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Frontiers in Endocrinology 2023Graves' disease is an autoimmune disorder caused by auto-antibodies against the thyroid stimulating hormone receptor (TSHR). Overstimulation of the TSHR induces...
INTRODUCTION
Graves' disease is an autoimmune disorder caused by auto-antibodies against the thyroid stimulating hormone receptor (TSHR). Overstimulation of the TSHR induces hyperthyroidism and thyroid eye disease (TED) as the most common extra thyroidal manifestation of Graves' disease. In TED, the TSHR cross talks with the insulin-like growth factor 1 receptor (IGF-1R) in orbital fibroblasts leading to inflammation, deposition of hyaluronan and adipogenesis. The bone marrow may play an important role in autoimmune diseases, but its role in Graves' disease and TED is unknown. Here, we investigated whether induction of experimental Graves' disease and accompanying TED involves bone marrow activation and whether interference with IGF-1R signaling prevents this activation.
RESULTS
Immunization of mice with TSHR resulted in an increase the numbers of CD4-positive T-lymphocytes (p ≤0.0001), which was normalized by linsitinib (p = 0.0029), an increase of CD19-positive B-lymphocytes (p= 0.0018), which was unaffected by linsitinib and a decrease of GR1-positive cells (p= 0.0038), which was prevented by linsitinib (p= 0.0027). In addition, we observed an increase of Sca-1 positive hematopietic stem cells (p= 0.0007) and of stromal cell-derived factor 1 (SDF-1) (p ≤0.0001) after immunization with TSHR which was prevented by linsitinib (Sca-1: p= 0.0008, SDF-1: p ≤0.0001). TSHR-immunization also resulted in upregulation of CCL-5, IL-6 and osteopontin (all p ≤0.0001) and a concomitant decrease of the immune-inhibitory cytokines IL-10 (p= 0.0064) and PGE2 (p ≤0.0001) in the bone marrow (all p≤ 0.0001). Treatment with the IGF-1R antagonist linsitinib blocked these events (all p ≤0.0001). We further demonstrate a down-regulation of arginase-1 expression (p= 0.0005) in the bone marrow in TSHR immunized mice, with a concomitant increase of local arginine (p ≤0.0001). Linsitinib induces an upregulation of arginase-1 resulting in low arginase levels in the bone marrow. Reconstitution of arginine in bone marrow cells prevented immune-inhibition by linsitinib.
CONCLUSION
Collectively, these data indicate that the bone marrow is activated in experimental Graves' disease and TED, which is prevented by linsitinib. Linsitinib-mediated immune-inhibition is mediated, at least in part, by arginase-1 up-regulation, consumption of arginine and thereby immune inhibition.
Topics: Mice; Animals; Graves Ophthalmopathy; Arginase; Bone Marrow; Graves Disease; Receptors, Thyrotropin; Autoimmune Diseases; Arginine
PubMed: 37810891
DOI: 10.3389/fendo.2023.1252727 -
Blood Oct 2023Mechanistic studies of immune bone marrow failure are difficult because of the scarcity of residual cells, the involvement of multiple cell types, and the inherent... (Review)
Review
Mechanistic studies of immune bone marrow failure are difficult because of the scarcity of residual cells, the involvement of multiple cell types, and the inherent complexities of hematopoiesis and immunity. Single-cell genomic technologies and bioinformatics allow extensive, multidimensional analysis of a very limited number of cells. We review emerging applications of single-cell techniques, and early results related to disease pathogenesis: effector and target cell populations and relationships, cell-autonomous and nonautonomous phenotypes in clonal hematopoiesis, transcript splicing, chromosomal abnormalities, and T-cell receptor usage and clonality. Dense and complex data from single-cell techniques provide insights into pathophysiology, natural history, and therapeutic drug effects.
Topics: Humans; Pancytopenia; Anemia, Aplastic; Bone Marrow Failure Disorders; Hematopoiesis; Syndrome; Genomics
PubMed: 37478398
DOI: 10.1182/blood.2022018581 -
Journal of Clinical Oncology : Official... Oct 2023In myelodysplastic syndromes (MDS), severe thrombocytopenia is associated with poor prognosis. This multicenter trial presents the second-part long-term efficacy and... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
In myelodysplastic syndromes (MDS), severe thrombocytopenia is associated with poor prognosis. This multicenter trial presents the second-part long-term efficacy and safety results of eltrombopag in patients with low-risk MDS and severe thrombocytopenia.
METHODS
In this single-blind, randomized, placebo-controlled, phase-II trial of adult patients with International Prognostic Scoring System low- or intermediate-1-risk MDS, patients with a stable platelet (PLT) count (<30 × 10/mm) received eltrombopag or placebo until disease progression. Primary end points were duration of PLT response (PLT-R; calculated from the time of PLT-R to date of loss of PLT-R, defined as bleeding/PLT count <30 × 10/mm or last date in observation) and long-term safety and tolerability. Secondary end points included incidence and severity of bleeding, PLT transfusions, quality of life, leukemia-free survival, progression-free survival, overall survival and pharmacokinetics.
RESULTS
From 2011 to 2021, of 325 patients screened, 169 patients were randomly assigned oral eltrombopag (N = 112) or placebo (N = 57) at a starting dose of 50 mg once daily to maximum of 300 mg. PLT-R, with 25-week follow-up (IQR, 14-68) occurred in 47/111 (42.3%) eltrombopag patients versus 6/54 (11.1%) in placebo (odds ratio, 5.9; 95% CI, 2.3 to 14.9; < .001). In eltrombopag patients, 12/47 (25.5%) lost the PLT-R, with cumulative thrombocytopenia relapse-free survival at 60 months of 63.6% (95% CI, 46.0 to 81.2). Clinically significant bleeding (WHO bleeding score ≥ 2) occurred less frequently in the eltrombopag arm than in the placebo group (incidence rate ratio, 0.54; 95% CI, 0.38 to 0.75; = .0002). Although no difference in the frequency of grade 1-2 adverse events (AEs) was observed, a higher proportion of eltrombopag patients experienced grade 3-4 AEs (χ = 9.5, = .002). AML evolution and/or disease progression occurred in 17% (for both) of eltrombopag and placebo patients with no difference in survival times.
CONCLUSION
Eltrombopag was effective and relatively safe in low-risk MDS with severe thrombocytopenia. This trial is registered with ClinicalTrials.gov identifier: NCT02912208 and EU Clinical Trials Register: EudraCT No. 2010-022890-33.
Topics: Adult; Humans; Disease Progression; Hemorrhage; Hydrazines; Myelodysplastic Syndromes; Neoplasm Recurrence, Local; Quality of Life; Single-Blind Method; Thrombocytopenia
PubMed: 37294914
DOI: 10.1200/JCO.22.02699 -
Haematologica Nov 2023Janus kinase (JAK) 2 inhibitors are now part of the therapeutic armamentarium for primary and secondary myelofibrosis (MF). Patients with MF endure shortened survival...
Janus kinase (JAK) 2 inhibitors are now part of the therapeutic armamentarium for primary and secondary myelofibrosis (MF). Patients with MF endure shortened survival and poor quality of life. Allogeneic stem cell transplantation (ASCT) is currently the only treatment modality in MF with the potential to cure the disease or prolong survival. By contrast, current drug therapy in MF targets quality of life and does not modify the natural history of the disease. The discovery of JAK2 and other JAK-STAT activating mutations (i.e., CALR and MPL) in myeloproliferative neoplasms, including MF, has facilitated the development of several JAK inhibitors that are not necessarily specific to the oncogenic mutations themselves but have proven effective in countering JAK-STAT signaling, resulting in suppression of inflammatory cytokines and myeloproliferation. This non-specific activity resulted in clinically favorable effects on constitutional symptoms and splenomegaly and, consequently, approval by the Food and Drug Administration (FDA) of three small molecule JAK inhibitors: ruxolitinib, fedratinib, and pacritinib. A fourth JAK inhibitor, momelotinib, is poised for FDA approval soon and has been shown to provide additional benefit in alleviating transfusion-dependent anemia in MF. The salutary effect of momelotinib on anemia has been attributed to inhibition of activin A receptor, type 1 (ACVR1) and recent information suggests a similar effect from pacritinib. ACRV1 mediates SMAD2/3 signaling which contributes to upregulation of hepcidin production and iron-restricted erythropoiesis. Targeting ACRV1 raises therapeutic prospects in other myeloid neoplasms associated with ineffective erythropoiesis, such as myelodysplastic syndromes with ring sideroblasts or SF3B1 mutation, especially those with co-expression of a JAK2 mutation and thrombocytosis.
Topics: Humans; Primary Myelofibrosis; Janus Kinase Inhibitors; Quality of Life; Janus Kinase 2; Myeloproliferative Disorders; Protein Kinase Inhibitors; Nitriles; Anemia; Neoplasms; Activin Receptors, Type I
PubMed: 36861402
DOI: 10.3324/haematol.2022.282612 -
Best Practice & Research. Clinical... Dec 2023The bone marrow failure syndromes (BMFS) are a diverse group of acquired and inherited diseases which may manifest in cytopenias, haematological malignancy and/or... (Review)
Review
The bone marrow failure syndromes (BMFS) are a diverse group of acquired and inherited diseases which may manifest in cytopenias, haematological malignancy and/or syndromic multisystem disease. Patients with BMFS frequently experience poor outcomes, and improved treatment strategies are needed. Collation of clinical characteristics and patient outcomes in a national disease-specific registry represents a powerful tool to identify areas of need and support clinical and research collaboration. Novel treatment strategies such as gene therapy, particularly in rare diseases, will depend on the ability to identify eligible patients alongside the molecular genetic features of their disease that may be amenable to novel therapy. The Australian Aplastic Anaemia and other Bone Marrow Failure Syndromes Registry (AAR) aims to improve outcomes for all paediatric and adult patients with BMFS in Australia by describing the demographics, treatments (including supportive care) and outcomes, and serving as a resource for research and practice improvement.
Topics: Adult; Humans; Child; Anemia, Aplastic; Bone Marrow Diseases; Australia; Bone Marrow Failure Disorders; Syndrome; Registries
PubMed: 38092475
DOI: 10.1016/j.beha.2023.101516 -
Annual Review of Nutrition Aug 2023Riboflavin, in its cofactor forms flavin adenine dinucleotide (FAD) and flavin mononucleotide (FMN), plays fundamental roles in energy metabolism, cellular antioxidant... (Review)
Review
Riboflavin, in its cofactor forms flavin adenine dinucleotide (FAD) and flavin mononucleotide (FMN), plays fundamental roles in energy metabolism, cellular antioxidant potential, and metabolic interactions with other micronutrients, including iron, vitamin B, and folate. Severe riboflavin deficiency, largely confined to low-income countries, clinically manifests as cheilosis, angular stomatitis, glossitis, seborrheic dermatitis, and severe anemia with erythroid hypoplasia. Subclinical deficiency may be much more widespread, including in high-income countries, but typically goes undetected because riboflavin biomarkers are rarely measured in human studies. There are adverse health consequences of low and deficient riboflavin status throughout the life cycle, including anemia and hypertension, that could contribute substantially to the global burden of disease. This review considers the available evidence on causes, detection, and consequences of riboflavin deficiency, ranging from clinical deficiency signs to manifestations associated with less severe deficiency, and the related research, public health, and policy priorities.
Topics: Humans; Riboflavin Deficiency; Riboflavin; Causality; Antioxidants; Bone Marrow Failure Disorders; Disease Progression; Lip Diseases
PubMed: 37603429
DOI: 10.1146/annurev-nutr-061121-084407 -
Experimental Hematology Aug 2023TET2 is a member of the Ten-eleven translocation (Tet) family of DNA dioxygenases that regulate gene expression by promoting DNA demethylation (enzymatic activity) and...
TET2 is a member of the Ten-eleven translocation (Tet) family of DNA dioxygenases that regulate gene expression by promoting DNA demethylation (enzymatic activity) and partnering with chromatin regulatory complexes (nonenzymatic functions). TET2 is highly expressed in the hematopoietic lineage, where its molecular functions are the subject of continuous investigations because of the prevalence of TET2 mutations in hematologic malignancies. Previously, we have implicated Tet2 catalytic and noncatalytic functions in the regulation of myeloid and lymphoid lineages, respectively. However, the impact of these functions of Tet2 on hematopoiesis as the bone marrow ages remains unclear. Here, we conducted comparative transplantations and transcriptomic analyses of 3-, 6-, 9-, and 12-month-old Tet2 catalytic mutant (Mut) and knockout (KO) bone marrow. Tet2 Mut bone marrow of all ages exclusively caused hematopoietic disorders of the myeloid lineage. In contrast, young Tet2 KO bone marrow developed both lymphoid and myeloid diseases, whereas older Tet2 KO bone marrow predominantly elicited myeloid disorders with shorter latency than age-matched Tet2 Mut bone marrow. We identified robust gene dysregulation in Tet2 KO Lin cells at 6 months that involved lymphoma and myelodysplastic syndrome and/or leukemia-causing genes, many of which were hypermethylated early in life. There was a shift from lymphoid to myeloid gene deregulation in Tet2 KO Lin cells with age, underpinning the higher incidence of myeloid diseases. These findings expand on the dynamic regulation of bone marrow by Tet2 and show that its catalytic-dependent and -independent roles have distinct impacts on myeloid and lymphoid lineages with age.
Topics: Humans; Infant; Bone Marrow; Hematologic Neoplasms; Myelodysplastic Syndromes; Hematopoiesis; Hematologic Diseases; Dioxygenases; Mutation
PubMed: 37225048
DOI: 10.1016/j.exphem.2023.05.004 -
International Journal of Molecular... Dec 2023Myelofibrosis (MF), Myeloproliferative neoplasms (MPNs), and MDS/MPN overlap syndromes have a broad range of clinical presentations and molecular abnormalities, making... (Review)
Review
Myelofibrosis (MF), Myeloproliferative neoplasms (MPNs), and MDS/MPN overlap syndromes have a broad range of clinical presentations and molecular abnormalities, making their diagnosis and classification complex. This paper reviews molecular aberration, epigenetic modifications, chromosomal anomalies, and their interactions with cellular and other immune mechanisms in the manifestations of these disease spectra, clinical features, classification, and treatment modalities. The advent of new-generation sequencing has broadened the understanding of the genetic factors involved. However, while great strides have been made in the pharmacological treatment of these diseases, treatment of advanced disease remains hematopoietic stem cell transplant.
Topics: Humans; Myeloproliferative Disorders; Primary Myelofibrosis; Chromosome Aberrations; Neoplasms; Mutation
PubMed: 38139212
DOI: 10.3390/ijms242417383 -
Leukemia Aug 2023Aberrant innate immune signaling has been identified as a potential key driver of the complex pathophysiology of myelodysplastic neoplasms (MDS). This study of a large,...
Aberrant innate immune signaling has been identified as a potential key driver of the complex pathophysiology of myelodysplastic neoplasms (MDS). This study of a large, clinically and genetically well-characterized cohort of treatment-naïve MDS patients confirms intrinsic activation of inflammatory pathways in general mediated by caspase-1, interleukin (IL)-1β and IL-18 in low-risk (LR)-MDS bone marrow and reveals a previously unrecognized heterogeneity of inflammation between genetically defined LR-MDS subgroups. Principal component analysis resolved two LR-MDS phenotypes with low (cluster 1) and high (cluster 2) levels of IL1B gene expression, respectively. Cluster 1 contained 14/17 SF3B1-mutated cases, while cluster 2 contained 8/8 del(5q) cases. Targeted gene expression analysis of sorted cell populations showed that the majority of the inflammasome-related genes, including IL1B, were primarily expressed in the monocyte compartment, consistent with a dominant role in determining the inflammatory bone marrow environment. However, the highest levels of IL18 expression were found in hematopoietic stem and progenitor cells (HSPCs). The colony forming activity of healthy donor HSPCs exposed to monocytes from LR-MDS was increased by the IL-1β-neutralizing antibody canakinumab. This work reveals distinct inflammatory profiles in LR-MDS that are of likely relevance to the personalization of emerging anti-inflammatory therapies.
Topics: Humans; Myelodysplastic Syndromes; Hematopoietic Stem Cells; Bone Marrow; Signal Transduction; Gene Expression Profiling
PubMed: 37420006
DOI: 10.1038/s41375-023-01949-2 -
Blood Advances Aug 2023TP53-mutated myeloid malignancies are associated with complex cytogenetics and extensive structural variants, which complicates detailed genomic analysis by conventional...
TP53-mutated myeloid malignancies are associated with complex cytogenetics and extensive structural variants, which complicates detailed genomic analysis by conventional clinical techniques. We performed whole-genome sequencing (WGS) of 42 acute myeloid leukemia (AML)/myelodysplastic syndromes (MDS) cases with paired normal tissue to better characterize the genomic landscape of TP53-mutated AML/MDS. WGS accurately determines TP53 allele status, a key prognostic factor, resulting in the reclassification of 12% of cases from monoallelic to multihit. Although aneuploidy and chromothripsis are shared with most TP53-mutated cancers, the specific chromosome abnormalities are distinct to each cancer type, suggesting a dependence on the tissue of origin. ETV6 expression is reduced in nearly all cases of TP53-mutated AML/MDS, either through gene deletion or presumed epigenetic silencing. Within the AML cohort, mutations of NF1 are highly enriched, with deletions of 1 copy of NF1 present in 45% of cases and biallelic mutations in 17%. Telomere content is increased in TP53-mutated AMLs compared with other AML subtypes, and abnormal telomeric sequences were detected in the interstitial regions of chromosomes. These data highlight the unique features of TP53-mutated myeloid malignancies, including the high frequency of chromothripsis and structural variation, the frequent involvement of unique genes (including NF1 and ETV6) as cooperating events, and evidence for altered telomere maintenance.
Topics: Humans; Chromothripsis; Mutation; Chromosome Aberrations; Leukemia, Myeloid, Acute; Myeloproliferative Disorders; Myelodysplastic Syndromes; Genomics; Tumor Suppressor Protein p53
PubMed: 37339484
DOI: 10.1182/bloodadvances.2023010156