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International Journal of Molecular... Sep 2023Mastocytosis is a clinically heterogenous, usually acquired disease of the mast cells with a survival time that depends on the time of onset. It ranges from skin-limited...
Mastocytosis is a clinically heterogenous, usually acquired disease of the mast cells with a survival time that depends on the time of onset. It ranges from skin-limited to systemic disease, including indolent and more aggressive variants. The presence of the oncogenic KIT p. D816V gene somatic mutation is a crucial element in the pathogenesis. However, further epigenetic regulation may also affect the expression of genes that are relevant to the pathology. Epigenetic alterations are responsible for regulating the expression of genes that do not modify the DNA sequence. In general, it is accepted that DNA methylation inhibits the binding of transcription factors, thereby down-regulating gene expression. However, so far, little is known about the epigenetic factors leading to the clinical onset of mastocytosis. Therefore, it is essential to identify possible epigenetic predictors, indicators of disease progression, and their link to the clinical picture to establish appropriate management and a therapeutic strategy. The aim of this study was to analyze genome-wide methylation profiles to identify differentially methylated regions (DMRs) in patients with mastocytosis compared to healthy individuals, as well as the genes located in those regulatory regions. Genome-wide DNA methylation profiling was performed in peripheral blood collected from 80 adult patients with indolent systemic mastocytosis (ISM), the most prevalent subvariant of mastocytosis, and 40 healthy adult volunteers. A total of 117 DNA samples met the criteria for the bisulfide conversion step and microarray analysis. Genome-wide DNA methylation analysis was performed using a MethylationEPIC BeadChip kit. Further analysis was focused on the genomic regions rather than individual CpG sites. Co-methylated regions (CMRs) were assigned via the CoMeBack method. To identify DMRs between the groups, a linear regression model with age as the covariate on CMRs was performed using Limma. Using the available data for cases only, an association analysis was performed between methylation status and tryptase levels, as well as the context of allergy, and anaphylaxis. KEGG pathway mapping was used to identify genes differentially expressed in anaphylaxis. Based on the DNA methylation results, the expression of 18 genes was then analyzed via real-time PCR in 20 patients with mastocytosis and 20 healthy adults. A comparison of the genome-wide DNA methylation profile between the mastocytosis patients and healthy controls revealed significant differences in the methylation levels of 85 selected CMRs. Among those, the most intriguing CMRs are 31 genes located within the regulatory regions. In addition, among the 10 CMRs located in the promoter regions, 4 and 6 regions were found to be either hypo- or hypermethylated, respectively. Importantly, three oncogenes-, , and -were identified as differentially methylated in mastocytosis patients, for the first time. Functional annotation revealed the most important biological processes in which the differentially methylated genes were involved as transcription, multicellular development, and signal transduction. The biological process related to histone H2A monoubiquitination (GO:0035518) was found to be enriched in association with higher tryptase levels, which may be associated with more aberrant mast cells and, therefore, more atypical mast cell disease. The signal in the BAIAP2 gene was detected in the context of anaphylaxis, but no significant differential methylation was found in the context of allergy. Furthermore, increased expression of genes encoding integral membrane components ( and ) was found in mastocytosis patients. This study confirms that patients with mastocytosis differ significantly in terms of methylation levels in selected CMRs of genes involved in specific molecular processes. The results of gene expression profiling indicate the increased expression of genes belonging to the integral component of the membrane in mastocytosis patients ( and ). Further work is warranted, especially in relation to the disease subvariants, to identify links between the methylation status and the symptoms and novel therapeutic targets.
Topics: Adult; Humans; DNA Methylation; Mastocytosis, Systemic; Epigenesis, Genetic; Anaphylaxis; Tryptases; Oncogenes; DNA; Gene Expression; CpG Islands; Forkhead Transcription Factors
PubMed: 37762215
DOI: 10.3390/ijms241813910 -
Immunology and Allergy Clinics of North... Nov 2023A KIT activating mutation (usually KIT D816V) is detected in neoplastic cells in greater than 90% of indolent patients with systemic mastocytosis (SM). In more advanced... (Review)
Review
A KIT activating mutation (usually KIT D816V) is detected in neoplastic cells in greater than 90% of indolent patients with systemic mastocytosis (SM). In more advanced variants of SM, additional genetic defects can be found in several myeloid malignancy-related genes, which can be detected by applying next-generation sequencing. Currently, the techniques recommended to detect the KIT D816V mutation and quantify the mutational burden in peripheral blood, bone marrow, or other organs/tissues are allele specific-quantitative PCR or droplet digital PCR. These techniques are useful for diagnosis, prognostication, follow-up and monitoring of therapeutic efficacy of cytoreductive agents in patients with SM.
Topics: Humans; Proto-Oncogene Proteins c-kit; Mastocytosis; Mutation; Mastocytosis, Systemic; Bone Marrow; Mast Cells
PubMed: 37758404
DOI: 10.1016/j.iac.2023.04.008 -
Frontiers in Immunology 2023Mast cell leukemia is a rare and aggressive disease, predominantly with D816V mutation. With poor response to conventional poly-chemotherapy, mast cell leukemia...
Mast cell leukemia is a rare and aggressive disease, predominantly with D816V mutation. With poor response to conventional poly-chemotherapy, mast cell leukemia responded to the midostaurin treatment with a 50% overall response rate (ORR), but complete remission rate is approximately 0%. Therefore, the potential mechanisms of midostaurin resistance and the exact impacts of midostaurin on both gene expression profile and mast cell leukemia microenvironment are essential for design tailored combination therapy targeting both the tumor cells and the tumor microenvironment. Here we report a 59-year-old male mast cell leukemia patient with F522C mutation treated with midostaurin. Single-cell sequencing of peripheral blood and whole exome sequencing (WES) of bone marrow were performed before and 10 months after midostaurin treatment. In accordance with the clinical response, compared to the pretreatment aberration, the decline of mast cells and increase of T-, NK, B-cells in peripheral blood, and the decrease of the F522C mutation burden in bone marrow were observed. Meanwhile, the emergence of mutation, upregulations of genes expression (, , , ) on tumor cells, and increased frequencies of T and NK cells with , and expression were observed after midostaurin treatment, predicting the disease progression of this patient. As far as we know, this is the first case reporting the clinical, immunological, and molecular changes in mast cell leukemia patients before and after midostaurin treatment, illustrating the mechanisms of midostaurin resistance in mast cell leukemia, providing important clues to develop a sequential option to circumvent tumor progression after targeting oncogene addiction and prolong patients' survival.
Topics: Male; Humans; Middle Aged; Leukemia, Mast-Cell; Staurosporine; Combined Modality Therapy; Mast Cells; Tumor Microenvironment
PubMed: 37638009
DOI: 10.3389/fimmu.2023.1210909 -
The Journal of Allergy and Clinical... Jan 2024Mastocytosis and monoclonal mast cell (MC) activation syndrome (MMAS) are heterogeneous conditions characterized by the accumulation of atypical MCs. Despite the...
BACKGROUND
Mastocytosis and monoclonal mast cell (MC) activation syndrome (MMAS) are heterogeneous conditions characterized by the accumulation of atypical MCs. Despite the recurrent involvement of KIT mutations, the pathophysiologic origin of mastocytosis and MMAS is unclear. Although hereditary α-tryptasemia (HαT, related to TPSAB1 gene duplication) is abnormally frequent in these diseases, it is not known whether the association is coincidental or causal.
OBJECTIVE
We evaluated the prevalence of HαT in all mastocytosis subtypes and MMAS and assessed the pathophysiologic association with HαT.
METHODS
Clinical data, laboratory data, KIT mutations, TPSAB1 duplication (assessed by droplet digital PCR), and HαT prevalence were retrospectively recorded for all patients with mastocytosis and MMAS registered in the French national referral center database and compared to a control cohort. To increase the power of our analysis for advanced systemic mastocytosis (advSM), we pooled our cohort with literature cases.
RESULTS
We included 583 patients (27 with MMAS and 556 with mastocytosis). The prevalence of HαT in mastocytosis was 12.6%, significantly higher than in the general population (5.7%, P = .002) and lower than in MMAS (33.3%, P = .02). HαT patients were more likely to have anaphylactic reactions and less likely to have cutaneous lesions than HαT patients (43.0% vs 24.4%, P = .006; 57.7% vs 75.6%, respectively, P = .006). In the pooled analysis, the prevalence of HαT was higher in advSM (11.5%) than in control cohorts (5.2%, P = .01).
CONCLUSION
Here we confirm the increase incidence of anaphylaxis in HαT mastocytosis patients. The increased prevalence of HαT in all subtypes of systemic mastocytosis (including advSM) is suggestive of pathophysiologic involvement.
Topics: Humans; Mastocytosis, Systemic; Retrospective Studies; Prevalence; Mastocytosis; Anaphylaxis; Mast Cells; Tryptases
PubMed: 37633651
DOI: 10.1016/j.jaci.2023.08.015 -
The Journal of Allergy and Clinical... Oct 2023Physiological levels of basal serum tryptase vary among healthy individuals, depending on the numbers of mast cells, basal secretion rate, copy numbers of the TPSAB1... (Review)
Review
Physiological levels of basal serum tryptase vary among healthy individuals, depending on the numbers of mast cells, basal secretion rate, copy numbers of the TPSAB1 gene encoding alpha tryptase, and renal function. Recently, there has been a growing debate about the normal range of tryptase because individuals with the hereditary alpha tryptasemia (HαT) trait may or may not be symptomatic, and if symptomatic, uncertainty exists as to whether this trait directly causes clinical phenotypes or aggravates certain conditions. In fact, most HαT-positive cases are regarded as asymptomatic concerning mast cell activation. To address this point, experts of the European Competence Network on Mastocytosis (ECNM) and the American Initiative in Mast Cell Diseases met at the 2022 Annual ECNM meeting and discussed the physiological tryptase range. Based on this discussion, our faculty concluded that the normal serum tryptase range should be defined in asymptomatic controls, inclusive of individuals with HαT, and based on 2 SDs covering the 95% confidence interval. By applying this definition in a literature screen, the normal basal tryptase in asymptomatic controls (HαT-positive persons included) ranges between 1 and 15 ng/mL. This definition should avoid overinterpretation, unnecessary referrals, and unnecessary anxiety or anticipatory fear of illness in healthy individuals.
Topics: Humans; Tryptases; Reference Values; Mast Cells; Mastocytosis
PubMed: 37572755
DOI: 10.1016/j.jaip.2023.08.008 -
Diagnosis (Berlin, Germany) Nov 2023To describe patterns observed in antibody titer trendlines in patients with mast cell activation syndrome (MCAS, a prevalent but underrecognized chronic multisystem...
OBJECTIVES
To describe patterns observed in antibody titer trendlines in patients with mast cell activation syndrome (MCAS, a prevalent but underrecognized chronic multisystem inflammatory disorder of great clinical heterogeneity) and offer clinical lessons learned from such pattern recognition.
METHODS
The available records of 104 MCAS patients drawn from the authors' practices were reviewed, including all antibody tests therein.
RESULTS
All patients had positive/elevated antibodies of various sorts at various points, but for most of the antibodies which were found to be positive at least some points, the diseases classically associated with those antibodies were not present, marking such antibodies as clinically insignificant mimickers (likely consequent to inflammatory effects of MCAS on the immune system itself driving spurious/random antibody production) rather than "on-target" and pathogenic antibodies reflecting true disease warranting treatment. We also observed two distinct patterns in trendlines of the titers of the mimickers vs. the trendline pattern expected in a true case of an antibody-associated disease (AAD).
CONCLUSIONS
Our observations suggest most positive antibody tests in MCAS patients represent detection of clinically insignificant mimicking antibodies. As such, to reduce incorrect diagnoses of AADs and inappropriate treatment in MCAS patients, caution is warranted in interpreting positive antibody tests in these patients. Except in clinically urgent/emergent situations, patience in determining the trendline of a positive antibody in an MCAS patient, and more carefully assessing whether the AAD is truly present, is to be preferred.
Topics: Humans; Mastocytosis; Mast Cell Activation Syndrome
PubMed: 37566881
DOI: 10.1515/dx-2023-0032 -
Archives of Pathology & Laboratory... Feb 2024Mast cells are essential components of the immune system and play crucial pathogenetic roles in several digestive diseases, including mastocytic enterocolitis and... (Review)
Review
CONTEXT.—
Mast cells are essential components of the immune system and play crucial pathogenetic roles in several digestive diseases, including mastocytic enterocolitis and eosinophilic gastrointestinal disorders. Pathologists have rarely been asked to evaluate the distribution and density of mast cells in gastrointestinal (GI) biopsy specimens. However, such requests are becoming more common because of an increasing awareness of the role of mast cells in functional GI disease and in both esophageal and nonesophageal eosinophilic gastrointestinal disorders.
OBJECTIVE.—
To provide pathologists with tools to incorporate the assessment of mast cells in the evaluation of esophageal, gastric, and intestinal specimens by developing a systematic approach to their evaluation, counting, and reporting.
DESIGN.—
This study consisted of a review of the literature followed by multiple consensus sessions to decide where to count mast cells and what a countable mast cell is.
RESULTS.—
We reviewed 135 papers addressing the content of mast cells in the digestive tract, selected 21 that detailed how cells were counted (microscope lens, area of high-power fields, locations evaluated, type of cells considered as countable), and summarized their data in a table. Then, drawing from both the acceptable literature and our own extensive experience, we reached a tentative consensus on: (1) the normal numbers in the different segments of the GI tract; (2) the morphology of countable mast cells; and (3) the locations and strategies for counting them.
CONCLUSIONS.—
The result is a set of suggestions for reporting mast cell counts, their distribution, and their location in a way clinicians can understand and use for management decisions.
Topics: Humans; Mast Cells; Pathologists; Gastrointestinal Tract; Mastocytosis; Gastrointestinal Diseases
PubMed: 37450346
DOI: 10.5858/arpa.2023-0070-OA -
The Journal of Allergy and Clinical... Oct 2023
Topics: Male; Humans; Child; Mastocytosis, Systemic; Spinal Fractures; Mastocytosis
PubMed: 37399946
DOI: 10.1016/j.jaip.2023.06.045 -
Clinical Case Reports Jul 2023When managing patients with differentiated thyroid cancers (DTC) and lytic bone lesions, physicians should consider etiologies other than DTC bony metastases when there...
KEY CLINICAL MESSAGE
When managing patients with differentiated thyroid cancers (DTC) and lytic bone lesions, physicians should consider etiologies other than DTC bony metastases when there is no biochemical and functional radiographic evidence of extensive DTC burden.
ABSTRACT
Systemic mastocytosis (SM) is a clonal expansion of mast cells associated with an increased risk of solid malignancies. There is no known association between systemic mastocytosis and thyroid cancer. We report a young woman who presented with cervical lymphadenopathy, palpable thyroid nodule, and lytic bone lesions who was diagnosed with papillary thyroid cancer (PTC). The patient's post-surgical thyroglobulin was lower than expected for metastatic thyroid cancer, and the lytic bone lesions did not demonstrate uptake of I. Upon further evaluation, the patient was found to have SM. We report a case of co-occurrence of PTC and SM.
PubMed: 37397583
DOI: 10.1002/ccr3.7507 -
International Journal of Dermatology... Jun 2023Mastocytosis, a clonal proliferation of mast cells commonly involving the skin and bone marrow, has a varied clinical presentation ranging from cutaneous lesions to...
UNLABELLED
Mastocytosis, a clonal proliferation of mast cells commonly involving the skin and bone marrow, has a varied clinical presentation ranging from cutaneous lesions to systemic disease. Cutaneous mastocytosis is managed symptomatically, but systemic mastocytosis is treated with targeted therapy against the mutated receptor tyrosine kinase c-KIT, the pathogenic driver of mastocytosis. However, there are no guidelines for the treatment of cutaneous mastocytosis refractory to symptomatic management. We herein report a method to select genetically informed therapy for symptomatic and recalcitrant cutaneous mastocytosis.
CASE PRESENTATION
We performed a mutational analysis of dermal mast cells after enrichment by laser capture in a 23-year-old woman with recalcitrant cutaneous mastocytosis. The analysis revealed a aspartic acid to valine substitution at codon 816 (D816V) mutation in the protein c-KIT. Based on these results, we initiated treatment with the multi-kinase/KIT inhibitor midostaurin, a treatment effective against the D816V c-KIT mutation. After 3 months of treatment, the patient exhibited a reduction in the number and size of cutaneous lesions and reported resolution of pruritus and decreased severity of other mast cell-related symptoms.
DISCUSSION
The treatment of mastocytosis relies heavily on whether the disease is limited to the skin or systemic. However, there are no guidelines for cutaneous mastocytosis that does not respond to symptomatic management. In the present report describing a patient with recalcitrant cutaneous mastocytosis, we describe a strategy in which skin mutational analysis is used to guide the selection of targeted therapy.
CONCLUSION
Performing mast cell mutational analyses in the skin provides a means to select targeted therapy for symptomatic and refractory cutaneous mastocytosis.
PubMed: 37396019
DOI: 10.1097/JD9.0000000000000243