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Cells Apr 2024The unfolded protein response is an intricate system of sensor proteins in the endoplasmic reticulum (ER) that recognizes misfolded proteins and transmits information...
TurboID-Based IRE1 Interactome Reveals Participants of the Endoplasmic Reticulum-Associated Protein Degradation Machinery in the Human Mast Cell Leukemia Cell Line HMC-1.2.
The unfolded protein response is an intricate system of sensor proteins in the endoplasmic reticulum (ER) that recognizes misfolded proteins and transmits information via transcription factors to either regain proteostasis or, depending on the severity, to induce apoptosis. The main transmembrane sensor is IRE1α, which contains cytoplasmic kinase and RNase domains relevant for its activation and the mRNA splicing of the transcription factor XBP1. Mast cell leukemia (MCL) is a severe form of systemic mastocytosis. The inhibition of IRE1α in the MCL cell line HMC-1.2 has anti-proliferative and pro-apoptotic effects, motivating us to elucidate the IRE1α interactors/regulators in HMC-1.2 cells. Therefore, the TurboID proximity labeling technique combined with MS analysis was applied. Gene Ontology and pathway enrichment analyses revealed that the majority of the enriched proteins are involved in vesicle-mediated transport, protein stabilization, and ubiquitin-dependent ER-associated protein degradation pathways. In particular, the AAA ATPase VCP and the oncoprotein MTDH as IRE1α-interacting proteins caught our interest for further analyses. The pharmacological inhibition of VCP activity resulted in the increased stability of IRE1α and MTDH as well as the activation of IRE1α. The interaction of VCP with both IRE1α and MTDH was dependent on ubiquitination. Moreover, MTDH stability was reduced in IRE1α-knockout cells. Hence, pharmacological manipulation of IRE1α-MTDH-VCP complex(es) might enable the treatment of MCL.
Topics: Humans; Protein Serine-Threonine Kinases; Endoribonucleases; Cell Line, Tumor; Leukemia, Mast-Cell; Endoplasmic Reticulum-Associated Degradation; Valosin Containing Protein; Membrane Proteins
PubMed: 38727283
DOI: 10.3390/cells13090747 -
Hematology Reports Mar 2024Factor VII (FVII) deficiency is a rare bleeding disorder that can be classified as congenital or acquired, and the majority of acquired cases are due to vitamin K...
Factor VII (FVII) deficiency is a rare bleeding disorder that can be classified as congenital or acquired, and the majority of acquired cases are due to vitamin K deficiency or liver disease. Isolated acquired FVII deficiency is a rare occurrence and has been associated with inhibitors or auto-antibodies. Here, we describe a patient with polycythemia vera who developed systemic mastocytosis and FVII deficiency simultaneously. FVII deficiency was not caused by inhibitors and improved with antineoplastic treatment. Acquired FVII deficiency has been reported in cases of sepsis, possibly due to proteolytic degradation induced by the activation of monocytes or endothelial cells. Malignancies have been shown to cause a depletion in circulating FVII through the direct binding of cancer cells. This case report suggests a potential association between SM associated with a hematological neoplasm (SM-AHN) and acquired FVII deficiency. Further evaluations are recommended in patients with systemic mastocytosis to gain a better understanding of the relationship between pathological mast cells and clotting factor concentrations.
PubMed: 38534884
DOI: 10.3390/hematolrep16010014 -
Leukemia Apr 2024We identified 71 patients with AdvSM (aggressive SM [ASM], SM with an associated hematologic neoplasm [SM-AHN, e.g., acute myeloid leukemia, SM-AML], mast cell leukemia...
We identified 71 patients with AdvSM (aggressive SM [ASM], SM with an associated hematologic neoplasm [SM-AHN, e.g., acute myeloid leukemia, SM-AML], mast cell leukemia [MCL]) in two national registries (DRST/GREM) who received an allogeneic hematopoietic cell transplantation (alloHCT) performed in Germany from 1999-2021. Median overall survival (OS) of ASM/SM-AHN (n = 30, 45%), SM-AML (n = 28, 39%) and MCL ± AHN (n = 13, 19%) was 9.0, 3.3 and 0.9 years (P = 0.007). Improved median OS was associated with response of SM (17/41, 41%; HR 0.4 [0.2-0.9], P = 0.035) and/or of AHN (26/43, 60%, HR 0.3 [0.1-0.7], P = 0.004) prior to alloHCT. Adverse predictors for OS included absence of KIT D816V (10/61, 16%, HR 2.9 [1.2-6.5], P < 0.001) and a complex karyotype (9/60, 15%, HR 4.2 [1.8-10.0], P = 0.016). HLA-match, conditioning type or transplantation at centers reporting above-average alloHCTs (≥7) had no impact on OS. Taking into account competing events at years 1, 3 and 5, relapse-related mortality and non-relapse mortality rate were 15%/23%, 20%/30% and 23%/35%, respectively. Irrespective of subtype, subsequent treatment response was achieved in 13/30 (43%) patients and was highest on midostaurin/avapritinib (7/9, 78%). We conclude that outcome of alloHCT in AdvSM is more affected by disease phenotype and treatment response prior to transplant than by transplant characteristics.
Topics: Humans; Mastocytosis, Systemic; Retrospective Studies; Leukemia, Mast-Cell; Hematopoietic Stem Cell Transplantation; Leukemia, Myeloid, Acute
PubMed: 38448757
DOI: 10.1038/s41375-024-02186-x -
Acta Medica Portuguesa Mar 2024
Topics: Humans; COVID-19; COVID-19 Vaccines; Mastocytosis, Systemic
PubMed: 38430469
DOI: 10.20344/amp.20851 -
Journal of Veterinary Internal Medicine 2024The therapeutic role and prognostic relevance of lymphadenectomy in mast cell tumor (MCT) has historically been evaluated on regional rather than sentinel lymph nodes.
BACKGROUND
The therapeutic role and prognostic relevance of lymphadenectomy in mast cell tumor (MCT) has historically been evaluated on regional rather than sentinel lymph nodes.
HYPOTHESIS/OBJECTIVES
To update information about the association of histological nodal (HN) classes with clinical outcome in dogs with MCT after tumor excision and extirpation of normal-sized sentinel nodes (SLN) guided by radiopharmaceutical.
ANIMALS
Ninety-four dogs with histologically-confirmed treatment-naïve MCT (71 cutaneous, 22 subcutaneous and 1 conjunctival MCT) were included if without: distant metastases, lymphadenomegaly, concurrent mixed cutaneous, and subcutaneous MCT.
METHODS
This was a monoistitutional cohort study. Tumors characteristics were retrieved and SLNs were classified according to Weishaar's system. Incidence of MCT-related events (local, nodal, distant relapse), de novo MCT or other tumors and death (MCT-related and non-MCT-related), were recorded. Incidence curves were compared among the HN classes.
RESULTS
Twenty-seven dogs had HN0, 19 HN1, 37 HN2, and 11 HN3 SLN. Thirteen (2 HN0, 4 HN2, and 7 HN3) received adjuvant chemotherapies. Kiupel high grade, increasing number of SLN and lymphocentrums were associated with higher HN classes. Five dogs died for MCT-related causes: 1 low-grade (HN0) and 1 subcutaneous (HN3) had a local relapse, 2 high-grade had distant relapse (HN3-HN0) and 1 dog developed disease progression from a de novo subcutaneous MCT. No nodal relapse was registered. Fourteen dogs developed de novo MCTs.
CONCLUSION/DISCUSSION
Low grade/low-risk MCT with nonpalpable and normal sized SLN have a favorable outcome independently from the HN. Result should be considered strictly related to the successful SLN detection guided pre- and intraoperative by radiopharmaceutical markers.
Topics: Animals; Dogs; Dog Diseases; Female; Male; Lymphatic Metastasis; Sentinel Lymph Node; Lymph Node Excision; Cohort Studies; Mastocytoma; Mast-Cell Sarcoma; Treatment Outcome
PubMed: 38426589
DOI: 10.1111/jvim.16997 -
The Journal of Allergy and Clinical... May 2024Systemic mastocytosis (SM) is a clonal disorder of mast cells (MCs) frequently associated with vertebral osteoporosis (OP) and subsequent vertebral fractures (VFs). The...
BACKGROUND
Systemic mastocytosis (SM) is a clonal disorder of mast cells (MCs) frequently associated with vertebral osteoporosis (OP) and subsequent vertebral fractures (VFs). The natural history of this OP remains unclear. Importantly, we do not know whether OP represents an early event triggered alongside MC abnormalities, and whether MC clonality is sufficient to trigger osteoporosis.
OBJECTIVE
To describe OP in patients with medullar clonality in cutaneous mastocytosis (CM) and monoclonal mast cell activation syndrome (MMAS) and to compare their osteoporosis characteristics with those of nonadvanced SM patients (bone marrow mastocytosis and indolent systemic mastocytosis).
METHODS
We retrospectively analyzed clinical, biological, and densitometric data of 27 CM, 13 MMAS, and 135 SM patients from the Mastocytosis Expert Center (CEREMAST) in Toulouse, France.
RESULTS
The OP (respectively 3.7, 30.8, and 34.1%) and VFs (0.0%, 15.4%, and 20%) were less frequent in CM than in MMAS and SM, despite the presence of clonal MCs in the bone marrow. Most patients with OP and VFs in the non-SM groups had the usual risk factors for OP. Interestingly, the only non-SM patient with a typical SM-like OP had high bone marrow tryptase, developed bone marrow KIT mutation during follow-up, and had a family history of SM. Our data show that OP is not a common clinical finding in CM but is frequent in MMAS. When OP and VFs occur in CM and MMAS patients, they differ from the usual phenotype of SM bone fragility.
CONCLUSIONS
Our findings suggest that, in most CM patients, the meaning and management of OP differs from that of OP in MMAS and nonadvanced SM. Prospective longitudinal studies and the validation of predictors are needed to identify CM and MMAS patients developing SM-related OP.
Topics: Humans; Osteoporosis; Female; Male; Middle Aged; Adult; Prevalence; Retrospective Studies; Aged; Mastocytosis, Cutaneous; Mastocytosis, Systemic; Mast Cells; France; Bone Marrow; Proto-Oncogene Proteins c-kit; Spinal Fractures
PubMed: 38423295
DOI: 10.1016/j.jaip.2024.02.021 -
Acta Oncologica (Stockholm, Sweden) Feb 2024Mastocytosis is a disease characterized by accumulation of aberrant mast cells and mediator-related symptoms and is divided into systemic mastocytosis (SM) and cutaneous...
BACKGROUND
Mastocytosis is a disease characterized by accumulation of aberrant mast cells and mediator-related symptoms and is divided into systemic mastocytosis (SM) and cutaneous mastocytosis (CM). The epidemiology of mastocytosis remains incompletely understood.
OBJECTIVE
To estimate the incidence, prevalence, overall survival (OS) and burden of comorbidities in adult mastocytosis patients identified in Swedish population-based registries.
METHODS
Individuals (≥ 20 years of age) with a mastocytosis diagnosis in the National Patient Register (NPR) and/or the Swedish Cancer Register (SCR) between 2001 and 2018, were identified. In a matched cohort design, for each case five randomly selected mastocytosis-free comparators matched on age, sex, and county of residence were chosen from the Population Register. The Kaplan-Meier method was used to compare OS between individuals with mastocytosis and comparators. Information on concomitant disease at baseline was assessed by use of the Charlson Comorbidity Index (CCI).
RESULTS
We identified 2,040 adults with a mastocytosis diagnosis yielding an annual incidence of 1.56 per 100,000 (95% CI 1.29-1.87) and a prevalence of 23.9 per 100,000 (95% CI 22.8-25.0). The comorbidity burden was higher, and the OS lower, in patients with mastocytosis compared to comparators.
INTERPRETATION
We found a higher incidence and prevalence of mastocytosis compared to assessments in other settings and confirmed that the prognosis generally is favorable. Of special note was evidence of a higher comorbidity burden in mastocytosis patients compared to the background population.
LIMITATIONS
Underreporting and inconsistencies in the use of diagnostic codes.
Topics: Adult; Humans; Mast Cells; Mastocytosis; Mastocytosis, Systemic; Prognosis; Sweden; Young Adult; Male; Female
PubMed: 38380845
DOI: 10.2340/1651-226X.2024.31406 -
International Journal of Molecular... Jan 2024Mastocytosis is a heterogeneous disease characterized by the expansion and accumulation of neoplastic mast cells in various tissues. Diffuse cutaneous mastocytosis (DCM)... (Review)
Review
Mastocytosis is a heterogeneous disease characterized by the expansion and accumulation of neoplastic mast cells in various tissues. Diffuse cutaneous mastocytosis (DCM) is a rare and most severe form of cutaneous mastocytosis, which typically occurs in childhood. There have been reports of a familial DCM with specific gene mutations, indicating both sporadic and hereditary factors involved in its pathogenesis. DCM is associated with severe MC mediator-related symptoms and an increased risk of anaphylaxis. The diagnosis is based on the appearance of skin lesions, which typically show generalized thickening, erythroderma, blistering dermographism, and a positive Darier's sign. Recognition, particularly in infants, is challenging due to DCMs resemblance to other bullous skin disorders. Therefore, in unclear cases, a skin biopsy is crucial. Treatment focuses on symptom management, mainly including antihistamines and mast cell stabilizers. In extremely severe cases, systemic steroids, tyrosine kinase inhibitors, phototherapy, or omalizumab may be considered. Patients should be equipped with an adrenaline autoinjector. Herein, we conducted a comprehensive review of literature data on DCM since 1962, which could help to better understand both the management and prognosis of DCM, which depends on the severity of skin lesions, intensity of mediator-related symptoms, presence of anaphylaxis, and treatment response.
Topics: Infant; Humans; Anaphylaxis; Rare Diseases; Mastocytosis, Cutaneous; Mastocytosis; Skin; Lupus Erythematosus, Cutaneous; Mast Cells
PubMed: 38338679
DOI: 10.3390/ijms25031401 -
Current Allergy and Asthma Reports Mar 2024Mast cell (MC) activation syndromes (MCAS) are conditions defined by recurrent episodes of severe systemic anaphylaxis or similar systemic events triggered by MC-derived... (Review)
Review
PURPOSE OF REVIEW
Mast cell (MC) activation syndromes (MCAS) are conditions defined by recurrent episodes of severe systemic anaphylaxis or similar systemic events triggered by MC-derived mediators that can be measured in biological fluids. Since some symptoms of MC activation may occur due to other, non-MC etiologies and lead to confusion over diagnosis, it is of crucial importance to document the involvement of MC and their products in the patients´ symptomatology.
RECENT FINDINGS
The most specific and generally accepted marker of severe systemic MC activation is an event-related, transient increase in the serum tryptase level over the individual baseline of the affected individual. However, baseline concentrations of serum tryptase vary among donors, depending on the genetic background, age, kidney function, and underlying disease. As a result, it is of critical importance to provide a flexible equation that defines the diagnostic increase in tryptase qualifying as MCAS criterion in all patients, all situations, and all ranges of baseline serum tryptase. In 2012, the consensus group proposed the 120% + 2 ng/ml formula, which covers the great majority of groups, including cases with low, normal, or elevated basal serum tryptase level. This formula has been validated in subsequent studies and has proven to be a robust and consistent diagnostic criterion of MCAS. The present article is discussing the impact of this formula and possible limitations as well as alternative markers and mediators that may be indicative of MCAS.
Topics: Humans; Mast Cells; Mastocytosis; Tryptases; Anaphylaxis; Biomarkers
PubMed: 38308674
DOI: 10.1007/s11882-024-01124-2 -
Scientific Reports Jan 2024Hereditary α tryptasemia (HαT) is an autosomal dominant trait characterized by increased TPSAB1 copy number (CN) encoding α-tryptase. The determination of HαT is...
Hereditary α tryptasemia (HαT) is an autosomal dominant trait characterized by increased TPSAB1 copy number (CN) encoding α-tryptase. The determination of HαT is being discussed as an important biomarker to be included in risk assessment models and future diagnostic algorithms for patients with mastocytosis and anaphylaxis. Due to the complex genetic structure at the human tryptase locus, genetic testing for tryptase gene composition is presently notably limited and infrequently pursued. This study aimed to develop, optimise and validate a multiplex droplet digital PCR (ddPCR) assay that can reliably quantify α- and β-tryptase encoding sequences in a single reaction. To optimise the ddPCR conditions and establish an amplitude-based multiplex ddPCR assay, additional primers and probes, a thermal gradient with varying annealing temperatures, different primers/probe concentrations, and various initial DNA quantities were tested. Results obtained from all 114 samples analysed using multiplex ddPCR were identical to those obtained through the use of original duplex assays. Utilizing this multiplex ddPCR assay, in contrast to conducting distinct duplex ddPCRs, presents noteworthy benefits for tryptase genotyping. These advantages encompass a substantial threefold decrease in material costs and considerable time savings. Consequently, this approach exhibits high suitability and particularly captures interest for routine clinical implementation.
Topics: Humans; Tryptases; Genotype; Multiplex Polymerase Chain Reaction; Genetic Testing; Mastocytosis
PubMed: 38287122
DOI: 10.1038/s41598-024-52983-8