{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T06:16:40Z","timestamp":1790749000501,"version":"4.1.0"},"reference-count":122,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2020,6,2]],"date-time":"2020-06-02T00:00:00Z","timestamp":1591056000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100005010","name":"Associazione Italiana per la Ricerca sul Cancro","doi-asserted-by":"publisher","award":["23001"],"award-info":[{"award-number":["23001"]}],"id":[{"id":"10.13039\/501100005010","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>In recent years, molecular characterization and management of patients with systemic mastocytosis (SM) have greatly benefited from the application of advanced technologies. Highly sensitive and accurate assays for KIT D816V mutation detection and quantification have allowed the switch to non-invasive peripheral blood testing for patient screening; allele burden has prognostic implications and may be used to monitor therapeutic efficacy. Progress in genetic profiling of KIT, together with the use of next-generation sequencing panels for the characterization of associated gene mutations, have allowed the stratification of patients into three subgroups differing in terms of pathogenesis and prognosis: (i) patients with mast cell-restricted KIT D816V; (ii) patients with multilineage KIT D816V-involvement; (iii) patients with \u201cmulti-mutated disease\u201d. Thanks to these findings, new prognostic scoring systems combining clinical and molecular data have been developed. Finally, non-genetic SETD2 histone methyltransferase loss of function has recently been identified in advanced SM. Assessment of SETD2 protein levels and activity might provide prognostic information and has opened new research avenues exploring alternative targeted therapeutic strategies. This review discusses how progress in recent years has rapidly complemented previous knowledge improving the molecular characterization of SM, and how this has the potential to impact on patient diagnosis and management.<\/jats:p>","DOI":"10.3390\/ijms21113987","type":"journal-article","created":{"date-parts":[[2020,6,2]],"date-time":"2020-06-02T09:19:27Z","timestamp":1591089567000},"page":"3987","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Recent Advances in the Molecular Biology of Systemic Mastocytosis: Implications for Diagnosis, Prognosis, and Therapy"],"prefix":"10.3390","volume":"21","author":[{"given":"Margherita","family":"Martelli","sequence":"first","affiliation":[{"name":"Department of Experimental, Diagnostic and Specialty Medicine, Hematology\/Oncology \u201cL. e A. Ser\u00e0gnoli\u201d, University of Bologna, 40138 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cecilia","family":"Monaldi","sequence":"additional","affiliation":[{"name":"Department of Experimental, Diagnostic and Specialty Medicine, Hematology\/Oncology \u201cL. e A. Ser\u00e0gnoli\u201d, University of Bologna, 40138 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"De Santis","sequence":"additional","affiliation":[{"name":"Department of Experimental, Diagnostic and Specialty Medicine, Hematology\/Oncology \u201cL. e A. Ser\u00e0gnoli\u201d, University of Bologna, 40138 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samantha","family":"Bruno","sequence":"additional","affiliation":[{"name":"Department of Experimental, Diagnostic and Specialty Medicine, Hematology\/Oncology \u201cL. e A. Ser\u00e0gnoli\u201d, University of Bologna, 40138 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manuela","family":"Mancini","sequence":"additional","affiliation":[{"name":"Department of Experimental, Diagnostic and Specialty Medicine, Hematology\/Oncology \u201cL. e A. Ser\u00e0gnoli\u201d, University of Bologna, 40138 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michele","family":"Cavo","sequence":"additional","affiliation":[{"name":"Department of Experimental, Diagnostic and Specialty Medicine, Hematology\/Oncology \u201cL. e A. Ser\u00e0gnoli\u201d, University of Bologna, 40138 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simona","family":"Soverini","sequence":"additional","affiliation":[{"name":"Department of Experimental, Diagnostic and Specialty Medicine, Hematology\/Oncology \u201cL. e A. Ser\u00e0gnoli\u201d, University of Bologna, 40138 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,6,2]]},"reference":[{"key":"ref_1","first-page":"166","article-title":"Beitrage zur Kenntnis der granulierten. Bindegewebszellen und der eosinophilen Leukozyten","volume":"3","author":"Ehrlich","year":"1879","journal-title":"Arch. Anat. Physiol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"444","DOI":"10.1038\/mi.2014.131","article-title":"Potential effector and immunoregulatory functions of mast cells in mucosal immunity","volume":"8","author":"Reber","year":"2015","journal-title":"Mucosal Immunol."},{"key":"ref_3","unstructured":"Swerdlow, S.H. (2017). WHO classification of tumours of haematopoietic and lymphoid tissues 4th ed (revised)., IARC Press."},{"key":"ref_4","first-page":"1420","article-title":"Mastocytosis: 2016 updated WHO classification and novel emerging treatment concepts","volume":"129","author":"Valent","year":"2017","journal-title":"Blood J. Am. Soc. Hematol."},{"key":"ref_5","first-page":"5727","article-title":"Systemic mastocytosis in 342 consecutive adults: survival studies and prognostic factors","volume":"113","author":"Lim","year":"2009","journal-title":"Blood J. Am. Soc. Hematol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"692","DOI":"10.1002\/ajh.24382","article-title":"Clinical presentation and management practice of systemic mastocytosis. A survey on 460 Italian patients","volume":"91","author":"Pieri","year":"2016","journal-title":"Am. J. Hematol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"514","DOI":"10.1016\/j.jaci.2009.05.003","article-title":"Prognosis in adult indolent systemic mastocytosis: a long-term study of the Spanish Network on Mastocytosis in a series of 145 patients","volume":"124","author":"Escribano","year":"2009","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1097\/MOH.0b013e3283366c59","article-title":"Systemic mastocytosis in adults: a review on prognosis and treatment based on 342 Mayo Clinic patients and current literature","volume":"17","author":"Pardanani","year":"2010","journal-title":"Curr. Opin. Hematol."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Trizuljak, J., Sperr, W.R., Nekvindov\u00e1, L., Oude Elberink, H., Gleixner, K.V., Gorska, A., Lange, M., Hartmann, K., Illerhaus, A., and Bonifacio, M. (2020). Clinical Features and Survival of Patients with Indolent Systemic Mastocytosis defined by the Updated WHO Classification. Allergy.","DOI":"10.1111\/all.14248"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"E1","DOI":"10.1002\/ajh.25302","article-title":"Smoldering mastocytosis: Survival comparisons with indolent and aggressive mastocytosis","volume":"94","author":"Tefferi","year":"2019","journal-title":"Am. J. Hematol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"3341","DOI":"10.1002\/j.1460-2075.1987.tb02655.x","article-title":"Human proto-oncogene c-kit: a new cell surface receptor tyrosine kinase for an unidentified ligand","volume":"6","author":"Yarden","year":"1987","journal-title":"EMBO J."},{"key":"ref_12","first-page":"6064","article-title":"Receptor functions and ligand-dependent transforming potential of a chimeric kit proto-oncogene","volume":"10","author":"Lev","year":"1990","journal-title":"Mol. Cell. Biol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"939","DOI":"10.1016\/0955-0674(91)90111-B","article-title":"The kit ligand encoded at the murine Steel locus: a pleiotropic growth and differentiation factor","volume":"3","author":"Besmer","year":"1991","journal-title":"Curr. Opin. Cell Biol."},{"key":"ref_14","first-page":"38","article-title":"Interactions of colony stimulating factors, other modulating cytokines and hematopoietic progenitor cells. Laboratory and clinical studies","volume":"6","author":"Broxmeyer","year":"1992","journal-title":"Leukemia"},{"key":"ref_15","first-page":"2207","article-title":"Organization and nucleotide sequence of the human KIT (mast\/stem cell growth factor receptor) proto-oncogene","volume":"7","author":"Giebel","year":"1992","journal-title":"Oncogene"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1225","DOI":"10.1182\/blood.V88.4.1225.bloodjournal8841225","article-title":"Involvement of transcription factor encoded by the mi locus in the expression of c-kit receptor tyrosine kinase in cultured mast cells of mice","volume":"88","author":"Tsujimura","year":"1996","journal-title":"Blood"},{"key":"ref_17","first-page":"2901","article-title":"Modulation of c-kit mRNA and protein by hemopoietic growth factors","volume":"11","author":"Welham","year":"1991","journal-title":"Mol. Cell. Biol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1002\/stem.5530110804","article-title":"Structure-function analyses of the kit receptor for the steel factor","volume":"11","author":"Blechman","year":"1993","journal-title":"Stem Cells"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1151","DOI":"10.1182\/blood.V82.4.1151.1151","article-title":"Expression of isoforms of the human receptor tyrosine kinase c-kit in leukemic cell lines and acute myeloid leukemia","volume":"82","author":"Crosier","year":"1993","journal-title":"Blood"},{"key":"ref_20","first-page":"1259","article-title":"Cloning and structural analysis of the human c-kit gene","volume":"7","author":"Kaufman","year":"1992","journal-title":"Oncogene"},{"key":"ref_21","first-page":"1101","article-title":"c-kit ligand and Flt3 ligand: stem\/progenitor cell factors with overlapping yet distinct activities","volume":"91","author":"Lyman","year":"1998","journal-title":"Blood J. Am. Soc. Hematol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2451","DOI":"10.1002\/j.1460-2075.1991.tb07784.x","article-title":"Signal transduction by normal isoforms and W mutant variants of the Kit receptor tyrosine kinase","volume":"10","author":"Reith","year":"1991","journal-title":"EMBO J."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1517\/13543784.2013.740010","article-title":"Therapeutic targeting of c-KIT in cancer","volume":"22","author":"Ashman","year":"2013","journal-title":"Expert Opin. Investig. Drugs"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"661","DOI":"10.1182\/blood-2002-01-0203","article-title":"Evidence for the involvement of a hematopoietic progenitor cell in systemic mastocytosis from single-cell analysis of mutations in the c-kit gene","volume":"100","author":"Yavuz","year":"2002","journal-title":"Blood"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"464","DOI":"10.1038\/nrm1399","article-title":"Juxtamembrane autoinhibition in receptor tyrosine kinases","volume":"5","author":"Hubbard","year":"2004","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"611","DOI":"10.1038\/modpathol.3800108","article-title":"A distinct expression pattern and point mutation of c-kit in papillary renal cell carcinomas","volume":"17","author":"Lin","year":"2004","journal-title":"Mod. Pathol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1126\/science.279.5350.577","article-title":"Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors","volume":"279","author":"Hirota","year":"1998","journal-title":"Science (80-)"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"571","DOI":"10.1016\/S0145-2126(01)00028-5","article-title":"Classes of c-KIT activating mutations: proposed mechanisms of action and implications for disease classification and therapy","volume":"25","author":"Longley","year":"2001","journal-title":"Leuk. Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1046\/j.1523-1747.1999.00488.x","article-title":"Clustering of activating mutations in c-KIT\u2019s juxtamembrane coding region in canine mast cell neoplasms","volume":"112","author":"Ma","year":"1999","journal-title":"J. Investig. Dermatol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"13399","DOI":"10.1074\/jbc.274.19.13399","article-title":"Inhibition of spontaneous receptor phosphorylation by residues in a putative \u03b1-helix in the KIT intracellular juxtamembrane region","volume":"274","author":"Ma","year":"1999","journal-title":"J. Biol. Chem."},{"key":"ref_31","first-page":"S18","article-title":"Activating mutations of the c-kit proto-oncogene in a human mast cell leukemia cell line","volume":"8","author":"Kanakura","year":"1994","journal-title":"Leukemia"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"790","DOI":"10.1182\/blood.V85.3.790.bloodjournal853790","article-title":"Constitutively activating mutations of c-kit receptor tyrosine kinase confer factor-independent growth and tumorigenicity of factor-dependent hematopoietic cell lines","volume":"85","author":"Kitayama","year":"1995","journal-title":"Blood"},{"key":"ref_33","first-page":"1285","article-title":"Mast cell leukemia","volume":"121","author":"Lhermitte","year":"2013","journal-title":"Blood J. Am. Soc. Hematol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"804","DOI":"10.1038\/jid.2009.281","article-title":"Pediatric mastocytosis is a clonal disease associated with D816V and other activating c-KIT mutations","volume":"130","author":"Bodemer","year":"2010","journal-title":"J. Investig. Dermatol."},{"key":"ref_35","first-page":"210","article-title":"Identification of a polymorphism in the transmembrane domain of the protooncogene c-kit in healthy subjects","volume":"13","author":"Nagata","year":"1996","journal-title":"Exp. Clin. Immunogenet."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Laine, E., de Beauch\u00eane, I.C., Perahia, D., Auclair, C., and Tchertanov, L. (2011). Mutation D816V alters the internal structure and dynamics of c-KIT receptor cytoplasmic region: implications for dimerization and activation mechanisms. PLoS Comput. Biol., 7.","DOI":"10.1371\/journal.pcbi.1002068"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1128\/MCB.01153-06","article-title":"Neoplasia driven by mutant c-KIT is mediated by intracellular, not plasma membrane, receptor signaling","volume":"27","author":"Xiang","year":"2007","journal-title":"Mol. Cell. Biol."},{"key":"ref_38","first-page":"1365","article-title":"Phosphatidylinositol 3 kinase contributes to the transformation of hematopoietic cells by the D816V c-Kit mutant","volume":"98","author":"Chian","year":"2001","journal-title":"Blood J. Am. Soc. Hematol."},{"key":"ref_39","first-page":"2463","article-title":"Oncogenic Kit controls neoplastic mast cell growth through a Stat5\/PI3-kinase signaling cascade","volume":"112","author":"Harir","year":"2008","journal-title":"Blood J. Am. Soc. Hematol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"2416","DOI":"10.2353\/ajpath.2009.080953","article-title":"Expression of activated STAT5 in neoplastic mast cells in systemic mastocytosis: subcellular distribution and role of the transforming oncoprotein KIT D816V","volume":"175","author":"Baumgartner","year":"2009","journal-title":"Am. J. Pathol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"2324","DOI":"10.1182\/blood-2004-08-3247","article-title":"A novel NF-\u03baB inhibitor, IMD-0354, suppresses neoplastic proliferation of human mast cells with constitutively activated c-kit receptors","volume":"105","author":"Tanaka","year":"2005","journal-title":"Blood"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1065","DOI":"10.1182\/blood-2005-06-2433","article-title":"Rapamycin inhibits growth and survival of D816V-mutated c-kit mast cells","volume":"108","author":"Lepelletier","year":"2006","journal-title":"Blood"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1923","DOI":"10.1182\/blood-2004-04-1450","article-title":"PKC\u03b4 plays opposite roles in growth mediated by wild-type Kit and an oncogenic Kit mutant","volume":"105","author":"Jelacic","year":"2005","journal-title":"Blood"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1038\/nrclinonc.2013.10","article-title":"Development of PI3K inhibitors: lessons learned from early clinical trials","volume":"10","author":"Rodon","year":"2013","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"2344","DOI":"10.1016\/j.ajpath.2011.01.020","article-title":"Identification of oncostatin M as a STAT5-dependent mediator of bone marrow remodeling in KIT D816V-positive systemic mastocytosis","volume":"178","author":"Hoermann","year":"2011","journal-title":"Am. J. Pathol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"599","DOI":"10.1038\/gene.2010.35","article-title":"Mast cell homeostasis and the JAK\u2013STAT pathway","volume":"11","author":"Morales","year":"2010","journal-title":"Genes Immun."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1333","DOI":"10.1016\/j.celrep.2014.10.039","article-title":"Regulation of Stat5 by FAK and PAK1 in oncogenic FLT3-and KIT-driven leukemogenesis","volume":"9","author":"Chatterjee","year":"2014","journal-title":"Cell Rep."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"4449","DOI":"10.1172\/JCI67509","article-title":"Pak and Rac GTPases promote oncogenic KIT\u2013induced neoplasms","volume":"123","author":"Martin","year":"2013","journal-title":"J. Clin. Investig."},{"key":"ref_49","first-page":"3629","article-title":"KIT signaling regulates MITF expression through miRNAs in normal and malignant mast cell proliferation","volume":"117","author":"Lee","year":"2011","journal-title":"Blood J. Am. Soc. Hematol."},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Blatt, K., Herrmann, H., Mirkina, I., Hadzijusufovic, E., Peter, B., Strommer, S., Hoermann, G., Mayerhofer, M., Hoetzenecker, K., and Klepetko, W. (2012). The PI3-kinase\/mTOR-targeting drug NVP-BEZ235 inhibits growth and IgE-dependent activation of human mast cells and basophils. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0029925"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"269","DOI":"10.3109\/10428190903486220","article-title":"Experience with everolimus (RAD001), an oral mammalian target of rapamycin inhibitor, in patients with systemic mastocytosis","volume":"51","author":"Parikh","year":"2010","journal-title":"Leuk. Lymphoma"},{"key":"ref_52","first-page":"6803","article-title":"mTORC1 and mTORC2 differentially regulate homeostasis of neoplastic and non-neoplastic human mast cells","volume":"118","author":"Kim","year":"2011","journal-title":"Blood J. Am. Soc. Hematol."},{"key":"ref_53","first-page":"2669","article-title":"Role of SHP2 phosphatase in KIT-induced transformation: identification of SHP2 as a druggable target in diseases involving oncogenic KIT","volume":"120","author":"Mali","year":"2012","journal-title":"Blood J. Am. Soc. Hematol."},{"key":"ref_54","first-page":"2593","article-title":"The tyrosine kinase FES is an essential effector of KITD816V proliferation signal","volume":"110","author":"Voisset","year":"2007","journal-title":"Blood J. Am. Soc. Hematol."},{"key":"ref_55","first-page":"1525","article-title":"Altered apoptosis and cell cycling of mast cells in bone marrow lesions of patients with systemic mastocytosis","volume":"89","author":"Baldus","year":"2004","journal-title":"Haematologica"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1002\/(SICI)1096-8652(199903)60:3<191::AID-AJH4>3.0.CO;2-Y","article-title":"Expression of bcl-2 by human bone marrow mast cells and its overexpression in mast cell leukemia","volume":"60","author":"Escribano","year":"1999","journal-title":"Am. J. Hematol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"819","DOI":"10.1016\/S0002-9440(10)63442-6","article-title":"Expression of Bcl-2 and Bcl-xL in cutaneous and bone marrow lesions of mastocytosis","volume":"163","author":"Hartmann","year":"2003","journal-title":"Am. J. Pathol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"3031","DOI":"10.1182\/blood-2006-07-032714","article-title":"Identification of MCL1 as a novel target in neoplastic mast cells in systemic mastocytosis: inhibition of mast cell survival by MCL1 antisense oligonucleotides and synergism with PKC412","volume":"109","author":"Aichberger","year":"2007","journal-title":"Blood"},{"key":"ref_59","first-page":"5342","article-title":"Identification of proapoptotic Bim as a tumor suppressor in neoplastic mast cells: role of KIT D816V and effects of various targeted drugs","volume":"114","author":"Aichberger","year":"2009","journal-title":"Blood J. Am. Soc. Hematol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1189\/jlb.1112609","article-title":"The pan-Bcl-2 blocker obatoclax promotes the expression of Puma, Noxa, and Bim mRNA and induces apoptosis in neoplastic mast cells","volume":"95","author":"Peter","year":"2014","journal-title":"J. Leukoc. Biol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"2366","DOI":"10.1182\/blood-2006-04-015545","article-title":"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","volume":"108","author":"Teodosio","year":"2006","journal-title":"Blood"},{"key":"ref_62","first-page":"586","article-title":"Variable presence of KITD816V in clonal haematological non-mast cell lineage diseases associated with systemic mastocytosis (SM\u2013AHNMD)","volume":"220","author":"Sotlar","year":"2010","journal-title":"J. Pathol. A J. Pathol. Soc. Gt. Britain Irel."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1574","DOI":"10.1038\/sj.leu.2404680","article-title":"Quantitative profiling of codon 816 KIT mutations can aid in the classification of systemic mast cell disease","volume":"21","author":"Zhao","year":"2007","journal-title":"Leukemia"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1016\/S1525-1578(10)60529-6","article-title":"Demonstration that mast cells, T cells, and B cells bearing the activating kit mutation D816V occur in clusters within the marrow of patients with mastocytosis","volume":"6","author":"Taylor","year":"2004","journal-title":"J. Mol. Diagn."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"603","DOI":"10.1016\/S0145-2126(01)00038-8","article-title":"Diagnostic criteria and classification of mastocytosis: a consensus proposal","volume":"25","author":"Valent","year":"2001","journal-title":"Leuk. Res."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1115","DOI":"10.1038\/leu.2015.4","article-title":"Molecular profiling of myeloid progenitor cells in multi-mutated advanced systemic mastocytosis identifies KIT D816V as a distinct and late event","volume":"29","author":"Jawhar","year":"2015","journal-title":"Leukemia"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1016\/j.scr.2015.04.005","article-title":"Impaired function of bone marrow stromal cells in systemic mastocytosis","volume":"15","author":"Nemeth","year":"2015","journal-title":"Stem Cell Res."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1111\/j.1365-2362.2007.01807.x","article-title":"Standards and standardization in mastocytosis: consensus statements on diagnostics, treatment recommendations and response criteria","volume":"37","author":"Valent","year":"2007","journal-title":"Eur. J. Clin. Investig."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1046\/j.1365-2141.2001.02783.x","article-title":"Mutation analysis of C-KIT in patients with myelodysplastic syndromes without mastocytosis and cases of systemic mastocytosis","volume":"113","author":"Jordan","year":"2001","journal-title":"Br. J. Haematol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1007\/s00277-013-1964-1","article-title":"The KIT D816V expressed allele burden for diagnosis and disease monitoring of systemic mastocytosis","volume":"93","author":"Erben","year":"2014","journal-title":"Ann. Hematol."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"737","DOI":"10.1016\/S0002-9440(10)63870-9","article-title":"One-step detection of c-kit point mutations using PNA-mediated PCR-clamping and hybridization probes","volume":"162","author":"Sotlar","year":"2003","journal-title":"Am. J. Pathol"},{"key":"ref_72","doi-asserted-by":"crossref","unstructured":"Sotlar, K. (2013). C-kit mutational analysis in paraffin material. Hematological Malignancies, Springer.","DOI":"10.1007\/978-1-62703-357-2_4"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1002\/ajh.23672","article-title":"Sensitive KIT D816V mutation analysis of blood as a diagnostic test in mastocytosis","volume":"89","author":"Kristensen","year":"2014","journal-title":"Am. J. Hematol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1016\/j.jmoldx.2010.10.004","article-title":"Improved detection of the KIT D816V mutation in patients with systemic mastocytosis using a quantitative and highly sensitive real-time qPCR assay","volume":"13","author":"Kristensen","year":"2011","journal-title":"J. Mol. Diagn."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1111\/j.1600-0609.2012.01789.x","article-title":"Circulating KIT D 816 V mutation-positive non-mast cells in peripheral blood are characteristic of indolent systemic mastocytosis","volume":"89","author":"Kristensen","year":"2012","journal-title":"Eur. J. Haematol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1373\/clinchem.2017.277897","article-title":"Digital PCR: a sensitive and precise method for KIT D816V quantification in mastocytosis","volume":"64","author":"Greiner","year":"2018","journal-title":"Clin. Chem."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"366","DOI":"10.3324\/haematol.2019.217950","article-title":"Molecular quantification of tissue disease burden is a new biomarker and independent predictor of survival in mastocytosis","volume":"105","author":"Greiner","year":"2020","journal-title":"Haematologica"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"810","DOI":"10.1111\/all.12409","article-title":"The KIT D 816 V allele burden predicts survival in patients with mastocytosis and correlates with the WHO type of the disease","volume":"69","author":"Hoermann","year":"2014","journal-title":"Allergy"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"1138","DOI":"10.1038\/modpathol.2015.72","article-title":"Detection of the KIT D816V mutation in peripheral blood of systemic mastocytosis: diagnostic implications","volume":"28","author":"Teodosio","year":"2015","journal-title":"Mod. Pathol."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"262","DOI":"10.1016\/j.jaci.2014.06.031","article-title":"Recognizing mastocytosis in patients with anaphylaxis: value of KIT D816V mutation analysis of peripheral blood","volume":"135","author":"Oropeza","year":"2015","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"1267","DOI":"10.1111\/all.12436","article-title":"Proposed diagnostic algorithm for patients with suspected mastocytosis: a proposal of the European Competence Network on Mastocytosis","volume":"69","author":"Valent","year":"2014","journal-title":"Allergy"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"1223","DOI":"10.1038\/leu.2015.24","article-title":"KIT mutation analysis in mast cell neoplasms: recommendations of the European Competence Network on Mastocytosis","volume":"29","author":"Arock","year":"2015","journal-title":"Leukemia"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1111\/ejh.12601","article-title":"Targeted ultradeep next-generation sequencing as a method for KIT D 816 V mutation analysis in mastocytosis","volume":"96","author":"Kristensen","year":"2016","journal-title":"Eur. J. Haematol."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"951","DOI":"10.1038\/leu.2011.293","article-title":"An immature immunophenotype of bone marrow mast cells predicts for multilineage D816V KIT mutation in systemic mastocytosis","volume":"26","author":"Teodosio","year":"2012","journal-title":"Leukemia"},{"key":"ref_85","first-page":"137","article-title":"Response and progression on midostaurin in advanced systemic mastocytosis: KIT D816V and other molecular markers","volume":"130","author":"Jawhar","year":"2017","journal-title":"Blood J. Am. Soc. Hematol."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"723","DOI":"10.1016\/j.jaci.2013.02.019","article-title":"MastOUH, M.C.O.U.H. KIT D816V mutation burden does not correlate to clinical manifestations of indolent systemic mastocytosis","volume":"132","author":"Kristensen","year":"2013","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"1635","DOI":"10.1084\/jem.20050807","article-title":"Mastocytosis in mice expressing human Kit receptor with the activating Asp816Val mutation","volume":"202","author":"Zappulla","year":"2005","journal-title":"J. Exp. Med."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"2814","DOI":"10.1182\/bloodadvances.2018020628","article-title":"Impact of somatic and germline mutations on the outcome of systemic mastocytosis","volume":"2","author":"Merker","year":"2018","journal-title":"Blood Adv."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"888","DOI":"10.1002\/ajh.24426","article-title":"Next-generation sequencing in systemic mastocytosis: derivation of a mutation-augmented clinical prognostic model for survival","volume":"91","author":"Pardanani","year":"2016","journal-title":"Am. J. Hematol."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"2460","DOI":"10.1182\/blood-2013-04-496448","article-title":"Comprehensive mutational profiling in advanced systemic mastocytosis","volume":"122","author":"Schwaab","year":"2013","journal-title":"Blood"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"3858","DOI":"10.1200\/JCO.2009.27.1361","article-title":"Next-generation sequencing technology reveals a characteristic pattern of molecular mutations in 72.8% of chronic myelomonocytic leukemia by detecting frequent alterations in TET2, CBL, RAS, and RUNX1","volume":"28","author":"Kohlmann","year":"2010","journal-title":"J. Clin. Oncol."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1038\/leu.2013.336","article-title":"Landscape of genetic lesions in 944 patients with myelodysplastic syndromes","volume":"28","author":"Haferlach","year":"2014","journal-title":"Leukemia"},{"key":"ref_93","first-page":"3080","article-title":"SRSF2 mutations in 275 cases with chronic myelomonocytic leukemia (CMML)","volume":"120","author":"Meggendorfer","year":"2012","journal-title":"Blood J. Am. Soc. Hematol."},{"key":"ref_94","first-page":"2220","article-title":"Clonal evolution and clinical correlates of somatic mutations in myeloproliferative neoplasms","volume":"123","author":"Lundberg","year":"2014","journal-title":"Blood J. Am. Soc. Hematol."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1038\/leu.2015.284","article-title":"Additional mutations in SRSF2, ASXL1 and\/or RUNX1 identify a high-risk group of patients with KIT D816V+ advanced systemic mastocytosis","volume":"30","author":"Jawhar","year":"2016","journal-title":"Leukemia"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"2342","DOI":"10.1038\/leu.2016.190","article-title":"Splenomegaly, elevated alkaline phosphatase and mutations in the SRSF2\/ASXL1\/RUNX1 gene panel are strong adverse prognostic markers in patients with systemic mastocytosis","volume":"30","author":"Jawhar","year":"2016","journal-title":"Leukemia"},{"key":"ref_97","doi-asserted-by":"crossref","unstructured":"Gandhi Damaj, M.J., Chandesris, O., Hanssens, K., Soucie, E., Canioni, D., Kolb, B., Durieu, I., Gyan, E., Livideanu, C., and Ch\u00e8ze, S. (2014). ASXL1 but not TET2 mutations adversely impact overall survival of patients suffering systemic mastocytosis with associated clonal hematologic non-mast-cell diseases. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0085362"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"828","DOI":"10.1182\/blood.V126.23.828.828","article-title":"ASXL1 and CBL mutations are independently predictive of inferior survival in advanced systemic mastocytosis","volume":"126","author":"Pardanani","year":"2015","journal-title":"Blood"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1002\/gcc.22526","article-title":"Incidence and prognostic impact of cytogenetic aberrations in patients with systemic mastocytosis","volume":"57","author":"Naumann","year":"2018","journal-title":"Genes Chromosom. Cancer"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"1461","DOI":"10.1002\/ajh.25265","article-title":"Cytogenetic abnormalities in systemic mastocytosis: WHO subcategory-specific incidence and prognostic impact among 348 informative cases","volume":"93","author":"Shah","year":"2018","journal-title":"Am. J. Hematol."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"1090","DOI":"10.1038\/s41375-019-0632-4","article-title":"Prognostic impact of eosinophils in mastocytosis: analysis of 2350 patients collected in the ECNM Registry","volume":"34","author":"Reiter","year":"2020","journal-title":"Leukemia"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"845","DOI":"10.1002\/ajh.25506","article-title":"Myelodysplasia as assessed by multiparameter flow cytometry refines prognostic stratification provided by genotypic risk in systemic mastocytosis","volume":"94","author":"Mannelli","year":"2019","journal-title":"Am. J. Hematol."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"914","DOI":"10.1038\/leu.2015.348","article-title":"CD123 immunostaining patterns in systemic mastocytosis: differential expression in disease subgroups and potential prognostic value","volume":"30","author":"Pardanani","year":"2016","journal-title":"Leukemia"},{"key":"ref_104","first-page":"456","article-title":"Frequency and prognostic impact of KIT and other genetic variants in indolent systemic mastocytosis","volume":"134","author":"Henriques","year":"2019","journal-title":"Blood J. Am. Soc. Hematol."},{"key":"ref_105","doi-asserted-by":"crossref","unstructured":"Jawhar, M., Schwaab, J., \u00c1lvarez-Twose, I., Shoumariyeh, K., Naumann, N., L\u00fcbke, J., Perkins, C., Mu\u00f1oz-Gonz\u00e1lez, J.I., Meggendorfer, M., and Kennedy, V. (2019). MARS: Mutation-Adjusted Risk Score for advanced systemic mastocytosis. J. Clin. Oncol.","DOI":"10.1200\/JCO.19.00640"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"2964","DOI":"10.1182\/bloodadvances.2018026245","article-title":"Mayo alliance prognostic system for mastocytosis: clinical and hybrid clinical-molecular models","volume":"2","author":"Pardanani","year":"2018","journal-title":"Blood Adv."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41408-019-0189-5","article-title":"World Health Organization class-independent risk categorization in mastocytosis","volume":"9","author":"Pardanani","year":"2019","journal-title":"Blood Cancer J."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"e638","DOI":"10.1016\/S2352-3026(19)30166-8","article-title":"International prognostic scoring system for mastocytosis (IPSM): a retrospective cohort study","volume":"6","author":"Sperr","year":"2019","journal-title":"Lancet Haematol."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1038\/leu.2017.183","article-title":"SETD2 and histone H3 lysine 36 methylation deficiency in advanced systemic mastocytosis","volume":"32","author":"Martinelli","year":"2018","journal-title":"Leukemia"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"406","DOI":"10.1038\/sj.emboj.7601967","article-title":"Dynamic histone H3 methylation during gene induction: HYPB\/Setd2 mediates all H3K36 trimethylation","volume":"27","author":"Edmunds","year":"2008","journal-title":"EMBO J."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"2881","DOI":"10.1093\/nar\/gks1472","article-title":"Histone methyltransferase SETD2 coordinates FACT recruitment with nucleosome dynamics during transcription","volume":"41","author":"Carvalho","year":"2013","journal-title":"Nucleic Acids Res."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"977","DOI":"10.1038\/nsmb.2123","article-title":"Splicing enhances recruitment of methyltransferase HYPB\/Setd2 and methylation of histone H3 Lys36","volume":"18","author":"Grosso","year":"2011","journal-title":"Nat. Struct. Mol. Biol."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"590","DOI":"10.1016\/j.cell.2013.03.025","article-title":"The histone mark H3K36me3 regulates human DNA mismatch repair through its interaction with MutS\u03b1","volume":"153","author":"Li","year":"2013","journal-title":"Cell"},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"e02482","DOI":"10.7554\/eLife.02482","article-title":"SETD2 is required for DNA double-strand break repair and activation of the p53-mediated checkpoint","volume":"3","author":"Carvalho","year":"2014","journal-title":"Elife"},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"950","DOI":"10.1016\/j.cell.2016.07.005","article-title":"Dual chromatin and cytoskeletal remodeling by SETD2","volume":"166","author":"Park","year":"2016","journal-title":"Cell"},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"5699","DOI":"10.1038\/onc.2015.24","article-title":"SETD2 loss-of-function promotes renal cancer branched evolution through replication stress and impaired DNA repair","volume":"34","author":"Kanu","year":"2015","journal-title":"Oncogene"},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"50719","DOI":"10.18632\/oncotarget.9368","article-title":"SETD2: an epigenetic modifier with tumor suppressor functionality","volume":"7","author":"Li","year":"2016","journal-title":"Oncotarget"},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1038\/ng.2894","article-title":"Identification of functional cooperative mutations of SETD2 in human acute leukemia","volume":"46","author":"Zhu","year":"2014","journal-title":"Nat. Genet."},{"key":"ref_119","doi-asserted-by":"crossref","unstructured":"Liu, W., Fu, Q., An, H., Chang, Y., Zhang, W., Zhu, Y., Xu, L., and Xu, J. (2015). Decreased expression of SETD2 predicts unfavorable prognosis in patients with nonmetastatic clear-cell renal cell carcinoma. Medicine (Baltimore), 94.","DOI":"10.1097\/MD.0000000000002004"},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"1363","DOI":"10.1016\/j.juro.2016.06.010","article-title":"Prognostic value of SETD2 expression in patients with metastatic renal cell carcinoma treated with tyrosine kinase inhibitors","volume":"196","author":"Wang","year":"2016","journal-title":"J. Urol."},{"key":"ref_121","unstructured":"Chen, B.-Y., Song, J., Hu, C.-L., Chen, S.-B., Zhang, Q., Xu, C.-H., Wu, J.-C., Hou, D., Sun, M., and Zhang, Y.-L. (2020). SETD2 deficiency predicts poor prognosis in MDS and accelerated MDS-associated leukemogenesis via S100a9. Blood J., blood-2019001963."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"2179","DOI":"10.1038\/leu.2016.134","article-title":"Genomic disruption of the histone methyltransferase SETD2 in chronic lymphocytic leukaemia","volume":"30","author":"Parker","year":"2016","journal-title":"Leukemia"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/11\/3987\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T09:34:51Z","timestamp":1760175291000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/11\/3987"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,6,2]]},"references-count":122,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2020,6]]}},"alternative-id":["ijms21113987"],"URL":"https:\/\/doi.org\/10.3390\/ijms21113987","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,6,2]]}}}