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Transgenerational transmission of systemic mast cell activation disease—genetic and epigenetic features

  • Gerhard J. Molderings
    Correspondence
    Reprint requests: Gerhard J. Molderings, MD, Institute of Human Genetics, University Hospital of Bonn, Sigmund-Freud-Strasse 25, D-53127 Bonn, Germany. Tel.: +49 (0) 228 287 51060; fax: +49 (0) 228 287 51011
    Affiliations
    Institute of Human Genetics, University Hospital of Bonn, Sigmund-Freud-Strasse 25, D-53127 Bonn, Germany
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Published:January 11, 2016DOI:https://doi.org/10.1016/j.trsl.2016.01.001
      Systemic mast cell activation disease (MCAD) comprises disorders characterized by an enhanced release of mast cell mediators accompanied by a varying accumulation of dysfunctional mast cells. Within the last years, evidence has been presented that MCAD is a multifactorial polygenic determined disease with the KITD816V mutation and its induced functional consequences considered as special case. The respective genes encode proteins for various signaling pathways, epigenetic regulators, the RNA splicing machinery, and transcription factors. Transgenerational transmission of MCAD appears to be quite common. The basics of the molecular mechanisms underlying predisposition of the disease, that is, somatic and germline mutations and the contribution of epigenetic processes have become identifiable. The aim of the present review is to present and discuss available genetic, epigenetic and epidemiological findings, and to present a model of MCAD pathogenesis.

      Abbreviations:

      MCAD (mast cell activation disease), MCAS (primary mast cell activation syndrome), SM (systemic mastocytosis), miRNA (microRNA), pts (patients), CFS (chronic fatigue syndrome), MITF (microphthalmia-associated transcription factor), mC (5'-methylcytosine), 5hmC (5-hydroxymethylcytosine), NGS (next-generation sequencing), HMC1 (human mast cell leukemia cell line)
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      References

        • Molderings G.J.
        • Brettner S.
        • Homann J.
        • Afrin L.B.
        Mast cell activation disease: a concise practical guide for diagnostic workup and therapeutic options.
        J Hematol Oncol. 2011; 4: 10
        • Valent P.
        • Akin C.
        • Arock M.
        • et al.
        Definitions, criteria and global classification of mast cell disorders with special reference to mast cell activation syndromes: a consensus proposal.
        Int Arch Allergy Immunol. 2012; 157: 215-225
        • Afrin L.B.
        • Molderings G.J.
        A concise, practical guide to diagnostic assessment for mast cell activation disease.
        World J Hematol. 2014; 3: 1-17
        • Kohno M.
        • Yamasaki S.
        • Tybolewicz V.L.
        • Saito T.
        Rapid and large amount of autocrine IL-3 production is responsible for mast cell survival by IgE in the absence of antigen.
        Blood. 2005; 105: 2059-2065
        • Aichberger K.J.
        • Gleixner K.V.
        • Mirkina I.
        • et al.
        Identification of proapoptotic Bim as a tumor suppressor in neoplastic mast cells: role of KIT D816V and effects of various targeted drugs.
        Blood. 2009; 114: 5342-5351
        • Karlberg M.
        • Ekoff M.
        • Labi V.
        • Strasser A.
        • Huang D.
        • Nilsson G.
        Pro-apoptotic Bax is the major and Bak an auxiliary effector in cytokine deprivation-induced mast cell apoptosis.
        Cell Death Dis. 2010; 1: e43
        • Lanternier F.
        • Cohen-Akenine A.
        • Palmerini F.
        • et al.
        Phenotypic and genotypic characteristics of mastocytosis according to the age of onset.
        PLoS One. 2008; 3: e1906
        • Escribano L.
        • Alvarez-Twose I.
        • Sánchez-Muñoz L.
        • et al.
        Prognosis in adult indolent systemic mastocytosis: a long-term study of the Spanish network on mastocytosis in a series of 145 patients.
        J Allergy Clin Immunol. 2009; 124: 514-521
        • Alvarez-Twose I.
        • González de Olano D.
        • Sánchez-Muñoz L.
        • et al.
        Clinical, biological, and molecular characteristics of clonal mast cell disorders presenting with systemic mast cell activation symptoms.
        J Allergy Clin Immunol. 2010; 125: 1269-1278
      1. Merante S, Magliacane D, Neri I et al. The New Italian Mastocytosis Registry. 53rd ASH Annual Meeting and Exposition 2010, Poster 3805, http://ash.confex.com/ash/2010/webprogram/Paper28567.html

        • Haenisch B.
        • Nöthen M.M.
        • Molderings G.J.
        Systemic mast cell activation disease: the role of molecular genetic alterations in pathogenesis, heritability and diagnostics.
        Immunology. 2012; 137: 197-205
        • van Doormaal J.J.
        • Arends S.
        • Brunekreeft K.L.
        • et al.
        Prevalence of indolent systemic mastocytosis in a Dutch region.
        J Allergy Clin Immunol. 2013; 131: 1429-1431
        • Cohen S.S.
        • Skovbo S.
        • Vestergaard H.
        • et al.
        Epidemiology of systemic mastocytosis in Denmark.
        Br J Haematol. 2014; 166: 521-528
        • Lim K.H.
        • Tefferi A.
        • Lasho T.L.
        • et al.
        Systemic mastocytosis in 342 consecutive adults: survival studies and prognostic factors.
        Blood. 2009; 113: 5727-5736
        • Molderings G.J.
        • Haenisch B.
        • Bogdanow M.
        • Fimmers R.
        • Nöthen M.M.
        Familial occurrence of systemic mast cell activation disease.
        PLoS One. 2013; 8: e76241
        • Lucas H.J.
        • Brauch C.M.
        • Settas L.
        • Theoharides T.C.
        Fibromyalgia—new concepts of pathogenesis and treatment.
        Int J Immunopathol Pharmacol. 2006; 19: 5-10
        • Blanco I.
        • Béritze N.
        • Argüelles M.
        • et al.
        Abnormal overexpression of mastocytes in skin biopsies of fibromyalgia patients.
        Clin Rheumatol. 2010; 29: 1403-1412
        • Maeshima E.
        • Furukawa K.
        A case of fibromyalgia syndrome with anaphylaxis induced by intradermal injection of purified protein derivative.
        Mod Rheumatol. 2013; 23: 593-596
        • Santos J.
        • Guilarte M.
        • Alonso C.
        • Malagelada J.R.
        Pathogenesis of irritable bowel syndrome: the mast cell connection.
        Scand J Gastroenterol. 2005; 40: 129-140
        • Klooker T.K.
        • Braak B.
        • Koopman K.E.
        • et al.
        The mast cell stabiliser ketotifen decreases visceral hypersensitivity and improves intestinal symptoms in patients with irritable bowel syndrome.
        Gut. 2010; 59: 1213-1221
        • Frieling T.
        • Meis K.
        • Kolck U.W.
        • et al.
        Evidence for mast cell activation in patients with therapy-resistant irritable bowel syndrome.
        Z Gastroenterol. 2011; 49: 191-194
        • Akin C.
        • Scott L.M.
        • Kocabas C.N.
        • et al.
        Demonstration of an aberrant mast cell population with clonal markers in a subset of patients with “idiopathic” anaphylaxis.
        Blood. 2007; 110: 2331-2333
        • Gülen T.
        • Hägglund H.
        • Sander B.
        • Dahlén B.
        • Nilsson G.
        The presence of mast cell clonality in patients with unexplained anaphylaxis.
        Clin Exp Allergy. 2014; 44: 1179-1187
        • Matito A.
        • Alvarez-Twose I.
        • Morgado J.M.
        • Sánchez-Muñoz L.
        • Orfao A.
        • Escribano L.
        Anaphylaxis as a clinical manifestation of clonal mast cell disorders.
        Curr Allergy Asthma Rep. 2014; 14: 450
        • Decker W.W.
        • Campbell R.L.
        • Manivannan V.
        • et al.
        The etiology and incidence of anaphylaxis in Rochester, Minnesota: a report from the Rochester Epidemiology Project.
        J Allergy Clin Immunol. 2008; 122: 1161-1165
        • Simons F.E.
        • Sampson H.A.
        Anaphylaxis epidemic: fact or fiction?.
        J Allergy Clin Immunol. 2008; 122: 1166-1168
        • Canavan C.
        • West J.
        • Card T.
        The epidemiology of irritable bowel syndrome.
        Clin Epidemiol. 2014; 6: 71-80
        • Zhang L.Y.
        • Smith M.L.
        • Schultheis B.
        • et al.
        A novel K5091 mutation of KIT identified in familial mastocytosis—in vitro and in vivo responsiveness to imatinib therapy.
        Leuk Res. 2006; 30: 373-378
        • Hartmann K.
        • Wardelmann E.
        • Ma Y.
        • et al.
        Novel germline mutation of KIT associated with familial gastrointestinal stromal tumors and mastocytosis.
        Gastroenterology. 2005; 129: 1042-1046
        • Broesby-Olsen S.
        • Kristensen T.K.
        • Møller M.B.
        • et al.
        Adult-onset systemic mastocytosis in monozygotic twins with KIT D816V and JAK2 V617F mutations.
        J Allergy Clin Immunol. 2012; 130: 806-808
        • Zanotti R.
        • Simioni L.
        • Garcia-Montero A.C.
        • et al.
        Somatic D816V KIT mutation in a case of adult-onset familial mastocytosis.
        J Allergy Clin Immunol. 2013; 131: 605-607
        • Sabato V.
        • Van De Vijver E.
        • Hagendorens M.
        • et al.
        Familial hypertryptasemia with associated mast cell activation syndrome.
        J Allergy Clin Immunol. 2014; 134: 1448-1450
        • Lyons J.J.
        • Sun G.
        • Stone K.D.
        • et al.
        Mendelian inheritance of elevated serum tryptase associated with atopy and connective tissue abnormalities.
        J Allergy Clin Immunol. 2014; 133: 1471-1474
        • Burks K.D.
        • Wenzel S.E.
        • Jones S.M.
        Familial cases of mast cell diseases [abstract].
        J Investig Med. 2005; 53: S300
        • Molderings G.J.
        • Meis K.
        • Kolck U.W.
        • Homann J.
        • Frieling T.
        Comparative analysis of mutation of tyrosine kinase kit in mast cells from patients with systemic mast cell activation syndrome and healthy subjects.
        Immunogenetics. 2010; 62: 721-727
        • Longley Jr., B.J.
        • Metcalfe D.D.
        • Tharp M.
        • et al.
        Activating and dominant inactivating c-kit catalytic domain mutations in distinct clinical forms of human mastocytosis.
        Proc Natl Acad Sci. 1999; 96: 1609-1614
        • Valent P.
        • Akin C.
        • Escribano L.
        • et al.
        Standards and standardization in mastocytosis: consensus statements on diagnostics, treatment recommendations and response criteria.
        Eur J Clin Invest. 2007; 37: 435-453
        • Madhappan B.
        • Kempuraj D.
        • Christodoulou S.
        • et al.
        High levels of intrauterine corticotropin-releasing hormone, urocortin, tryptase, and interleukin-8 in spontaneous abortions.
        Endocrinology. 2003; 144: 2285-2290
        • Jensen F.
        • Woudwyk M.
        • Teles A.
        • et al.
        Estradiol and progesterone regulate the migration of mast cells from the periphery to the uterus and induce their maturation and degranulation.
        PLoS One. 2010; 5: e14409
        • Valap S.
        • Millns P.
        • Bulchandani S.
        Management of a parturient with mast cell activation syndrome.
        Int J Obstet Anesth. 2013; 22: 83-84
        • Woidacki K.
        • Jensen F.
        • Zenclussen A.C.
        Mast cells as novel mediators of reproductive processes.
        Front Immunol. 2013; 4: 29
        • Madendag I.C.
        • Madendag Y.
        • Tarhan I.
        • Altinkaya S.O.
        • Danisman N.
        Mastocytosis in pregnancy.
        Taiwan J Obstet Gynecol. 2010; 49: 192-196
        • Matito A.
        • Alvarez-Twose I.
        • Morgado J.M.
        • Sánchez-Muñoz L.
        • Orfao A.
        • Escribano L.
        Clinical impact of pregnancy in mastocytosis: a study of the Spanish Network on Mastocytosis (REMA) in 45 cases.
        Int Arch Allergy Immunol. 2011; 156: 104-111
        • Watson K.D.
        • Arendt K.W.
        • Watson W.J.
        • Volcheck G.W.
        Systemic mastocytosis complicating pregnancy.
        Obstet Gynecol. 2012; 19: 486-489
        • Seidel H.
        • Molderings G.J.
        • Oldenburg J.
        • et al.
        Bleeding diathesis in patients with mast cell activation disease.
        Thromb Haemost. 2011; 106: 987-989
        • Chan L.
        • Tharp M.D.
        The detection of novel KIT mutations in mastocytosis.
        J Invest Dermatol. 2013; 133: S66
        • Lasho T.
        • Finke C.
        • Zblewski D.
        • et al.
        Concurrent activating KIT mutations in systemic mastocytosis.
        Br J Haematol. 2016; 173: 153-156
        • Bodemer C.
        • Hermine O.
        • Palmérini F.
        • et al.
        Pediatric mastocytosis is a clonal disease associated with D816V and other activating c-KIT mutations.
        J Invest Dermatol. 2010; 130: 804-815
        • Orfao A.
        • Garcia-Montero A.C.
        • Sanchez L.
        • Escribano L.
        • REMA
        Recent advances in the understanding of mastocytosis: the role of KIT mutations.
        Br J Haematol. 2007; 138: 12-30
        • Caruana G.
        • Cambareri A.C.
        • Ashman L.K.
        Isoforms of c-KIT differ in activation of signalling pathways and transformation of NIH3T3 fibroblasts.
        Oncogene. 1999; 18: 5573-5581
        • Steensma D.P.
        • Dewald G.W.
        • Lasho T.L.
        • et al.
        The JAK2 V617F activating tyrosine kinase mutation is an infrequent event in both “atypical” myeloproliferative disorders and myelodysplastic syndromes.
        Blood. 2005; 106: 1207-1209
        • Foster R.
        • Byrnes E.
        • Meldrum C.
        • et al.
        Association of paediatric mastocytosis with a polymorphism resulting in an amino acid substitution (M541L) in the transmembrane domain of c-KIT.
        Br J Dermatol. 2008; 159: 1160-1169
        • Buttner C.
        • Henz B.M.
        • Welker P.
        • Sepp N.T.
        • Grabbe J.
        Identification of activating c-kit mutations in adult-, but not in childhood-onset indolent mastocytosis: a possible explanation for divergent clinical behavior.
        J Invest Dermatol. 1998; 111: 1227-1231
        • Sotlar K.
        • Horny H.P.
        • Simonitsch I.
        • et al.
        CD25 indicates the neoplastic phenotype of mast cells: a novel immunohistochemical marker for the diagnosis of systemic mastocytosis (SM) in routinely processed bone marrow biopsy specimens.
        Am J Surg Pathol. 2004; 28: 1319-1325
        • Pignon J.M.
        • Giraudier S.
        • Duquesnoy P.
        • et al.
        A new c-kit mutation in a case of aggressive mast cell disease.
        Br J Haematol. 1997; 96: 374-376
        • Garcia-Montero A.C.
        • Jara-Acevedo M.
        • Teodosio C.
        • et al.
        KIT mutation in mast cells and other bone marrow hematopoietic cell lineages in systemic mast cell disorders: a prospective study of the Spanish Network on Mastocytosis (REMA) in a series of 113 patients.
        Blood. 2006; 08: 2366-2372
        • Kristensen T.
        • Broesby-Olsen S.
        • Vestergaard H.
        • et al.
        Circulating KIT D816V mutation positive non-mast cells in peripheral blood are characteristic of indolent systemic mastocytosis.
        Eur J Haematol. 2012; 89: 42-46
        • Teodosio C.
        • García-Montero A.C.
        • Jara-Acevedo M.
        • et al.
        An immature immunophenotype of bone marrow mast cells predicts for multilineage D816V KIT mutation in systemic mastocytosis.
        Leukemia. 2012; 26: 951-958
        • Speight R.A.
        • Nicolle A.
        • Needham S.J.
        • Verrill M.W.
        • Bryon J.
        • Panter S.
        Rare germline mutation of KIT with imatinib-resistant multiple GI stromal tumors and mastocytosis.
        J Clin Oncol. 2013; 31: e245-e247
        • de Melo Campos P.
        • Machado-Neto J.A.
        • Scopim-Ribeiro R.
        • et al.
        Familial mastocytosis: identification of KIT K509I mutation and its in vitro sensitivity to imatinib, dasatinib and PK412.
        Blood. 2013; 122: 5267
        • Chan E.C.
        • Bai Y.
        • Kirshenbaum A.S.
        • et al.
        Mastocytosis associated with a rare germline KIT K509I mutation displays a well-differentiated mast cell phenotype.
        J Allergy Clin Immunol. 2014; 134: 178-187
        • Akin C.
        • Fumo G.
        • Yavuz A.S.
        • Lipsky P.E.
        • Neckers L.
        • Metcalfe D.D.
        A novel form of mastocytosis associated with a transmembrane c- Kit mutation and response to imatinib.
        Blood. 2004; 103: 3222-3225
        • Escribano L.
        • Nunez-Lopez R.
        • Jara M.
        • et al.
        Indolent systemic mastocytosis with germline D816V somatic c-kit mutation evolving to an acute myeloid leukemia.
        J Allery Clin Immunol. 2006; 117: S125
        • Molderings G.J.
        The genetic basis of mast cell activation disease—looking through a glass darkly.
        Crit Rev Oncol Hematol. 2015; 93: 75-89
        • Chatterjee A.
        • Ghosh J.
        • Kapur R.
        Mastocytosis: a mutated KIT receptor induced myeloproliferative disorder.
        Oncotarget. 2015; 6: 18250-18264
        • Soucie E.
        • Hanssens K.
        • Mercher T.
        • et al.
        In aggressive forms of mastocytosis, TET2 loss cooperates with c-KITD816V to transform mast cells.
        Blood. 2012; 120: 4846-4849
        • Traina F.
        • Visconte V.
        • Jankowska A.M.
        • et al.
        Single nucleotide polymorphism array lesions, TET2, DNMT3A, ASXL1 and CBL mutations are present in systemic mastocytosis.
        PLoS One. 2012; 7: e43090
        • Hanssens K.
        • Brenet F.
        • Agopian J.
        • et al.
        SRSF2-p95 hotspot mutation is highly associated with advanced forms of mastocytosis and mutations in epigenetic regulator genes.
        Haematologica. 2014; 99: 830-835
        • Damaj G.
        • Joris M.
        • Chandesris O.
        • et al.
        ASXL1 but not TET2 mutations adversely impact overall survival of patients suffering systemic mastocytosis with associated clonal hematologic non-mast-cell diseases.
        PLoS One. 2014; 9: e85362
        • Schwaab J.
        • Schnittger S.
        • Sotlar K.
        • et al.
        Comprehensive mutational profiling in advanced systemic mastocytosis.
        Blood. 2014; 122: 2460-2466
        • Molderings G.J.
        • Kolck U.W.
        • Scheurlen C.
        • Brüss M.
        • Homann J.
        • Von Kügelgen I.
        Multiple novel alterations in Kit tyrosine kinase in patients with gastrointestinally pronounced systemic mast cell activation disorder.
        Scand J Gastroenterol. 2007; 42: 1045-1053
        • Wöhrl S.
        • Moritz K.B.
        • Bracher A.
        • Fischer G.
        • Stingl G.
        • Loewe R.
        A c-kit mutation in exon 18 in familial mastocytosis.
        J Invest Dermatol. 2013; 133: 839-841
        • Verzijl A.
        • Heide R.
        • Oranje A.P.
        • van Schaik R.H.
        C-kit Asp-816-Val mutation analysis in patients with mastocytosis.
        Dermatology. 2007; 214: 15-20
        • Haenisch B.
        • Fröhlich H.
        • Herms S.
        • Molderings G.J.
        Evidence for contribution of epigenetic mechanisms in the pathogenesis of systemic mast cell activation disease.
        Immunogenetics. 2014; 66: 287-297
        • Leoni C.
        • Montagner S.
        • Deho' L.
        • et al.
        Reduced DNA methylation and hydroxymethylation in patients with systemic mastocytosis.
        Eur J Haematol. 2015; 95: 566-575
        • Petronis A.
        Epigenetics as a unifying principle inn the aetiology of complex traits and diseases.
        Nature. 2010; 465: 721-727
        • Fraga M.F.
        • Ballestar E.
        • Paz M.F.
        • et al.
        Epigenetic differences arise during the lifetime of monozygotic twins.
        Proc Natl Acad Sci U S A. 2005; 102: 10604-10609
        • Rassoulzadegan M.
        • Grandjean V.
        • Gounon P.
        • Vincent S.
        • Gillot I.
        • Cuzin F.
        RNA-mediated non-mendelian inheritance of an epigenetic change in the mouse.
        Nature. 2006; 441: 469-474
        • Morgan H.D.
        • Sutherland H.G.
        • Martin D.I.
        • Whitelaw E.
        Epigenetic inheritance at the agouti locus in the mouse.
        Nat Genet. 1999; 23: 314-318
        • Rakyan V.K.
        • Chong S.
        • Champ M.E.
        • et al.
        Transgenerational inheritance of epigenetic states at the murine axin(fu) allele occurs after maternal and paternal transmission.
        Proc Natl Acad Sci U S A. 2003; 100: 2538-2543
        • Blewitt M.E.
        • Vickaryous N.K.
        • Paldi A.
        • Koseki H.
        • Whitelaw E.
        Dynamic reprogramming of DNA methylation at an epigenetically sensitive allele in mice.
        PLoS Genet. 2006; 2: e49
        • Lombardi V.C.
        • Ruscetti F.W.
        • Das Gupta J.
        • et al.
        Detection of an infectious retrovirus, XMRV, in blood cells of patients with chronic fatigue syndrome.
        Science. 2009; 326: 585-589
        • Lo S.C.
        • Pripuzova N.
        • Li B.
        • et al.
        Detection of MLV-related virus gene sequences in blood of patients with chronic fatigue syndrome and healthy blood donors.
        Proc Natl Acad Sci U S A. 2010; 107: 15874-15879
        • Erlwein O.
        • Kaye S.
        • McClure M.O.
        • et al.
        Failure to detect the novel retrovirus XMRV in chronic fatigue syndrome.
        PLoS One. 2010; 5: e8519
        • Groom H.C.
        • Boucherit V.C.
        • Makinson K.
        • et al.
        Absence of xenotropic murine leukaemia virus-related virus in UK patients with chronic fatigue syndrome.
        Retrovirology. 2010; 7: e10
        • van Kuppeveld F.J.
        • de Jong A.S.
        • Lanke K.H.
        • et al.
        Prevalence of xenotropic murine leukaemia virus-related virus in patients with chronic fatigue syndrome in the Netherlands: Retrospective analysis of samples from an established cohort.
        BMJ. 2010; 340: c1018
        • Switzer W.M.
        • Jia H.
        • Hohn O.
        • et al.
        Absence of evidence of xenotropic murine leukemia virus-related virus infection in persons with chronic fatigue syndrome and healthy controls in the United States.
        Retrovirology. 2010; 7: 57
        • Motakis E.
        • Guhl S.
        • Ishizu Y.
        • et al.
        Redefinition of the human mast cell transcriptome by deep-CAGE sequencing.
        Blood. 2014; 123: e58-e67
        • Panaro M.A.
        • Calvello R.
        • Lisi S.
        • Saccia M.
        • Mitolo C.I.
        • Cianciulli A.
        Viral sequence integration into introns of chemokine receptor genes.
        Immunopharmacol Immunotoxicol. 2009; 31: 589-594
        • Panaro M.A.
        • Calvello R.
        • Lisi S.
        • Saccia M.
        • Cianciulli A.
        • Cavallo P.
        Chemokine receptor-related viral protein products.
        Immunopharmacol Immunotoxicol. 2010; 32: 17-27
        • Panaro M.A.
        • Calvello R.
        • Mitolo C.I.
        • Sisto M.
        • Saccia M.
        • Cianciulli A.
        An analysis of the human and mouse CXCR5 gene introns.
        Immunopharmacol Immunotoxicol. 2011; 33: 342-346
        • Buzdin A.
        • Khodosevich K.
        • Memedov I.
        • et al.
        A technique for genome-wide identification of differences in the interspersed repeats integrations between closely related genomes and its application to detection of human-specific integrations of HERV-K LTRs.
        Genomics. 2002; 79: 413-422
        • Wu X.
        • Burgess S.M.
        Integration target site selection for retroviruses and transposable elements.
        Cell Mol Life Sci. 2004; 61: 2588-2596
        • Laufs S.
        • Nagy K.Z.
        • Giordano F.A.
        • Hotz-Wagenblatt A.
        • Zeller W.J.
        • Fruehauf S.
        Insertion of retroviral vectors in NOD/SCID repopulating human peripheral blood progenitor cells occurs preferentially in the vicinity of transcription start regions and in introns.
        Mol Ther. 2004; 10: 874-881
        • Nienhuis A.W.
        • Dunbar C.E.
        • Sorrentino B.P.
        Genotoxicity of retroviral integration in hematopoietic cells.
        Mol Ther. 2006; 13: 1031-1049
        • Hirsch H.H.
        • Nair A.P.
        • Moroni C.
        Suppressible and nonsuppressible autocrine mast cell tumors are distinguished by insertion of an endogenous retroviral element (IAP) into the interleukin 3 gene.
        J Exp Med. 1993; 178: 403-411
        • Moses A.V.
        • Jarvis M.A.
        • Raggo C.
        • et al.
        A functional genomics approach to Kaposi's sarcoma.
        Ann N Y Acad Sci. 2002; 975: 180-191
        • Jongen-Lavrencic M.
        • Sun S.M.
        • Dijkstra M.K.
        • Valk P.J.
        • Lowenberg B.
        MicroRNA expression profiling in relation to the genetic heterogeneity of acute myeloid leukemia.
        Blood. 2008; 111: 5078-5085
        • Khalil A.M.
        • Guttman M.
        • Huarte M.
        • et al.
        Many human large intergenic noncoding RNAs associate with chromatin-modifying complexes and affect gene expression.
        Proc Natl Acad Sci U S A. 2009; 106: 11667-11672
        • Mayoral R.J.
        • Pipkin M.E.
        • Pachkov M.
        • van Nimwegen E.
        • Rao A.
        • Monticelli S.
        MicroRNA-221-222 regulate the cell cycle in mast cells.
        J Immunol. 2009; 182: 433-445
        • Mayoral R.J.
        • Deho L.
        • Rusca N.
        • et al.
        MiR-221 influences effector functions and actin cytoskeleton in mast cells.
        PLoS One. 2011; 6: e26133
        • Rusca N.
        • Dehò L.
        • Montagner S.
        • et al.
        MiR-146a and NF-kappaB1 regulate mast cell survival and T lymphocyte differentiation.
        Mol Cell Biol. 2012; 32: 4432-4444
        • Molnár V.
        • Érsek B.
        • Wiener Z.
        • et al.
        MicroRNA-132 targets HB-EGF upon IgE-mediated activation in murine and human mast cells.
        Cell Mol Life Sci. 2012; 69: 793-808
        • Shin J.
        • Pan H.
        • Zhong X.P.
        Regulation of mast cell survival and function by tuberous sclerosis complex 1.
        Blood. 2012; 119: 3306-3314
        • Xiang Y.
        • Eyers F.
        • Young I.G.
        • Rosenberg H.F.
        • Foster P.S.
        • Yang M.
        Identification of microRNAs regulating the developmental pathways of bone marrow derived mast cells.
        PLoS One. 2014; 9: e98139
        • Lee Y.N.
        • Brandal S.
        • Noel P.
        • et al.
        KIT signaling regulates MITF expression through miRNAs in normal and malignant mast cell proliferation.
        Blood. 2011; 117: 3629-3640
        • Valadi H.
        • Ekström K.
        • Bossios A.
        • Sjöstrand M.
        • Lee J.J.
        • Lötvall J.O.
        Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells.
        Nat Cell Biol. 2007; 9: 654-659
        • Niedoszytko M.
        • Oude Elberink J.N.
        • Bruinenberg M.
        • et al.
        Gene expression profile, pathways, and transcriptional system regulation in indolent systemic mastocytosis.
        Allergy. 2011; 66: 229-237
        • D'Ambrosio C.
        • Akin C.
        • Wu Y.
        • Magnusson M.K.
        • Metcalfe D.D.
        Gene expression analysis in mastocytosis reveals a highly consistent profile with candidate molecular markers.
        J Allergy Clin Immunol. 2003; 112: 1162-1170
        • Butterfield J.H.
        • Weiler D.
        • Dewald G.
        • Gleich G.J.
        Establishment of an immature mast cell line from a patient with mast cell leukemia.
        Leuk Res. 1998; 12: 345-355
        • Haenisch B.
        • Herms S.
        • Molderings G.J.
        The transcriptome of the human mast cell leukemia cells HMC-1.2: an approach to identify specific changes in the gene expression profile in KitD816V systemic mastocytosis.
        Immunol Res. 2013; 56: 155-162
        • Kashiwakura J.
        • Yokoi H.
        • Saito H.
        • Okayama Y.
        T cell proliferation by direct cross-talk between OX40 ligand on human mast cells and OX40 on human T cells: comparison of gene expression profiles between human tonsillar and lung-cultured mast cells.
        J Immunol. 2004; 173: 5247-5257
        • Jayapal M.
        • Tay H.K.
        • Reghunathan R.
        • et al.
        Genome-wide gene expression profiling of human mast cells stimulated by IgE or FcepsilonRI-aggregation reveals a complex network of genes involved in inflammatory responses.
        BMC Genomics. 2006; 7: 210
        • Akin C.
        • Valent P.
        • Metcalfe D.D.
        Mast cell activation syndrome: proposed diagnostic criteria.
        J Allergy Clin Immunol. 2010; 126: 1099-1104
        • Suter C.M.
        • Martin D.I.
        • Ward R.L.
        Germline epimutation of mlh1 in individuals with multiple cancers.
        Nat Genet. 2004; 36: 497-501
        • Whitelaw N.C.
        • Whitelaw E.
        Transgenerational epigenetic inheritance in health and disease.
        Curr Opin Genet Dev. 2008; 18: 273-279
        • Issa J.P.
        The myelodysplastic syndrome as a prototypical epigenetic disease.
        Blood. 2013; 121: 3811-3817
        • Shen H.
        • Laird P.W.
        Interplay between the cancer genome and epigenome.
        Cell. 2013; 153: 38-55
      2. Abdulkadir H, Grootens J, Kjellander M et al. Histone deacetylase inhibitor SAHA mediates epigenetic silencing of KIT D816V mutated systemic mastocytosis primary mast cells and selective apoptosis of mutated mast cells. ASH Annual Meeting (December 5-8, 2015): Abstract 2834.