Tryptophan metabolism is dysregulated in individuals with Fanconi anemia

Bartlett, Allison L.; Romick-Rosendale, Lindsey E.; Nelson, Adam; Abdullah, Sheyar; Luebbering, Nathan; Bartlett, Jamen; Brusadelli, Marion G.; Palumbo, Joseph S.; Lake, Kelly E; Litts, Bridget; Duell, Alexandra; Urbanski, Annette; Lane, Adam; Myers, Kasiani C.; Wells, Susanne I.; Davies, Stella M.

doi:10.1182/bloodadvances.2020002794

Cited by 6 publications

(4 citation statements)

References 65 publications

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“…In addition to the aforementioned syndrome-inducing anemia, Fanconi anemia is a genetic DNA repair disorder that is characterized by progressive bone marrow failure and predisposition to malignancy [ 179 ]. TGF-β signal-mediated growth inhibition is one of the causes of bone marrow failure in Fanconi anemia by impairing the function of hematopoietic stem and progenitor cells [ 180 , 181 ].…”

Section: The Function Of Tgf-β Signals In Diseasementioning

confidence: 99%

TGF-beta signal transduction: biology, function and therapy for diseases

et al. 2022

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The transforming growth factor beta (TGF-β) is a crucial cytokine that get increasing concern in recent years to treat human diseases. This signal controls multiple cellular responses during embryonic development and tissue homeostasis through canonical and/or noncanonical signaling pathways. Dysregulated TGF-β signal plays an essential role in contributing to fibrosis via promoting the extracellular matrix deposition, and tumor progression via inducing the epithelial-to-mesenchymal transition, immunosuppression, and neovascularization at the advanced stage of cancer. Besides, the dysregulation of TGF-beta signal also involves in other human diseases including anemia, inflammatory disease, wound healing and cardiovascular disease et al. Therefore, this signal is proposed to be a promising therapeutic target in these diseases. Recently, multiple strategies targeting TGF-β signals including neutralizing antibodies, ligand traps, small-molecule receptor kinase inhibitors targeting ligand–receptor signaling pathways, antisense oligonucleotides to disrupt the production of TGF-β at the transcriptional level, and vaccine are under evaluation of safety and efficacy for the forementioned diseases in clinical trials. Here, in this review, we firstly summarized the biology and function of TGF-β in physiological and pathological conditions, elaborated TGF-β associated signal transduction. And then, we analyzed the current advances in preclinical studies and clinical strategies targeting TGF-β signal transduction to treat diseases.

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Section: The Function Of Tgf-β Signals In Diseasementioning

confidence: 99%

TGF-beta signal transduction: biology, function and therapy for diseases

et al. 2022

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“…Recently, dysregulated tryptophan metabolism and hyperserotonemia were proposed as mechanisms of metabolic disturbances in FA. 42 Larger studies with broader representation of various FA gene groups may provide mechanistic insights and identify gene-specific associations in metabolism. We noted that four of the ten women with FANCA variants who became pregnant had the c.3624C>T synonymous variant which causes aberrant splicing.…”

Section: Discussionmentioning

confidence: 99%

Genotype-phenotype and outcome associations in patients with Fanconi anemia: the National Cancer Institute cohort

et al. 2022

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Fanconi anemia (FA) is caused by pathogenic variants in the FA/BRCA DNA repair pathway genes, and is characterized by congenital abnormalities, bone marrow failure (BMF) and increased cancer risk. We conducted a genotype-phenotype and outcomes study of 203 patients with FA in our cohort. We compared across the genes, FA/BRCA DNA repair pathways (upstream, ID complex and downstream), and type of pathogenic variants (hypomorphic or null). We explored differences between the patients evaluated in our clinic (clinic cohort) and those who provided data remotely (field cohort). Patients with variants in upstream complex pathway had less severe phenotype [lacked VACTERL-H (Vertebral, Anal, Cardiac, Trachea-esophageal fistula, Esophageal/duodenal atresia, Renal, Limb, Hydrocephalus) association and/or PHENOS (Pigmentation, small-Head, small-Eyes, Neurologic, Otologic, Short stature) features]. ID complex was associated with VACTERL-H. The clinic cohort had more PHENOS features than the field cohort. PHENOS was associated with increased risk of BMF, and VACTERL-H with hypothyroidism. The cumulative incidence of severe BMF was 70%, solid tumors (ST) 20% and leukemia 6.5% as the first event. Head and neck and gynecological cancers were the most common ST, with further increased risk after hematopoietic cell transplantation. Among patients with FANCA, variants in exons 27-30 were associated with higher frequency of ST. Overall median survival was 37 years; patients with leukemia or FANCD1/BRCA2 variants had poorest survival. Patients with variants in the upstream complex had better survival than ID or downstream complex (p=0.001 and 0.016, respectively). FA is phenotypically and genotypically heterogeneous; detailed characterization provides new insights towards understanding this complex syndrome and guiding clinical management.

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“…The KP also plays a key role in successful HSC transplantation, which involves the transplantation of donor HSCs, either autologous or allogenic, for the treatment of certain haematological malignancies including leukaemia and Fanconi anaemia. 176 A potential complication common to allogenic HSC transplantation is GVHD, which is classified into acute (aGVHD) and chronic (cGVHD) forms. GVHD occurs when the donor T cells initiate an immune response against the recipient’s healthy cells.…”

Section: Stem Cellsmentioning

confidence: 99%

A Review of the Evidence for Tryptophan and the Kynurenine Pathway as a Regulator of Stem Cell Niches in Health and Disease

Summers,

Thomas Broome,

Pang

et al. 2024

Int J�Tryptophan�Res

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Stem cells are ubiquitously found in various tissues and organs in the body, and underpin the body’s ability to repair itself following injury or disease initiation, though repair can sometimes be compromised. Understanding how stem cells are produced, and functional signaling systems between different niches is critical to understanding the potential use of stem cells in regenerative medicine. In this context, this review considers kynurenine pathway (KP) metabolism in multipotent adult progenitor cells, embryonic, haematopoietic, neural, cancer, cardiac and induced pluripotent stem cells, endothelial progenitor cells, and mesenchymal stromal cells. The KP is the major enzymatic pathway for sequentially catabolising the essential amino acid tryptophan (TRP), resulting in key metabolites including kynurenine, kynurenic acid, and quinolinic acid (QUIN). QUIN metabolism transitions into the adjoining de novo pathway for nicotinamide adenine dinucleotide (NAD) production, a critical cofactor in many fundamental cellular biochemical pathways. How stem cells uptake and utilise TRP varies between different species and stem cell types, because of their expression of transporters and responses to inflammatory cytokines. Several KP metabolites are physiologically active, with either beneficial or detrimental outcomes, and evidence of this is presented relating to several stem cell types, which is important as they may exert a significant impact on surrounding differentiated cells, particularly if they metabolise or secrete metabolites differently. Interferon-gamma (IFN-γ) in mesenchymal stromal cells, for instance, highly upregulates rate-limiting enzyme indoleamine-2,3-dioxygenase (IDO-1), initiating TRP depletion and production of metabolites including kynurenine/kynurenic acid, known agonists of the Aryl hydrocarbon receptor (AhR) transcription factor. AhR transcriptionally regulates an immunosuppressive phenotype, making them attractive for regenerative therapy. We also draw attention to important gaps in knowledge for future studies, which will underpin future application for stem cell-based cellular therapies or optimising drugs which can modulate the KP in innate stem cell populations, for disease treatment.

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Tryptophan metabolism is dysregulated in individuals with Fanconi anemia

Cited by 6 publications

References 65 publications

TGF-beta signal transduction: biology, function and therapy for diseases

TGF-beta signal transduction: biology, function and therapy for diseases

Genotype-phenotype and outcome associations in patients with Fanconi anemia: the National Cancer Institute cohort

A Review of the Evidence for Tryptophan and the Kynurenine Pathway as a Regulator of Stem Cell Niches in Health and Disease

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