stem cell-based therapies are highlighted for potential endometriosis treatment because of their immunomodulatory effects and tropism toward inflamed lesion foci. Potential applications of stem cell therapy in treatment of endometriosis-associated infertility in particular for safety and efficacy are discussed.

Abstract 2358: Uncovering novel mechanisms of resistance in AML using integrative functional genomics

Abstract Treatment options that effectively cure patients diagnosed with acute myeloid leukemia (AML) continue to represent an area of unmet need in oncology clinical care. While remission rates in AML patients can reach upwards of 90% under the current frontline therapy paradigm, nearly all patients relapse with treatment refractory disease less than 5 years after diagnosis. Relapse driven by therapy resistant cells that persist in the body after treatment (defined as minimal residual disease, or MRD) is the principal source of fatality in AML patients. Therefore, understanding how and where these leukemic cells survive treatment in vivo may help advance the rational development of highly synergistic combination therapies for the treatment of AML. Using a functional genomic approach (in vivo RNAi) and a new mouse model of AML chemoresistance (ChemoR) generated in our labs, we have identified several putative mediators of therapy resistance. Transcriptional profiling of the ChemoR model allowed us to generate a chemoresistance gene signature that we overlapped with the results of the shRNA screen to identify high-confidence genes of interest. The top genes from a ranked list of the most highly overexpressed (OE) genes in ChemoR cells and the top depleted genes from the shRNA screen in the context of therapy treatment were selected as high interest hits and subsequently tagged for individual follow-up experiments. Early validation studies suggest that some of our hits protect leukemic cells resident only at specific anatomical niches from therapy, while other proteins appear to be general chemosensitizers both in vivo and in vitro, and in both murine and human AML. Subsequent work will focus on elucidating the mechanisms by which these proteins promote resistance to frontline therapies in AML. Citation Format: Azucena Ramos, Luis R. Millan Barea, Alexandre Puissant, Nina Fenouille, Gabriela Alexe, Kimberly Stegmaier, Michael T. Hemann. Uncovering novel mechanisms of resistance in AML using integrative functional genomics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2358.