DNA methylation profile in patients with indolent systemic mastocytosis

Abstract Background Mastocytosis is a clinically heterogeneous, usually acquired disease of the mast cells with a survival time that depends on the onset of the disease and ranges from skin‐limited to systemic disease, including indolent and more aggressive variants. The crucial element in pathogene...

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Autores principales:	Aleksandra Górska, Ewa Jabłońska, Edyta Reszka, Marek Niedoszytko, Magdalena Lange, Marta Gruchała‐Niedoszytko, Justyna Jarczak, Dominik Strapagiel, Magdalena Górska‐Ponikowska, Paulina Bastian, Iwona Pelikant‐Małecka, Leszek Kalinowski, Bogusław Nedoszytko
Formato:	article
Lenguaje:	EN
Publicado:	Wiley 2021
Materias:	DNA methylation epigenetics KIT mutation mastocytosis Immunologic diseases. Allergy RC581-607
Acceso en línea:	https://doaj.org/article/5dfa142e2b0b4c2caf9ca17b00a8a9ea
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spelling	oai:doaj.org-article:5dfa142e2b0b4c2caf9ca17b00a8a9ea2021-11-29T08:10:37ZDNA methylation profile in patients with indolent systemic mastocytosis2045-702210.1002/clt2.12074https://doaj.org/article/5dfa142e2b0b4c2caf9ca17b00a8a9ea2021-11-01T00:00:00Zhttps://doi.org/10.1002/clt2.12074https://doaj.org/toc/2045-7022Abstract Background Mastocytosis is a clinically heterogeneous, usually acquired disease of the mast cells with a survival time that depends on the onset of the disease and ranges from skin‐limited to systemic disease, including indolent and more aggressive variants. The crucial element in pathogenesis is the presence of oncogenic KIT somatic mutation D816V. Further epigenetic alterations are responsible for regulating the expression of genes. It is essential to identify indicators of disease progression, and the specific clinical picture to establish an appropriate therapeutic strategy. Objective The aim of this study was to analyze the relation of mastocytosis symptoms and epigenetic changes, and to identify epigenetic predictors of the disease. Methods Global DNA methylation profile analysis was performed in peripheral blood collected from 73 patients with indolent systemic mastocytosis (ISM) and 43 healthy adult volunteers. Levels of 5‐methylcytosine (5‐mC) and 5‐hydroxymethylcytosine (5‐hmC) were determined using an ELISA‐based method, while the methylation of the Alu and LINE‐1 repeats were assayed with the quantitative methylation‐specific PCR technique. A questionnaire interview was conducted among the study participants to collect data on possible epigenetic modifiers. Additionally, the methylation profile was compared between three human mast cell lines: ROSA KIT D816V, ROSA KIT WT, and HMC‐1.1 KIT V560G, in order to assess the association between KIT mutations and methylation profile. Results A significantly lower level of DNA hydroxymethylation (5‐hmC) in the blood was found in patients with ISM as compared to the controls (0.022% vs. 0.042%, p = 0.0001). Differences in the markers of global DNA methylation (5‐mC, Alu, LINE‐1) were not statistically significant, although they did indicate generally higher DNA methylation in patients with mastocytosis. The 5‐hmC level was significantly associated with allergy (p = 0.011) in patients with ISM, showing a higher level of 5‐hmC in patients with allergy as compared to patients without allergy. The in vitro study revealed significant differences between the studied cell lines at the level of 5‐mC, Alu, and LINE‐1. Conclusions This study confirms that epigenetic changes are involved in mastocytosis, and suggests that allergy may be an important epigenetic modifier of the disease. A possible association between KIT mutations and methylation status observed in human mast cell lines requires further investigation in human studies. Clinical Implications Epigenetic alterations are involved in mastocytosis pathology. The possible role of allergy as an important epigenetic modifier suggests the more impaired function of mast cells in ISM patients without allergy. Capsule summary Decreased DNA demethylation in the blood DNA of patients with ISM confirms that epigenetic alterations are involved in mastocytosis pathology. We observed a possible role of allergy as an important epigenetic modifier. There is a possible association between KIT mutations and the methylation status observed in human mast cell lines.Aleksandra GórskaEwa JabłońskaEdyta ReszkaMarek NiedoszytkoMagdalena LangeMarta Gruchała‐NiedoszytkoJustyna JarczakDominik StrapagielMagdalena Górska‐PonikowskaPaulina BastianIwona Pelikant‐MałeckaLeszek KalinowskiBogusław NedoszytkoWileyarticleDNA methylationepigeneticsKIT mutationmastocytosisImmunologic diseases. AllergyRC581-607ENClinical and Translational Allergy, Vol 11, Iss 9, Pp n/a-n/a (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	DNA methylation epigenetics KIT mutation mastocytosis Immunologic diseases. Allergy RC581-607
spellingShingle	DNA methylation epigenetics KIT mutation mastocytosis Immunologic diseases. Allergy RC581-607 Aleksandra Górska Ewa Jabłońska Edyta Reszka Marek Niedoszytko Magdalena Lange Marta Gruchała‐Niedoszytko Justyna Jarczak Dominik Strapagiel Magdalena Górska‐Ponikowska Paulina Bastian Iwona Pelikant‐Małecka Leszek Kalinowski Bogusław Nedoszytko DNA methylation profile in patients with indolent systemic mastocytosis
description	Abstract Background Mastocytosis is a clinically heterogeneous, usually acquired disease of the mast cells with a survival time that depends on the onset of the disease and ranges from skin‐limited to systemic disease, including indolent and more aggressive variants. The crucial element in pathogenesis is the presence of oncogenic KIT somatic mutation D816V. Further epigenetic alterations are responsible for regulating the expression of genes. It is essential to identify indicators of disease progression, and the specific clinical picture to establish an appropriate therapeutic strategy. Objective The aim of this study was to analyze the relation of mastocytosis symptoms and epigenetic changes, and to identify epigenetic predictors of the disease. Methods Global DNA methylation profile analysis was performed in peripheral blood collected from 73 patients with indolent systemic mastocytosis (ISM) and 43 healthy adult volunteers. Levels of 5‐methylcytosine (5‐mC) and 5‐hydroxymethylcytosine (5‐hmC) were determined using an ELISA‐based method, while the methylation of the Alu and LINE‐1 repeats were assayed with the quantitative methylation‐specific PCR technique. A questionnaire interview was conducted among the study participants to collect data on possible epigenetic modifiers. Additionally, the methylation profile was compared between three human mast cell lines: ROSA KIT D816V, ROSA KIT WT, and HMC‐1.1 KIT V560G, in order to assess the association between KIT mutations and methylation profile. Results A significantly lower level of DNA hydroxymethylation (5‐hmC) in the blood was found in patients with ISM as compared to the controls (0.022% vs. 0.042%, p = 0.0001). Differences in the markers of global DNA methylation (5‐mC, Alu, LINE‐1) were not statistically significant, although they did indicate generally higher DNA methylation in patients with mastocytosis. The 5‐hmC level was significantly associated with allergy (p = 0.011) in patients with ISM, showing a higher level of 5‐hmC in patients with allergy as compared to patients without allergy. The in vitro study revealed significant differences between the studied cell lines at the level of 5‐mC, Alu, and LINE‐1. Conclusions This study confirms that epigenetic changes are involved in mastocytosis, and suggests that allergy may be an important epigenetic modifier of the disease. A possible association between KIT mutations and methylation status observed in human mast cell lines requires further investigation in human studies. Clinical Implications Epigenetic alterations are involved in mastocytosis pathology. The possible role of allergy as an important epigenetic modifier suggests the more impaired function of mast cells in ISM patients without allergy. Capsule summary Decreased DNA demethylation in the blood DNA of patients with ISM confirms that epigenetic alterations are involved in mastocytosis pathology. We observed a possible role of allergy as an important epigenetic modifier. There is a possible association between KIT mutations and the methylation status observed in human mast cell lines.
format	article
author	Aleksandra Górska Ewa Jabłońska Edyta Reszka Marek Niedoszytko Magdalena Lange Marta Gruchała‐Niedoszytko Justyna Jarczak Dominik Strapagiel Magdalena Górska‐Ponikowska Paulina Bastian Iwona Pelikant‐Małecka Leszek Kalinowski Bogusław Nedoszytko
author_facet	Aleksandra Górska Ewa Jabłońska Edyta Reszka Marek Niedoszytko Magdalena Lange Marta Gruchała‐Niedoszytko Justyna Jarczak Dominik Strapagiel Magdalena Górska‐Ponikowska Paulina Bastian Iwona Pelikant‐Małecka Leszek Kalinowski Bogusław Nedoszytko
author_sort	Aleksandra Górska
title	DNA methylation profile in patients with indolent systemic mastocytosis
title_short	DNA methylation profile in patients with indolent systemic mastocytosis
title_full	DNA methylation profile in patients with indolent systemic mastocytosis
title_fullStr	DNA methylation profile in patients with indolent systemic mastocytosis
title_full_unstemmed	DNA methylation profile in patients with indolent systemic mastocytosis
title_sort	dna methylation profile in patients with indolent systemic mastocytosis
publisher	Wiley
publishDate	2021
url	https://doaj.org/article/5dfa142e2b0b4c2caf9ca17b00a8a9ea
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DNA methylation profile in patients with indolent systemic mastocytosis

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