Epigenetic Changes in Neoplastic Mast Cells and Potential Impact in Mastocytosis
Abstract
:1. Clinical Features and Classification of Mastocytosis
KIT Mutations
2. Epigenetic Changes in Mastocytosis
2.1. Histone Modifications in Neoplastic MC
2.2. Epigenetic Modifications of KIT
2.3. Methylation Status of Apoptosis-Associated and Tumor Suppressor Genes in HMC-1 Cells
2.4. Somatic Mutations in Genes Regulating Epigenetic Mechanisms
2.5. TET2
2.6. DNMT3
2.7. 5-mC, 5-hmC Level
2.8. MicroRNA
2.9. MITF and MicroRNA
3. Effects of Epigenetic Drugs on Growth and Viability of Neoplastic MC
4. Concluding Remarks
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
AML | Acute Myeloid Leukemia |
ASM | aggressive systemic mastocytosis |
ASXL1 | additional sex combs like 1 |
BET | Bromodomain and Extra-Terminal Motif |
CALR | calreticulin |
CBL | casitas B-cell lymphoma |
CEBPA | CCAAT/enhancer-binding protein-alpha |
CM | cutaneous mastocytosis |
CMML | chronic myelomonocytic leukemia |
DNMT1 | DNA methyl transferase 1 |
DNMT3A | DNA methyltransferase 3 alpha |
DNMT3B | DNA methyltransferase -3B |
ECM | extracutaneous mastocytoma |
ETV6 | ets family transcription factor |
EZH2 | enhancer of zeste homolog 2 |
FLT3 | Fms Related Tyrosine Kinase |
HDACi | histone deacetylase inhibitor |
HSC | hematopoietic stem cells |
IDH1/2 | isocitrate dehydrogenase 1/2 |
IgE | immunoglobulin E |
ISM | indolent systemic mastocytosis |
JAK2 | Janus Kinase-2 |
MCL | mast cell leukemia |
MDS | myelodysplastic syndrome |
miRNAs | micro RNAs |
MITF | microphthalmia-associated transcription factor |
MLL-PTD | partial tandem duplication of MLL |
ncRNA | non-coding RNA |
NPM1 | nucleophosmin 1 |
NRAS | neuroblastoma rat sarcoma viral oncogene homolog |
PTPN11 | protein tyrosine phosphatase non-receptor type 11 |
OS | overall survival |
RUNX1 | runt-related transcription factor 1 |
SAHA | suberoyl anilide hydroxamid acid |
SETBP1 | SET binding protein 1 |
SM | systemic mastocytosis |
SM-AHN | systemic mastocytosis with an associated hematologic neoplasm |
SRSF2 | serine/arginine-rich splicing factor 2 |
SSM | smouldering systemic mastocytosis |
SUZ12 | suppressor of zeste 12 homolog |
TDG | thymine DNA glycosylase |
TET2 | Ten-Eleven-Translocation 2 |
U2AF1 | U2 auxiliary factor 1 |
5-caC | 5-carboxylcytosine |
5-fC | 5-formylcytosine |
5-hmC | 5-hydroxymethylcytosine |
5-mC | 5-methylcytosine |
References
- Valent, P.; Sperr, W.R.; Schwartz, L.B.; Horny, H.-P. Diagnosis and classification of mast cell proliferative disorders: Delineation from immunologic diseases and non–mast cell hematopoietic neoplasms. J. Allergy Clin. Immunol. 2004, 114, 3–11. [Google Scholar] [CrossRef]
- Theoharides, T.C.; Valent, P.; Akin, C. Mast cells, mastocytosis, and related disorders. N. Engl. J. Med. 2015, 373, 163–172. [Google Scholar] [CrossRef]
- Valent, P.; Akin, C.; Gleixner, K.V.; Sperr, W.R.; Reiter, A.; Arock, M.; Triggiani, M. Multidisciplinary challenges in mastocytosis and how to address with personalized medicine approaches. Int. J. Mol. Sci. 2019, 20, 2976. [Google Scholar] [CrossRef] [Green Version]
- Valent, P.; Horny, H.-P.; Escribano, L.; Longley, B.J.; Li, C.Y.; Schwartz, L.B.; Marone, G.; Nuñez, R.; Akin, C.; Sotlar, K. Diagnostic criteria and classification of mastocytosis: A consensus proposal. Leuk. Res. 2001, 25, 603–625. [Google Scholar] [CrossRef]
- Valent, P.; Akin, C.; Sperr, W.R.; Escribano, L.; Arock, M.; Horny, H.-P.; Bennett, J.M.; Metcalfe, D.D. Aggressive systemic mastocytosis and related mast cell disorders: Current treatment options and proposed response criteria. Leuk. Res. 2003, 27, 635–641. [Google Scholar] [CrossRef]
- Valent, P.; Akin, C.; Hartmann, K.; Nilsson, G.; Reiter, A.; Hermine, O.; Sotlar, K.; Sperr, W.R.; Escribano, L.; George, T.I. Advances in the classification and treatment of mastocytosis: Current status and outlook toward the future. Cancer Res. 2017, 77, 1261–1270. [Google Scholar] [CrossRef] [Green Version]
- Valent, P.; Akin, C.; Escribano, L.; Födinger, M.; Hartmann, K.; Brockow, K.; Castells, M.; Sperr, W.; Kluin-Nelemans, H.; Hamdy, N. Standards and standardization in mastocytosis: Consensus statements on diagnostics, treatment recommendations and response criteria. Eur. J. Clin. Investig. 2007, 37, 435–453. [Google Scholar] [CrossRef]
- Valent, P.; Akin, C.; Metcalfe, D.D. Mastocytosis: 2016 updated WHO classification and novel emerging treatment concepts. Blood J. Am. Soc. Hematol. 2017, 129, 1420–1427. [Google Scholar] [CrossRef]
- Pardanani, A. Systemic mastocytosis in adults: 2017 update on diagnosis, risk stratification and management. Am. J. Hematol. 2016, 91, 1146–1159. [Google Scholar] [CrossRef] [Green Version]
- Valent, P.; Sotlar, K.; Sperr, W.; Escribano, L.; Yavuz, S.; Reiter, A.; George, T.; Kluin-Nelemans, H.; Hermine, O.; Butterfield, J. Refined diagnostic criteria and classification of mast cell leukemia (MCL) and myelomastocytic leukemia (MML): A consensus proposal. Ann. Oncol. 2014, 25, 1691–1700. [Google Scholar] [CrossRef]
- Soucie, E.; Brenet, F.; Dubreuil, P. Molecular basis of mast cell disease. Mol. Immunol. 2015, 63, 55–60. [Google Scholar] [CrossRef]
- Chatterjee, A.; Ghosh, J.; Kapur, R. Mastocytosis: A mutated KIT receptor induced myeloproliferative disorder. Oncotarget 2015, 6, 18250. [Google Scholar] [CrossRef] [PubMed]
- Valent, P.; Bettelheim, P. Cell surface structures on human basophils and mast cells: Biochemical and functional characterization. In Advances in Immunology; Elsevier: Amsterdam, The Netherlands, 1992; Volume 52, pp. 333–423. [Google Scholar]
- Valent, P.; Spanblochl, E.; Sperr, W.R.; Sillaber, C.; Zsebo, K.M.; Agis, H.; Strobl, H.; Geissler, K.; Bettelheim, P.; Lechner, K. Induction of differentiation of human mast cells from bone marrow and peripheral blood mononuclear cells by recombinant human stem cell factor/kit-ligand in long-term culture. Blood 1992, 80, 2237–2245. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Valent, P. The riddle of the mast cell: Kit (CD117)-ligand as the missing link? Immunol. Today 1994, 15, 111–114. [Google Scholar] [CrossRef]
- Garcia-Montero, A.C.; Jara-Acevedo, M.; Teodosio, C.; Sanchez, M.L.; Nunez, R.; Prados, A.; Aldanondo, I.; Sanchez, L.; Dominguez, M.; Botana, L.M. 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, 108, 2366–2372. [Google Scholar] [CrossRef]
- Pardanani, A.; Lasho, T.L.; Finke, C.; Zblewski, D.; Abdelrahman, R.; Wassie, E.; Gangat, N.; Hanson, C.A.; Ketterling, R.P.; Tefferi, A. ASXL1 and CBL mutations are independently predictive of inferior survival in advanced systemic mastocytosis. Blood 2015, 126, 828. [Google Scholar] [CrossRef]
- Arock, M.; Sotlar, K.; Akin, C.; Broesby-Olsen, S.; Hoermann, G.; Escribano, L.; Kristensen, T.K.; Kluin-Nelemans, H.C.; Hermine, O.; Dubreuil, P. KIT mutation analysis in mast cell neoplasms: Recommendations of the European Competence Network on Mastocytosis. Leukemia 2015, 29, 1223–1232. [Google Scholar] [CrossRef] [Green Version]
- Furitsu, T.; Tsujimura, T.; Tono, T.; Ikeda, H.; Kitayama, H.; Koshimizu, U.; Sugahara, H.; Butterfield, J.H.; Ashman, L.K.; Kanayama, Y. Identification of mutations in the coding sequence of the proto-oncogene c-kit in a human mast cell leukemia cell line causing ligand-independent activation of c-kit product. J. Clin. Investig. 1993, 92, 1736–1744. [Google Scholar] [CrossRef]
- de Melo Campos, P.; Machado-Neto, J.A.; Scopim-Ribeiro, R.; Visconte, V.; Tabarroki, A.; Duarte, A.S.; Barra, F.F.; Vassalo, J.; Rogers, H.J.; Lorand-Metze, I. Familial systemic mastocytosis with germline KIT K509I mutation is sensitive to treatment with imatinib, dasatinib and PKC412. Leuk. Res. 2014, 38, 1245–1251. [Google Scholar] [CrossRef] [Green Version]
- Lasho, T.; Finke, C.; Zblewski, D.; Hanson, C.A.; Ketterling, R.P.; Butterfield, J.H.; Tefferi, A.; Pardanani, A. Concurrent activating KIT mutations in systemic mastocytosis. Br. J. Haematol. 2016, 173, 153–156. [Google Scholar] [CrossRef]
- Alegría-Torres, J.A.; Baccarelli, A.; Bollati, V. Epigenetics and lifestyle. Epigenomics 2011, 3, 267–277. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Kanherkar, R.R.; Bhatia-Dey, N.; Csoka, A.B. Epigenetics across the human lifespan. Front. Cell Dev. Biol. 2014, 2, 49. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Barros, S.P.; Offenbacher, S. Epigenetics: Connecting environment and genotype to phenotype and disease. J. Dent. Res. 2009, 88, 400–408. [Google Scholar] [CrossRef]
- Simo-Riudalbas, L.; Esteller, M. Cancer genomics identifies disrupted epigenetic genes. Hum. Genet. 2014, 133, 713–725. [Google Scholar] [CrossRef] [PubMed]
- Martinelli, G.; Mancini, M.; De Benedittis, C.; Rondoni, M.; Papayannidis, C.; Manfrini, M.; Meggendorfer, M.; Calogero, R.; Guadagnuolo, V.; Fontana, M. SETD2 and histone H3 lysine 36 methylation deficiency in advanced systemic mastocytosis. Leukemia 2018, 32, 139–148. [Google Scholar] [CrossRef]
- Zhu, X.; He, F.; Zeng, H.; Ling, S.; Chen, A.; Wang, Y.; Yan, X.; Wei, W.; Pang, Y.; Cheng, H. Identification of functional cooperative mutations of SETD2 in human acute leukemia. Nat. Genet. 2014, 46, 287–293. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Melo, F.R.; Vita, F.; Berent-Maoz, B.; Levi-Schaffer, F.; Zabucchi, G.; Pejler, G. Proteolytic histone modification by mast cell tryptase, a serglycin proteoglycan-dependent secretory granule protease. J. Biol. Chem. 2014, 289, 7682–7690. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Melo, F.R.; Wallerman, O.; Paivandy, A.; Calounova, G.; Gustafson, A.-M.; Sabari, B.R.; Zabucchi, G.; Allis, C.D.; Pejler, G. Tryptase-catalyzed core histone truncation: A novel epigenetic regulatory mechanism in mast cells. J. Allergy Clin. Immunol. 2017, 140, 474–485. [Google Scholar] [CrossRef] [Green Version]
- Krajewski, D.; Kaczenski, E.; Rovatti, J.; Polukort, S.; Thompson, C.; Dollard, C.; Ser-Dolansky, J.; Schneider, S.S.; Kinney, S.R.; Mathias, C.B. Epigenetic regulation via altered histone acetylation results in suppression of mast cell function and mast cell-mediated food allergic responses. Front. Immunol. 2018, 9, 2414. [Google Scholar] [CrossRef] [PubMed]
- Ungerstedt, J.S. Epigenetic modifiers in myeloid malignancies: The role of histone deacetylase inhibitors. Int. J. Mol. Sci. 2018, 19, 3091. [Google Scholar] [CrossRef] [Green Version]
- Lyberg, K.; Ali, H.A.; Grootens, J.; Kjellander, M.; Tirfing, M.; Arock, M.; Hägglund, H.; Nilsson, G.; Ungerstedt, J. Histone deacetylase inhibitor SAHA mediates mast cell death and epigenetic silencing of constitutively active D816V KIT in systemic mastocytosis. Oncotarget 2017, 8, 9647. [Google Scholar] [CrossRef] [Green Version]
- Pardanani, A.; Lasho, T.; Elala, Y.; Wassie, E.; Finke, C.; Reichard, K.K.; Chen, D.; Hanson, C.A.; Ketterling, R.P.; Tefferi, A. Next-generation sequencing in systemic mastocytosis: Derivation of a mutation-augmented clinical prognostic model for survival. Am. J. Hematol. 2016, 91, 888–893. [Google Scholar] [CrossRef]
- Schwaab, J.; Schnittger, S.; Sotlar, K.; Walz, C.; Fabarius, A.; Pfirrmann, M.; Kohlmann, A.; Grossmann, V.; Meggendorfer, M.; Horny, H.-P. Comprehensive mutational profiling in advanced systemic mastocytosis. Blood 2013, 122, 2460–2466. [Google Scholar] [CrossRef] [Green Version]
- Tefferi, A.; Levine, R.; Lim, K.; Abdel-Wahab, O.; Lasho, T.; Patel, J.; Finke, C.; Mullally, A.; Li, C.; Pardanani, A. Frequent TET2 mutations in systemic mastocytosis: Clinical, KITD816V and FIP1L1-PDGFRA correlates. Leukemia 2009, 23, 900–904. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Traina, F.; Visconte, V.; Jankowska, A.M.; Makishima, H.; O’Keefe, C.L.; Elson, P.; Han, Y.; Hsieh, F.H.; Sekeres, M.A.; Mali, R.S. Single nucleotide polymorphism array lesions, TET2, DNMT3A, ASXL1 and CBL mutations are present in systemic mastocytosis. PLoS ONE 2012, 7, e43090. [Google Scholar] [CrossRef] [PubMed]
- Damaj, G.; Joris, M.; Chandesris, O.; Hanssens, K.; Soucie, E.; Canioni, D.; Kolb, B.; Durieu, I.; Gyan, E.; Livideanu, C. 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. [Google Scholar] [CrossRef]
- Fong, C.Y.; Morison, J.; Dawson, M.A. Epigenetics in the hematologic malignancies. Haematologica 2014, 99, 1772–1783. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Blecua, P.; Martinez-Verbo, L.; Esteller, M. The DNA methylation landscape of hematological malignancies: An update. Mol. Oncol. 2020, 14, 1616. [Google Scholar] [CrossRef]
- Pastor, W.A.; Aravind, L.; Rao, A. TETonic shift: Biological roles of TET proteins in DNA demethylation and transcription. Nat. Rev. Mol. Cell Biol. 2013, 14, 341–356. [Google Scholar] [CrossRef] [Green Version]
- Theoharides, T.C.; Tsilioni, I.; Ren, H. Recent advances in our understanding of mast cell activation—Or should it be mast cell mediator disorders? Expert Rev. Clin. Immunol. 2019, 15, 639–656. [Google Scholar] [CrossRef] [PubMed]
- De Vita, S.; Schneider, R.K.; Garcia, M.; Wood, J.; Gavillet, M.; Ebert, B.L.; Gerbaulet, A.; Roers, A.; Levine, R.L.; Mullally, A. Loss of function of TET2 cooperates with constitutively active KIT in murine and human models of mastocytosis. PLoS ONE 2014, 9, e96209. [Google Scholar] [CrossRef] [PubMed]
- Montagner, S.; Leoni, C.; Emming, S.; Della Chiara, G.; Balestrieri, C.; Barozzi, I.; Piccolo, V.; Togher, S.; Ko, M.; Rao, A. TET2 regulates mast cell differentiation and proliferation through catalytic and non-catalytic activities. Cell Rep. 2016, 15, 1566–1579. [Google Scholar] [CrossRef] [Green Version]
- Challen, G.A.; Sun, D.; Jeong, M.; Luo, M.; Jelinek, J.; Berg, J.S.; Bock, C.; Vasanthakumar, A.; Gu, H.; Xi, Y. Dnmt3a is essential for hematopoietic stem cell differentiation. Nat. Genet. 2012, 44, 23–31. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Jeong, M.; Park, H.J.; Celik, H.; Ostrander, E.L.; Reyes, J.M.; Guzman, A.; Rodriguez, B.; Lei, Y.; Lee, Y.; Ding, L. Loss of Dnmt3a immortalizes hematopoietic stem cells in vivo. Cell Rep. 2018, 23, 1–10. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Leoni, C.; Montagner, S.; Rinaldi, A.; Bertoni, F.; Polletti, S.; Balestrieri, C.; Monticelli, S. Dnmt3a restrains mast cell inflammatory responses. Proc. Natl. Acad. Sci. USA 2017, 114, E1490–E1499. [Google Scholar] [CrossRef] [Green Version]
- Leoni, C.; Montagner, S.; Deho’, L.; D’Antuono, R.; De Matteis, G.; Marzano, A.V.; Merante, S.; Orlandi, E.M.; Zanotti, R.; Monticelli, S. Reduced DNA methylation and hydroxymethylation in patients with systemic mastocytosis. Eur. J. Haematol. 2015, 95, 566–575. [Google Scholar] [CrossRef]
- Liz, J.; Esteller, M. lncRNAs and microRNAs with a role in cancer development. Biochim. Biophys. Acta Bioenerg. 2016, 1859, 169–176. [Google Scholar] [CrossRef] [Green Version]
- Shefler, I.; Salamon, P.; Mekori, Y.A. MicroRNA involvement in allergic and non-allergic mast cell activation. Int. J. Mol. Sci. 2019, 20, 2145. [Google Scholar] [CrossRef] [Green Version]
- Monticelli, S.; Ansel, K.M.; Xiao, C.; Socci, N.D.; Krichevsky, A.M.; Thai, T.-H.; Rajewsky, N.; Marks, D.S.; Sander, C.; Rajewsky, K. MicroRNA profiling of the murine hematopoietic system. Genome Biol. 2005, 6, R71. [Google Scholar] [CrossRef] [Green Version]
- 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. [Google Scholar] [CrossRef]
- 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. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Ekström, K.; Valadi, H.; Sjöstrand, M.; Malmhäll, C.; Bossios, A.; Eldh, M.; Lötvall, J. Characterization of mRNA and microRNA in human mast cell-derived exosomes and their transfer to other mast cells and blood CD34 progenitor cells. J. Extracell. Vesicles 2012, 1, 18389. [Google Scholar] [CrossRef] [PubMed]
- Shahlaee, A.H.; Brandal, S.; Lee, Y.-N.; Jie, C.; Takemoto, C.M. Distinct and shared transcriptomes are regulated by microphthalmia-associated transcription factor isoforms in mast cells. J. Immunol. 2007, 178, 378–388. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Tsujimura, T.; Morii, E.; Nozaki, M.; Hashimoto, K.; Moriyama, Y.; Takebayashi, K.; Kondo, T.; Kanakura, Y.; Kitamura, Y. Involvement of transcription factor encoded by the mi locus in the expression of c-kit receptor tyrosine kinase in cultured mast cells of mice. Blood 1996, 88, 1225–1233. [Google Scholar] [CrossRef] [Green Version]
- Lee, Y.-N.; Brandal, S.; Noel, P.; Wentzel, E.; Mendell, J.T.; McDevitt, M.A.; Kapur, R.; Carter, M.; Metcalfe, D.D.; Takemoto, C.M. KIT signaling regulates MITF expression through miRNAs in normal and malignant mast cell proliferation. Blood J. Am. Soc. Hematol. 2011, 117, 3629–3640. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Garzon, R.; Liu, S.; Fabbri, M.; Liu, Z.; Heaphy, C.E.; Callegari, E.; Schwind, S.; Pang, J.; Yu, J.; Muthusamy, N. MicroRNA-29b induces global DNA hypomethylation and tumor suppressor gene reexpression in acute myeloid leukemia by targeting directly DNMT3A and 3B and indirectly DNMT1. Blood J. Am. Soc. Hematol. 2009, 113, 6411–6418. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Wang, Q.; Zhao, D.-Y.; Xu, H.; Zhou, H.; Yang, Q.-Y.; Liu, F.; Zhou, G.-P. Down-regulation of microRNA-223 promotes degranulation via the PI3K/Akt pathway by targeting IGF-1R in mast cells. PLoS ONE 2015, 10, e0123575. [Google Scholar] [CrossRef] [PubMed]
- Leone, G.; D’Alo, F.; Zardo, G.; Voso, M.T.; Nervi, C. Epigenetic treatment of myelodysplastic syndromes and acute myeloid leukemias. Curr. Med. Chem. 2008, 15, 1274–1287. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Gnyszka, A.; Jastrzebski, Z.; Flis, S. DNA methyltransferase inhibitors and their emerging role in epigenetic therapy of cancer. Anticancer Res. 2013, 33, 2989–2996. [Google Scholar]
- Ghanim, V.; Herrmann, H.; Heller, G.; Peter, B.; Hadzijusufovic, E.; Blatt, K.; Schuch, K.; Cerny-Reiterer, S.; Mirkina, I.; Karlic, H. 5-azacytidine and decitabine exert proapoptotic effects on neoplastic mast cells: Role of FAS-demethylation and FAS re-expression, and synergism with FAS-ligand. Blood J. Am. Soc. Hematol. 2012, 119, 4242–4252. [Google Scholar] [CrossRef] [Green Version]
- Zuber, J.; Shi, J.; Wang, E.; Rappaport, A.R.; Herrmann, H.; Sison, E.A.; Magoon, D.; Qi, J.; Blatt, K.; Wunderlich, M. RNAi screen identifies Brd4 as a therapeutic target in acute myeloid leukaemia. Nature 2011, 478, 524–528. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Wedeh, G.; Cerny-Reiterer, S.; Eisenwort, G.; Herrmann, H.; Blatt, K.; Hadzijusufovic, E.; Sadovnik, I.; Müllauer, L.; Schwaab, J.; Hoffmann, T. Identification of bromodomain-containing protein-4 as a novel marker and epigenetic target in mast cell leukemia. Leukemia 2015, 29, 2230–2237. [Google Scholar] [CrossRef] [PubMed] [Green Version]
Gene (H. sapiens) | Gene ID | Protein Product | Protein Function and Biological Importance | Expression | Location, Exon Count |
---|---|---|---|---|---|
TET2 | 54790 | TET methylcytosine dioxygenase 2 | catalyzes the conversion of methylcytosine to 5-hydroxymethylcytosine. The encoded protein is involved in myelopoiesis, and defects in this gene have been associated with several myeloproliferative disorders | ubiquitous expression in bone marrow, appendix and 25 other tissues | 4q24 15 |
ASXL1 | 171023 | ASXL transcriptional regulator 1 | ligand-dependent co-activator for retinoic acid receptor in cooperation with nuclear receptor coactivator 1. Mutations in this gene are associated with MDS and CMML | ubiquitous expression in testis, lymph node and 25 other tissues | 20q11.21 18 |
DNMT3A | 1788 | DNA methyltransferase 3 alpha | de novo methylation, localizes to the cytoplasm and nucleus and its expression is developmentally regulated | ubiquitous expression in placenta, ovary and 25 other tissues | 2p23.3 34 |
IDH2 | 3418 | isocitrate dehydrogenase (NADP(+)) 2 | catalyzes the oxidative decarboxylation of isocitrate to 2-oxoglutarate; localized in mitochondria, plays a role in intermediary metabolism and energy production. This protein may tightly associate or interact with the pyruvate dehydrogenase complex | ubiquitous expression in heart, kidney and 24 other tissues | 15q26.1 12 |
EZH2 | 2146 | enhancer of zeste 2 polycomb repressive complex 2 subunit | involved in maintaining the transcriptional repressive state of genes over successive cell generations | broad expression in bone marrow, testis and 14 other tissues | 7q36.1 25 |
Genes with No. of Mutations/No. of Patients (%) | Samples; Molecular Screening | Ref. | |||
---|---|---|---|---|---|
All | ISM | ASM | SM-AHN | ||
TET2 12/42 (29) | TET2 2/13 (15) | TET2 2/5 (40) | BM; bidirectional sequences 1 | [35] | |
TET2 44/150 (29) | TET2 1/15 (7) | BM and PB; direct genomic sequences 2 | [36] | ||
ASXL1 25/150 (17) | ASXL1 1/15 (7) | ||||
DNMT3A 9/150 (6) | DNMT3A 2/15 (13) | ||||
EZH2 0 | EZH2 0 | ||||
IDH1/2 0 | IDH1/2 0 | ||||
TET2 15/39 (38) | BM and PB; NGS, 18 genes 3 | [34] | |||
ASXL1 8/39 (21) | |||||
EZH2 2/39 (5) | |||||
TET2 5/19 (26) | TET2 1/6 (2) | TET2 4/13 (31) | BM; NGS, 22 genes | [17] | |
ASXL1 5/19 (26) | ASXL1 1/6 (2) | ASXL1 4/13 (31) | |||
DNMT3A 2/19 (10) | DNMT3A 0 | DNMT3A 2/13 (15) | |||
TET2 44/150 (29) | TET2 3/44 (7) | TET2 5/25 (20) | TET2 36/80 (45) | BM; NGS, 27 genes 4 | [33] |
ASXL1 25/150 (17) | ASXL1 0 | ASXL1 4/25 (16) | ASXL1 21/80 (26) | ||
DNMT3A 9/150 (6) | DNMT3A 2/44 (5) | DNMT3A 0 | DNMT3A 7/80 (9) | ||
EZH2 3/150 (2) | EZH2 0 | EZH2 1/25 (4) | EZH2 2/80 (3) | ||
IDH1/2 4/150 (3) | IDH1/2 0 | IDH1/2 1/25 (4) | IDH1/2 3/80 (4) |
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Reszka, E.; Jabłońska, E.; Wieczorek, E.; Valent, P.; Arock, M.; Nilsson, G.; Nedoszytko, B.; Niedoszytko, M. Epigenetic Changes in Neoplastic Mast Cells and Potential Impact in Mastocytosis. Int. J. Mol. Sci. 2021, 22, 2964. https://doi.org/10.3390/ijms22062964
Reszka E, Jabłońska E, Wieczorek E, Valent P, Arock M, Nilsson G, Nedoszytko B, Niedoszytko M. Epigenetic Changes in Neoplastic Mast Cells and Potential Impact in Mastocytosis. International Journal of Molecular Sciences. 2021; 22(6):2964. https://doi.org/10.3390/ijms22062964
Chicago/Turabian StyleReszka, Edyta, Ewa Jabłońska, Edyta Wieczorek, Peter Valent, Michel Arock, Gunnar Nilsson, Bogusław Nedoszytko, and Marek Niedoszytko. 2021. "Epigenetic Changes in Neoplastic Mast Cells and Potential Impact in Mastocytosis" International Journal of Molecular Sciences 22, no. 6: 2964. https://doi.org/10.3390/ijms22062964