Histone Deacetylase Inhibitor SAHA Mediates Epigenetic Silencing of KIT D816V Mutated Systemic Mastocytosis Primary Mast Cells and Selective Apoptosis of Mutated Mast Cells

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2834-2834 ◽  
Author(s):  
Hani Abdulkadir ◽  
Jennine Grootens ◽  
Matilda Kjellander ◽  
Eva Hellstrom Lindberg ◽  
Gunnar Nilsson ◽  
...  
Keyword(s):  
Cell Death ◽  
Mast Cell ◽  
Mast Cells ◽  
Histone Deacetylase ◽  
Histone Deacetylase Inhibitors ◽  
Conflicts Of Interest ◽  
Systemic Mastocytosis ◽  
Specific Treatment ◽  
Epigenetic Silencing ◽  
Kit Receptor

Abstract Systemic mastocytosis (SM) is a myeloproliferative disease for which there is currently no specific therapy. Over 90% of the patients carry the D816V point mutation that renders the KIT receptor constitutively active. In the current study, we assessed the sensitivity of mast cell line HMC1.2 and primary SM patient mast cells to histone deacetylase inhibitors, and found that SAHA is most efficient. SAHA induced a rapid downregulation of KIT mRNA, with a subsequent reduction in total KIT protein as well as cell surface KIT. This was followed by major mast cell apoptosis. Primary SM patient mast cells cultured ex vivo were even more sensitive to SAHA than HMC1.2 cells, whereas healthy subject mast cells were unaffected. There was a correlation between cell death and SM disease severity, where cell death was more pronounced in the case of aggressive disease, with almost 100% cell death among mast cells from the mast cell leukemia patient. Using ChIP qPCR, we found that the level of active chromatin mark H3K18ac/totalH3 decreased significantly in the KIT region, due to an increase in H3 density. This epigenetic silencing was specific to the KIT region and not seen in control genes upstream and downstream of KIT. Primary analysis of ChIP-seq data for histone marks H3K4me3 and H3K27me3, demonstrates a downregulation of transcription factors involved in activation of KIT receptor, such as MAPK, for the SAHA treated samples. This indicates an indirect epigenetic silencing of KIT. Our results therefore demonstrate that SAHA epigenetically silences KIT, and work is ongoing to elucidate the exact mechanisms of KIT regulation. Altogether, SAHA maybe a specific treatment for SM. Disclosures No relevant conflicts of interest to declare.

scholarly journals Histone deacetylase inhibitor SAHA mediates mast cell death and epigenetic silencing of constitutively active D816V KIT in systemic mastocytosis

Oncotarget ◽  
2016 ◽  
Vol 8 (6) ◽  
pp. 9647-9659 ◽  
Author(s):  
Katarina Lyberg ◽  
Hani Abdulkadir Ali ◽  
Jennine Grootens ◽  
Matilda Kjellander ◽  
Malin Tirfing ◽  
...  
Keyword(s):  
Cell Death ◽  
Mast Cell ◽  
Histone Deacetylase ◽  
Histone Deacetylase Inhibitor ◽  
Systemic Mastocytosis ◽  
Epigenetic Silencing ◽  
Deacetylase Inhibitor ◽  
Constitutively Active

Imatinib Mesylate in the Treatment of Systemic Mastocytosis, a Phase I/II Trial.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1516-1516 ◽  
Author(s):  
H.J. Droogendijk ◽  
J.C. Kluin-Nelemans ◽  
P.L.A van Daele
Keyword(s):  
Bone Marrow ◽  
Cell Proliferation ◽  
Mast Cell ◽  
Mast Cells ◽  
Imatinib Mesylate ◽  
Systemic Mastocytosis ◽  
Skin Lesions ◽  
Tissue Response ◽  
Serum Tryptase ◽  
Kit Receptor

Abstract Introduction: mastocytosis comprimes a group of diseases characterized by abnormal proliferation and accumulation of mast cells in one or more organs. A cutaneous and systemic form of mastocytosis is distinguished. Systemic mastocytosis defines the disease process in which mast cell proliferation exceeds the skin. The clinical manifestations of systemic mastocytosis depend on the tissues involved and the tissue response to the accumulation of mast cells. Although in general the disease progresses slowly, it may develop into a malignant disease. Currently there is no cure for systemic mastocytosis. Mast cells develop from pluripotent bone marrow progenitor cells that express CD34 antigen and are dispersed as precursors which undergo proliferation and maturation in different tissues. Normal mast cell development involves the action of stam cell growth factor and c-kit receptors, which are expressed by mast cells at their different developmental stages. Deregulation and/or abnormalities of the c-kit receptor are assumed to play a causal role in disordered mast-cell proliferation. In most patients a mutation in the gene for c-kit exists. One of the mutations is the D816V mutation. Aim of the study:imatinib mesylate, formerly called ST1571, is a potent inhibitor of c-kit receptor tyrosine kinase activity. In this study, we evaluate whether imatinib mesylate is safe and effective in the treatment of patients with systemic mastocytosis. Primary end-points of study are reduction in urinary N-methylhistamine excretion, serum tryptase activity, skin lesions, number of mast cells in sections of bone marrow, hepato-and/or splenomegaly and symptoms.Adverse effects on therapy are also considered. Results: up to now, 10 patients with systemic mastocytosis are treated with 400 mg of imatinib mesylate orally once daily. During the first 2 weeks of the study the patients also received 30 mg of prednisolone daily. In general imatinib mesylate is well tolerated. The first results show a 38–80% reduction in urinary N-methylhistamine excretion and 30–66% reduction in serum tryptase activity. Skin lesions diminish in two of the six patients with cutaneous mastocytosis,. Number of mast cells in sections of bone marrow are reduced in 63% (5/8) of the patients. Hepato-and/or splenomegaly is slightly decreased in two of the three patients with organomegaly. Finally 60 % of all patients experiences relief of symptoms. In eight patients the D816V mutation was found. In contrast with former studies imatinib mesylate is also effective in these patients. Further results are to be awaited. Conclusion: imatinib mesylate is safe and seems effective in the treatment of patients with systemic mastocytosis (including patients with the D816V mutation).

Mutational Complexity Is Related To Disease Severity In Systemic Mastocytosis

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4094-4094
Author(s):  
Juliana Schwaab ◽  
Susanne Schnittger ◽  
Karl Sotlar ◽  
Christoph Walz ◽  
Alice Fabarius ◽  
...  
Keyword(s):  
Mast Cell ◽  
Mast Cells ◽  
Conflicts Of Interest ◽  
Systemic Mastocytosis ◽  
Single Gene ◽  
Missense Mutations ◽  
Molecular Feature ◽  
Additional Mutation ◽  
Molecular Aberrations ◽  
Kit D816v

Abstract Systemic mastocytosis (SM) is a rare hematologic neoplasm characterized by abnormal accumulation of mast cells in various tissues, predominantly skin, bone marrow and visceral organs. The morphologic phenotype and extent of organ infiltration/dysfunction are basis for the subclassification of SM into indolent SM (ISM), smoldering SM (SSM), SM with associated hematologic non-mast cell disease (SM-AHNMD), aggressive SM (ASM) and mast cell leukemia (MCL). A somatic point mutation in the kinase domain of the receptor tyrosine kinase (TK) KIT at position 816 (KIT D816V) is present in >95% of patients and plays a central role in the pathogenesis and diagnosis of SM. To further explore mechanisms contributing to the clinical diversity of SM, we analyzed 39 KIT D816V mutated patients with different SM subtypes [ISM, n=10; SSM, n=2; ISM-AHNMD, n=5 (CMML, n=2; MDS/MPNu, n=3); ASM, n=1; ASM-AHNMD, n=14 (CMML, n= 5, MDS/MPNu, n=4, HES/CEL, n=2; AML, n=3); MCL, n=3; MCL-AHNMD n=4 (MDS/MPNu, n=2; HES/CEL, n=1; MDS, n=1)] for the presence of additional mutations. We applied next-generation sequencing to investigate ASXL1, CBL, IDH1/2, JAK2, KRAS, MLL-PTD, NPM1, NRAS, TP53, SRSF2, SF3B1, SETBP1, U2AF1 at mutational hotspot regions, and analyzed the complete coding regions of EZH2, ETV6, RUNX1, and TET2. Additional molecular aberrations were identified in 24/27 (89%) patients with advanced SM (SM-AHNMD, 5/5; ASM/MCL, 19/23) while only 3/12 (25%) ISM/SSM patients carried one additional mutation each (U2AF1, SETBP1, CBL) (p<0.001). In TET2, 9 missense, 4 nonsense, 13 frameshift mutations and one in-frame deletion as well as one splice site mutation were found in 15/39 (39%) patients. Ten of 15 (67%) patients carried more than one TET2 mutation. In SRSF2, missense mutations were identified in 14/39 (36%) patients which were clustered at codon 95 (P95H, n=9; P95L, n=2; P95R, n=2), with one additional mutation identified at codon 18 (V18L, n=1). In RUNX1, 10 mutations (9 missense mutations, 1 frameshift) were identified in 9/39 (23%) patients. Ten CBL mutations were identified in 8 patients (8 missense mutations, 1 duplication, 1 splice mutation) and 8 ASXL1 mutations were identified in 8 patients (7 frameshift and 1 nonsense mutation). In 13 patients, two (TET2, n=8; KRAS, n=1), three (CBL, n=2) or four mutations (TET2, n=2) were found in a single gene. Less frequently affected genes were KRAS (n=4), NRAS, JAK2, U2AF1 (n=2, each), EZH2, SETBP1, and ETV6 (n=1, each). No mutations were identified in MLL, IDH1, IDH2, NPM1, SF3B1 and TP53. In advanced SM, 21/27 patients (78%) carried ³3 mutations and 11/27 patients (41%) exhibited ³5 mutations. The median number of mutations was 4. The concurrent presence of KIT-TET2-SRSF2 (10/39, 26%), KIT-SRSF2-RUNX1 (7/39, 18%), KIT-TET2-CBL (5/39, 13%), KIT-SRSF2-ASXL1 (4/39, 10%) and KIT-TET2-ASXL1 (4/39, 10%) was strongly associated with (A)SM/MCL-AHNMD in 16/16 (100%) of patients (CMML, 7/16, 44%; MDS/MPNu, 6/16, 38%; HES/CEL, 3/16, 19%). Clinical follow-up was available for 38 patients. Six of 38 (16%) patients died, all of whom had at least one additional mutation with 5 patients positive for ³3 and 2 patients for ³5 mutations. The median survival of all 26 patients with at least one additional mutation was 12 months. In contrast, none of the 12 cases with KIT D816V mutation only died. This translated into a significant inferior survival (p=0.019) for patients with additional mutations (figure 1). We therefore conclude that, in addition to the multilineage involvement by KIT D816V, the presence of additional molecular aberrations is a new molecular feature that may contribute essentially to the abnormal phenotype and behaviour of neoplastic mast cells in advanced SM and thus to the clinical diversity and prognosis of advanced mast cell disorders. Disclosures: No relevant conflicts of interest to declare.

Ectopic Expression of Lin28 Biases Myeloid Differentiation to Promote an Immature Mast Cell State and Is Implicated in Aggressive Mastocytosis

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5571-5571
Author(s):  
Leo D. Wang ◽  
Phi Nguyen ◽  
Robert G Rowe ◽  
Tata Nageswara Rao ◽  
George Q. Daley ◽  
...  
Keyword(s):  
Mast Cell ◽  
Mast Cells ◽  
Conflicts Of Interest ◽  
Systemic Mastocytosis ◽  
Expression Patterns ◽  
Ectopic Expression ◽  
In Vitro Assays ◽  
Human Mast Cell ◽  
Adult Mice

Abstract Dysregulated mast cell development leads to systemic mastocytosis, a clinically variable but often devastating family of hematologic disorders. Lin28 is a heterochronic gene and pluripotency factor implicated in many types of malignancy, and prior studies suggest that Lin28 expression can restore a fetal hematopoietic program in adult mice. However, the role of Lin28 in hematologic malignancy remains controversial. In our study, we induced expression of Lin28 in adult mice using a doxycycline-responsive transgenic system. Lin28 induction caused marked mast cell accumulation in target organs such as the skin and peritoneal cavity. In vitro assays revealed a skewing of myeloid commitment in Lin28-expressing hematopoietic progenitors, with increased levels of Lin28 in common myeloid progenitors and basophil-mast cell progenitors altering gene expression patterns to favor cell fate choices that enhance mast cell specification. In addition, Lin28-induced mast cells appeared phenotypically and functionally immature, and in vitro assays suggested a slowing of mast cell terminal differentiation in the context of Lin28 upregulation. Finally, interrogation of human mast cell leukemia samples revealed upregulation of LIN28 in abnormal mast cells from patients with aggressive systemic mastocytosis (ASM). This work identifies Lin28 as a novel regulator of innate immune function and a new protein of interest in mast cell disease. Disclosures No relevant conflicts of interest to declare.

Vascular Endothelial Growth Factors and Angiopoietins As New Players in Mastocytosis

2021 ◽  
Author(s):  
Simone Marcella ◽  
Angelica Petraroli ◽  
Mariantonia Braile ◽  
Roberta Parente ◽  
Anne Lise Ferrara ◽  
...  
Keyword(s):  
Growth Factors ◽  
Mast Cells ◽  
Systemic Mastocytosis ◽  
Vascular Endothelial Growth Factors ◽  
Vascular Endothelial ◽  
Serum Concentrations ◽  
Kit Receptor ◽  
Clinical Variants ◽  
Endothelial Growth Factors ◽  
Kit D816v

Abstract Mastocytosis is a disorder characterized by the abnormal proliferation and/or accumulation of mast cells in different organs. More than 90% of patients with systemic mastocytosis have a gain-of-function mutation in codon 816 of the KIT receptor on mast cells (MCs). The symptoms of mastocytosis patients are related to the MC-derived mediators that exert local and distant effects. MCs produce angiogenic and lymphangiogenic factors, including vascular endothelial growth factors (VEGFs) and angiopoietins (ANGPTs). Serum concentrations of VEGF-A, VEGF-C, VEGF-D, ANGPT1 and ANGPT2 were determined in 64 mastocytosis patients and 64 healthy controls. Intracellular concentrations and spontaneous release of these mediators were evaluated in the mast cell lines ROSAKIT WT and ROSA KIT D816V and in human lung mast cells (HLMCs). VEGF-A, ANGPT1, ANGPT2 and VEGF-C concentrations were higher in mastocytosis patients compared to controls. The VEGF-A, ANGPT2 and VEGF-C concentrations were correlated with the symptom severity. ANGPT1 concentrations were increased in all patients compared to controls. ANGPT2 levels were correlated with severity of clinical variants and with tryptase levels. VEGF-A, ANGPT1 and VEGF-C did not differ between indolent and advanced mastocytosis. ROSAKIT WT, ROSAKIT D816V and HLMCs contained and spontaneously released VEGFs and ANGPTs. Serum concentrations of VEGFs and ANGPTs are altered in mastocytosis patients.

scholarly journals Epigenetic Targeting of Autophagy via HDAC Inhibition in Tumor Cells: Role of p53

2018 ◽  
Vol 19 (12) ◽  
pp. 3952 ◽  
Author(s):  
Maria Mrakovcic ◽  
Lauren Bohner ◽  
Marcel Hanisch ◽  
Leopold F. Fröhlich
Keyword(s):  
Cell Death ◽  
Tumor Cells ◽  
Histone Deacetylase ◽  
Stress Responses ◽  
Histone Deacetylase Inhibitors ◽  
Tumor Therapy ◽  
Regulatory System ◽  
Anticancer Activities ◽  
Mutational Status

Tumor development and progression is the consequence of genetic as well as epigenetic alterations of the cell. As part of the epigenetic regulatory system, histone acetyltransferases (HATs) and deacetylases (HDACs) drive the modification of histone as well as non-histone proteins. Derailed acetylation-mediated gene expression in cancer due to a delicate imbalance in HDAC expression can be reversed by histone deacetylase inhibitors (HDACi). Histone deacetylase inhibitors have far-reaching anticancer activities that include the induction of cell cycle arrest, the inhibition of angiogenesis, immunomodulatory responses, the inhibition of stress responses, increased generation of oxidative stress, activation of apoptosis, autophagy eliciting cell death, and even the regulation of non-coding RNA expression in malignant tumor cells. However, it remains an ongoing issue how tumor cells determine to respond to HDACi treatment by preferentially undergoing apoptosis or autophagy. In this review, we summarize HDACi-mediated mechanisms of action, particularly with respect to the induction of cell death. There is a keen interest in assessing suitable molecular factors allowing a prognosis of HDACi-mediated treatment. Addressing the results of our recent study, we highlight the role of p53 as a molecular switch driving HDACi-mediated cellular responses towards one of both types of cell death. These findings underline the importance to determine the mutational status of p53 for an effective outcome in HDACi-mediated tumor therapy.

scholarly journals The rat c-kit ligand, stem cell factor, induces c-kit receptor-dependent mouse mast cell activation in vivo. Evidence that signaling through the c-kit receptor can induce expression of cellular function.

1992 ◽  
Vol 175 (1) ◽  
pp. 245-255 ◽  
Author(s):  
B K Wershil ◽  
M Tsai ◽  
E N Geissler ◽  
K M Zsebo ◽  
S J Galli
Keyword(s):  
Mast Cell ◽  
Stem Cell ◽  
Mast Cells ◽  
Stem Cell Factor ◽  
Cell Activation ◽  
Mast Cell Activation ◽  
Tyrosine Kinase Receptor ◽  
Kit Ligand ◽  
Kit Receptor

Interactions between products of the mouse W locus, which encodes the c-kit tyrosine kinase receptor, and the Sl locus, which encodes a ligand for c-kit receptor, which we have designated stem cell factor (SCF), have a critical role in the development of mast cells. Mice homozygous for mutations at either locus exhibit several phenotypic abnormalities including a virtual absence of mast cells. Moreover, the c-kit ligand SCF can induce the proliferation and maturation of normal mast cells in vitro or in vivo, and also can result in repair of the mast cell deficiency of Sl/Sld mice in vivo. We now report that administration of SCF intradermally in vivo results in dermal mast cell activation and a mast cell-dependent acute inflammatory response. This effect is c-kit receptor dependent, in that it is not observed when SCF is administered to mice containing dermal mast cells expressing functionally inactive c-kit receptors, is observed with both glycosylated and nonglycosylated forms of SCF, and occurs at doses of SCF at least 10-fold lower on a molar basis than the minimally effective dose of the classical dermal mast cell-activating agent substance P. These findings represent the first demonstration in vivo that a c-kit ligand can result in the functional activation of any cellular lineage expressing the c-kit receptor, and suggest that interactions between the c-kit receptor and its ligand may influence mast cell biology through complex effects on proliferation, maturation, and function.

scholarly journals Systemic mastocytosis with subcutaneous hemorrhage and edema in a Greyhound dog: case report and review of diagnostic criteria

2020 ◽  
Vol 33 (1) ◽  
pp. 95-100
Author(s):  
Alexander Aceino ◽  
Unity Jeffery ◽  
Julie Piccione ◽  
Carolyn L. Hodo
Keyword(s):  
Mast Cell ◽  
Mast Cells ◽  
Diagnostic Criteria ◽  
Complete Blood Count ◽  
Systemic Mastocytosis ◽  
Mast Cell Tumors ◽  
Multiple Organs ◽  
Subcutaneous Edema ◽  
Diagnostic Framework ◽  
Criteria For Diagnosis

Systemic mastocytosis, characterized by infiltration of multiple organs by neoplastic mast cells, is a well-described entity in human medicine with specific criteria for diagnosis, but is ill defined in veterinary literature. Hemostatic disorders are reported in humans affected by systemic mastocytosis but have not been well described in veterinary literature. A 5-y-old, spayed female Greyhound dog had a 1-mo history of progressive ventral cutaneous edema, hemorrhage, and pain. Cytology of an antemortem aspirate from the subcutis of the ventral abdomen was suggestive of mast cell neoplasia, but no discrete mass was present. The dog was euthanized and submitted for autopsy; marked subcutaneous edema and hemorrhage were confirmed. The ventral abdominal panniculus and dermis superficial to the panniculus carnosus were infiltrated by a dense sheet of neoplastic mast cells. The neoplastic cells contained toluidine blue–positive granules and formed aggregates within the bone marrow and several visceral organs, including the liver, spleen, heart, and kidney. Diffuse edema and hemorrhage is an unusual presentation of mast cell tumors in dogs. Antemortem tests, including complete blood count, coagulation profile, and viscoelastic coagulation testing, were suggestive of a primary hemostatic defect. We discuss here the diagnostic criteria used in humans, how these can be applied to veterinary patients, and the limitations of the current diagnostic framework.

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