{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,3]],"date-time":"2026-04-03T04:46:55Z","timestamp":1775191615606,"version":"3.50.1"},"reference-count":184,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2021,8,18]],"date-time":"2021-08-18T00:00:00Z","timestamp":1629244800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100007353","name":"Fondation J\u00e9r\u00f4me Lejeune","doi-asserted-by":"publisher","award":["JLF #1902"],"award-info":[{"award-number":["JLF #1902"]}],"id":[{"id":"10.13039\/100007353","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Children with Down syndrome (DS) are particularly prone to haematopoietic disorders. Paediatric myeloid malignancies in DS occur at an unusually high frequency and generally follow a well-defined stepwise clinical evolution. First, the acquisition of mutations in the GATA1 transcription factor gives rise to a transient myeloproliferative disorder (TMD) in DS newborns. While this condition spontaneously resolves in most cases, some clones can acquire additional mutations, which trigger myeloid leukaemia of Down syndrome (ML-DS). These secondary mutations are predominantly found in chromatin and epigenetic regulators\u2014such as cohesin, CTCF or EZH2\u2014and in signalling mediators of the JAK\/STAT and RAS pathways. Most of them are also found in non-DS myeloid malignancies, albeit at extremely different frequencies. Intriguingly, mutations in proteins involved in the three-dimensional organization of the genome are found in nearly 50% of cases. How the resulting mutant proteins cooperate with trisomy 21 and mutant GATA1 to promote ML-DS is not fully understood. In this review, we summarize and discuss current knowledge about the sequential acquisition of genomic alterations in ML-DS.<\/jats:p>","DOI":"10.3390\/cancers13164144","type":"journal-article","created":{"date-parts":[[2021,8,18]],"date-time":"2021-08-18T01:54:06Z","timestamp":1629251646000},"page":"4144","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["The Mutational Landscape of Myeloid Leukaemia in Down Syndrome"],"prefix":"10.3390","volume":"13","author":[{"given":"Carini Picardi Morais","family":"de Castro","sequence":"first","affiliation":[{"name":"Josep Carreras Leukaemia Research Institute (IJC), Campus Can Ruti, 08916 Badalona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria","family":"Cadefau","sequence":"additional","affiliation":[{"name":"Josep Carreras Leukaemia Research Institute (IJC), Campus Can Ruti, 08916 Badalona, Spain"},{"name":"Germans Trias i Pujol Research Institute (IGTP), Campus Can Ruti, 08916 Badalona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sergi","family":"Cuartero","sequence":"additional","affiliation":[{"name":"Josep Carreras Leukaemia Research Institute (IJC), Campus Can Ruti, 08916 Badalona, Spain"},{"name":"Germans Trias i Pujol Research Institute (IGTP), Campus Can Ruti, 08916 Badalona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,8,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Roper, R.J., and Reeves, R.H. (2006). Understanding the Basis for Down Syndrome Phenotypes. PLoS Genet., 2.","DOI":"10.1371\/journal.pgen.0020050"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1016\/0039-6257(90)90116-D","article-title":"Down syndrome","volume":"34","author":"Catalano","year":"1990","journal-title":"Surv. Ophthalmol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1151","DOI":"10.1038\/gim.2016.23","article-title":"Low risk of solid tumors in persons with Down syndrome","volume":"18","author":"Hasle","year":"2016","journal-title":"Genet. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1016\/S0140-6736(99)05264-2","article-title":"Risks of leukaemia and solid tumours in individuals with Down\u2019s syndrome","volume":"355","author":"Hasle","year":"2000","journal-title":"Lancet"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1111\/j.1365-2788.2006.00862.x","article-title":"The profile and incidence of cancer in Down syndrome","volume":"51","author":"Sullivan","year":"2007","journal-title":"J. Intellect. Disabil. Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1111\/bjh.13096","article-title":"Haematopoietic development and leukaemia in Down syndrome","volume":"167","author":"Roberts","year":"2014","journal-title":"Br. J. Haematol."},{"key":"ref_7","first-page":"608","article-title":"Distinctive demography, biology, and outcome of acute myeloid leukemia and myelodysplastic syndrome in children with Down syndrome: Children\u2019s Cancer Group Studies 2861 and 2891","volume":"91","author":"Lange","year":"1998","journal-title":"Blood"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2619","DOI":"10.1182\/blood-2008-11-163501","article-title":"Insights into the manifestations, outcomes, and mechanisms of leukemogenesis in down syndrome","volume":"113","author":"Malinge","year":"2009","journal-title":"Blood"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1293","DOI":"10.1038\/ng.2759","article-title":"The landscape of somatic mutations in Down syndrome-related myeloid disorders","volume":"45","author":"Yoshida","year":"2013","journal-title":"Nat. Genet."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"554","DOI":"10.1182\/blood-2013-03-491936","article-title":"Exome sequencing identifies putative drivers of progression of transient myeloproliferative disorder to AMKL in infants with Down syndrome","volume":"122","author":"Nikolaev","year":"2013","journal-title":"Blood"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1111\/j.1365-2141.2009.07789.x","article-title":"Acute megakaryoblastic leukaemia (AMKL) and transient myeloproliferative disorder (TMD) in Down syndrome: A multi-step model of myeloid leukaemogenesis","volume":"147","author":"Roy","year":"2009","journal-title":"Br. J. Haematol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"930","DOI":"10.1046\/j.1365-2141.2003.04229.x","article-title":"Transient leukaemia\u2014A benign form of leukaemia in newborn infants with trisomy 21","volume":"120","author":"Zipursky","year":"2003","journal-title":"Br. J. Haematol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"3908","DOI":"10.1182\/blood-2013-07-515148","article-title":"GATA1-mutant clones are frequent and often unsuspected in babies with Down syndrome: Identification of a population at risk of leukemia","volume":"122","author":"Roberts","year":"2013","journal-title":"Blood"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2991","DOI":"10.1182\/blood-2007-10-118810","article-title":"Treatment and prognostic impact of transient leukemia in neonates with Down syndrome","volume":"111","author":"Klusmann","year":"2008","journal-title":"Blood"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"610","DOI":"10.1111\/j.1365-2141.2008.07231.x","article-title":"Risk factors for early death in neonates with Down syndrome and transient leukaemia","volume":"142","author":"Muramatsu","year":"2008","journal-title":"Br. J. Haematol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2085","DOI":"10.1002\/ajmg.a.61748","article-title":"Complete blood count differences in a cohort of Down syndrome neonates with transient abnormal myelopoiesis screened for GATA1 pathogenic variants","volume":"182","year":"2020","journal-title":"Am. J. Med. Genet. Part A"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"4606","DOI":"10.1182\/blood-2005-06-2448","article-title":"A prospective study of the natural history of transient leukemia (TL) in neonates with Down syndrome (DS): Children\u2019s Oncology Group (COG) study POG-9481","volume":"107","author":"Massey","year":"2006","journal-title":"Blood"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1428","DOI":"10.1038\/sj.leu.2405060","article-title":"Myeloid leukemia in children 4 years or older with Down syndrome often lacks GATA1 mutation and cytogenetics and risk of relapse are more akin to sporadic AML","volume":"22","author":"Hasle","year":"2008","journal-title":"Leukemia"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"3304","DOI":"10.1182\/blood-2017-01-764324","article-title":"Improved outcomes for myeloid leukemia of Down syndrome: A report from the children\u2019s oncology group AAML0431 trial","volume":"129","author":"Taub","year":"2017","journal-title":"Blood"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"3314","DOI":"10.1182\/blood-2017-01-765057","article-title":"Therapy reduction in patients with Down syndrome and myeloid leukemia: The international ML-DS 2006 trial","volume":"129","author":"Uffmann","year":"2017","journal-title":"Blood"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1016\/j.ccell.2019.06.007","article-title":"Mechanisms of Progression of Myeloid Preleukemia to Transformed Myeloid Leukemia in Children with Down Syndrome","volume":"36","author":"Labuhn","year":"2019","journal-title":"Cancer Cell"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"4503","DOI":"10.1182\/blood-2008-05-157859","article-title":"Trisomy 21 enhances human fetal erythro-megakaryocytic development","volume":"112","author":"Chou","year":"2008","journal-title":"Blood"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"4507","DOI":"10.1182\/blood-2008-04-152967","article-title":"Abnormalities in the myeloid progenitor compartment in Down syndrome fetal liver precede acquisition of GATA1 mutations","volume":"112","author":"Roy","year":"2008","journal-title":"Blood"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1228","DOI":"10.1016\/j.celrep.2016.04.031","article-title":"Systematic Cellular Disease Models Reveal Synergistic Interaction of Trisomy 21 and GATA1 Mutations in Hematopoietic Abnormalities","volume":"15","author":"Banno","year":"2016","journal-title":"Cell Rep."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"17567","DOI":"10.1073\/pnas.1215468109","article-title":"Altered hematopoiesis in trisomy 21 as revealed through in vitro differentiation of isogenic human pluripotent cells","volume":"109","author":"MacLean","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"17579","DOI":"10.1073\/pnas.1211405109","article-title":"Perturbation of fetal liver hematopoietic stem and progenitor cell development by trisomy 21","volume":"109","author":"Roy","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Wagenblast, E., Ara\u00fajo, J., Gan, O.I., Cutting, S.K., Murison, A., Krivdova, G., Azkanaz, M., McLeod, J.L., Smith, S.A., and Gratton, B.A. (2021). Mapping the cellular origin and early evolution of leukemia in Down syndrome. Science, 373.","DOI":"10.1126\/science.abf6202"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"3337","DOI":"10.1182\/blood-2008-08-174813","article-title":"ETS2 and ERG promote megakaryopoiesis and synergize with alterations in GATA-1 to immortalize hematopoietic progenitor cells","volume":"113","author":"Stankiewicz","year":"2009","journal-title":"Blood"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"3966","DOI":"10.1182\/blood-2009-09-242107","article-title":"Trisomy of Erg is required for myeloproliferation in a mouse model of Down syndrome","volume":"115","author":"Ng","year":"2010","journal-title":"Blood"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"7596","DOI":"10.1158\/0008-5472.CAN-05-0147","article-title":"The proto-oncogene ERG in megakaryoblastic leukemias","volume":"65","author":"Rainis","year":"2005","journal-title":"Cancer Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"948","DOI":"10.1172\/JCI60455","article-title":"Increased dosage of the chromosome 21 ortholog Dyrk1a promotes megakaryoblastic leukemia in a murine model of down syndrome","volume":"122","author":"Malinge","year":"2012","journal-title":"J. Clin. Investig."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"e33","DOI":"10.1182\/blood-2013-05-503011","article-title":"Development of acute megakaryoblastic leukemia in Down syndrome is associated with sequential epigenetic changes","volume":"122","author":"Malinge","year":"2013","journal-title":"Blood"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"821","DOI":"10.1038\/s41467-021-21064-z","article-title":"The genome-wide impact of trisomy 21 on DNA methylation and its implications for hematopoiesis","volume":"12","author":"Muskens","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_34","unstructured":"Davisson, M.T., Schmidt, C., and Akeson, E.C. (2021, June 28). Segmental Trisomy of Murine Chromosome 16: A New Model System for Studying Down Syndrome, Available online: https:\/\/pubmed.ncbi.nlm.nih.gov\/2147289\/."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2083","DOI":"10.1089\/ars.2010.3798","article-title":"Defective hematopoietic stem cell and lymphoid progenitor development in the ts65dn mouse model of down syndrome: Potential role of oxidative stress","volume":"15","author":"Lorenzo","year":"2011","journal-title":"Antioxid. Redox Signal."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Ko, L.J., and Engel, J.D. (1993). DNA-binding specificities of the GATA transcription factor family. Mol. Cell. Biol., 13.","DOI":"10.1128\/MCB.13.7.4011"},{"key":"ref_37","first-page":"3999","article-title":"DNA-binding specificity of GATA family transcription factors","volume":"13","author":"Merika","year":"1993","journal-title":"Mol. Cell. Biol."},{"key":"ref_38","first-page":"99","article-title":"GATA transcription factors: Key regulators of hematopoiesis","volume":"23","author":"Weiss","year":"1995","journal-title":"Exp. Hematol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"668","DOI":"10.1073\/pnas.87.2.668","article-title":"The major human erythroid DNA-binding protein (GF-1): Primary sequence and localization of the gene to the X chromosome","volume":"87","author":"Zon","year":"1990","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1071","DOI":"10.1182\/blood.V82.4.1071.1071","article-title":"Dynamics of GATA transcription factor expression during erythroid differentiation","volume":"82","author":"Leonard","year":"1993","journal-title":"Blood"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"12355","DOI":"10.1073\/pnas.93.22.12355","article-title":"Arrested development of embryonic red cell precursors in mouse embryos lacking transcription factor GATA-1","volume":"93","author":"Fujiwara","year":"1996","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"3234","DOI":"10.1182\/blood.V81.12.3234.3234","article-title":"Expression of mRNA for the GATA-binding proteins in human eosinophils and basophils: Potential role in gene transcription","volume":"81","author":"Zon","year":"1993","journal-title":"Blood"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"444","DOI":"10.1038\/344444a0","article-title":"Expression of an erythroid transcription factor in megakaryocytic and mast cell lineages","volume":"344","author":"Martin","year":"1990","journal-title":"Nature"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1038\/344447a0","article-title":"Megakaryocytic and erythrocytic lineages share specific transcription factors","volume":"344","author":"Romeo","year":"1990","journal-title":"Nature"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"466","DOI":"10.1038\/362466a0","article-title":"Erythroid transcription factor GATA-1 is abundantly transcribed in mouse testis","volume":"362","author":"Ito","year":"1993","journal-title":"Nature"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1759","DOI":"10.1242\/dev.120.7.1759","article-title":"Developmental stage- and spermatogenic cycle-specific expression of transcription factor GATA-1 in mouse Sertoli cells","volume":"120","author":"Yomogida","year":"1994","journal-title":"Development"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"11598","DOI":"10.1073\/pnas.92.25.11598","article-title":"Alternative translation initiation site usage results in two functionally distinct forms of the GATA-1 transcription factor","volume":"92","author":"Calligaris","year":"1995","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"3965","DOI":"10.1093\/emboj\/16.13.3965","article-title":"A lineage-selective knockout establishes the critical role of transcription factor GATA-1 in megakaryocyte growth and platelet development","volume":"16","author":"Shivdasani","year":"1997","journal-title":"EMBO J."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1038\/ng955","article-title":"Acquired mutations in GATA1 in the megakaryoblastic leukemia of Down syndrome","volume":"32","author":"Wechsler","year":"2002","journal-title":"Nat. Genet."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"575","DOI":"10.3324\/haematol.2014.112714","article-title":"Global transcriptome and chromatin occupancy analysis reveal the short isoform of GATA1 is deficient for erythroid specification and gene expression","volume":"100","author":"Chlon","year":"2015","journal-title":"Haematologica"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1619","DOI":"10.1182\/blood.2019001234","article-title":"Chromatin occupancy and epigenetic analysis reveal new insights into the function of the GATA1 N terminus in erythropoiesis","volume":"134","author":"Ling","year":"2019","journal-title":"Blood"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"993","DOI":"10.1172\/JCI75714","article-title":"Pluripotent stem cells reveal erythroid-specific activities of the GATA1 N-terminus","volume":"125","author":"VanDorn","year":"2015","journal-title":"J. Clin. Investig."},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Matsuo, S., Nishinaka-Arai, Y., Kazuki, Y., Oshimura, M., Nakahata, T., Niwa, A., and Saito, M.K. (2021). Pluripotent stem cell model of early hematopoiesis in down syndrome reveals quantitative effects of short-form GATA1 protein on lineage specification. PLoS ONE, 16.","DOI":"10.1371\/journal.pone.0247595"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1106","DOI":"10.3324\/haematol.2019.244541","article-title":"Oncogenic Gata1 causes stage-specific megakaryocyte differentiation delay","volume":"106","author":"Juban","year":"2021","journal-title":"Haematologica"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1038\/ng.3772","article-title":"Pediatric non-Down syndrome acute megakaryoblastic leukemia is characterized by distinct genomic subsets with varying outcomes","volume":"49","author":"Branstetter","year":"2017","journal-title":"Nat. Genet."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"526","DOI":"10.1038\/s41586-018-0623-z","article-title":"Functional genomic landscape of acute myeloid leukaemia","volume":"562","author":"Tyner","year":"2018","journal-title":"Nature"},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Cancer Genome Atlas Research Network (2013). Genomic and Epigenomic Landscapes of Adult De Novo Acute Myeloid Leukemia. N. Engl. J. Med., 368, 2059\u20132074.","DOI":"10.1056\/NEJMoa1301689"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"552","DOI":"10.1111\/j.1365-2141.2007.06971.x","article-title":"Acute megakaryoblastic leukaemia (AMKL) in children: A comparison of AMKL with and without Down syndrome","volume":"140","author":"Hama","year":"2008","journal-title":"Br. J. Haematol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"244","DOI":"10.1002\/cytob.21198","article-title":"Acute megakaryoblastic leukemia associated with trisomy 21 demonstrates a distinct immunophenotype","volume":"88","author":"Wang","year":"2015","journal-title":"Cytom. Part B Clin. Cytom."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"a005975","DOI":"10.1101\/mcs.a005975","article-title":"Clinical impact of genomic characterization of 15 patients with acute megakaryoblastic leukemia\u2013related malignancies","volume":"7","author":"Lalonde","year":"2021","journal-title":"Mol. Case Stud."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"683","DOI":"10.1016\/j.ccr.2012.10.007","article-title":"An Inv(16)(p13.3q24.3)-Encoded CBFA2T3-GLIS2 Fusion Protein Defines an Aggressive Subtype of Pediatric Acute Megakaryoblastic Leukemia","volume":"22","author":"Gruber","year":"2012","journal-title":"Cancer Cell"},{"key":"ref_62","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_63","doi-asserted-by":"crossref","first-page":"1049","DOI":"10.1182\/blood-2018-10-844621","article-title":"Genetics of MDS","volume":"133","author":"Ogawa","year":"2019","journal-title":"Blood"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"867","DOI":"10.3389\/fonc.2019.00867","article-title":"Towards a Better Understanding of Cohesin Mutations in AML","volume":"9","author":"Cuartero","year":"2019","journal-title":"Front. Oncol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1038\/nrc3743","article-title":"Cohesin in cancer: Chromosome segregation and beyond","volume":"14","author":"Losada","year":"2014","journal-title":"Nat. Rev. Cancer"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1790","DOI":"10.1182\/blood-2014-04-567057","article-title":"Genetic alterations of the cohesin complex genes in myeloid malignancies","volume":"124","author":"Thota","year":"2014","journal-title":"Blood"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"914","DOI":"10.1182\/blood-2013-07-518746","article-title":"Mutations in the cohesin complex in acute myeloid leukemia: Clinical and prognostic implications","volume":"123","author":"Thol","year":"2014","journal-title":"Blood"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"1232","DOI":"10.1038\/ng.2731","article-title":"Recurrent mutations in multiple components of the cohesin complex in myeloid neoplasms","volume":"45","author":"Kon","year":"2013","journal-title":"Nat. Genet."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"1819","DOI":"10.1084\/jem.20151317","article-title":"Dose-dependent role of the cohesin complex in normal and malignant hematopoiesis","volume":"212","author":"Viny","year":"2015","journal-title":"J. Exp. Med."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"1464","DOI":"10.1038\/ng.2799","article-title":"Recurrent inactivation of STAG2 in bladder cancer is not associated with aneuploidy","volume":"45","author":"Sagrera","year":"2013","journal-title":"Nat. Genet."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"1833","DOI":"10.1084\/jem.20151323","article-title":"Cohesin loss alters adult hematopoietic stem cell homeostasis, leading to myeloproliferative neoplasms","volume":"212","author":"Mullenders","year":"2015","journal-title":"J. Exp. Med."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"957","DOI":"10.1016\/j.cub.2010.04.018","article-title":"Systematic Reduction of Cohesin Differentially Affects Chromosome Segregation, Condensation, and DNA Repair","volume":"20","author":"Mert","year":"2010","journal-title":"Curr. Biol."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"663","DOI":"10.1038\/s41408-017-0022-y","article-title":"Prognostic impacts and dynamic changes of cohesin complex gene mutations in de novo acute myeloid leukemia","volume":"7","author":"Tsai","year":"2017","journal-title":"Blood Cancer J."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"682","DOI":"10.1016\/j.stem.2019.08.003","article-title":"Cohesin Members Stag1 and Stag2 Display Distinct Roles in Chromatin Accessibility and Topological Control of HSC Self-Renewal and Differentiation","volume":"25","author":"Viny","year":"2019","journal-title":"Cell Stem Cell"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"712","DOI":"10.1038\/leu.2016.240","article-title":"The cohesin subunit Rad21 is a negative regulator of hematopoietic self-renewal through epigenetic repression of Hoxa7 and Hoxa9","volume":"31","author":"Fisher","year":"2017","journal-title":"Leukemia"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"932","DOI":"10.1038\/s41590-018-0184-1","article-title":"Control of inducible gene expression links cohesin to hematopoietic progenitor self-renewal and differentiation","volume":"19","author":"Cuartero","year":"2018","journal-title":"Nat. Immunol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"2988","DOI":"10.1016\/j.celrep.2016.02.082","article-title":"Genome-wide RNAi Screen Identifies Cohesin Genes as Modifiers of Renewal and Differentiation in Human HSCs","volume":"14","author":"Galeev","year":"2016","journal-title":"Cell Rep."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"675","DOI":"10.1016\/j.stem.2015.09.017","article-title":"Leukemia-Associated Cohesin Mutants Dominantly Enforce Stem Cell Programs and Impair Human Hematopoietic Progenitor Differentiation","volume":"17","author":"Mazumdar","year":"2015","journal-title":"Cell Stem Cell"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"789","DOI":"10.1038\/s41576-018-0060-8","article-title":"Organizational principles of 3D genome architecture","volume":"19","author":"Rowley","year":"2018","journal-title":"Nat. Rev. Genet."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1146\/annurev-genom-083115-022339","article-title":"CTCF and Cohesin in Genome Folding and Transcriptional Gene Regulation","volume":"17","author":"Merkenschlager","year":"2016","journal-title":"Annu. Rev. Genom. Hum. Genet."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"2038","DOI":"10.1016\/j.celrep.2016.04.085","article-title":"Formation of Chromosomal Domains by Loop Extrusion","volume":"15","author":"Fudenberg","year":"2016","journal-title":"Cell Rep."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"504","DOI":"10.1101\/gr.184986.114","article-title":"Spatial enhancer clustering and regulation of enhancer-proximal genes by cohesin","volume":"25","author":"Seitan","year":"2015","journal-title":"Genome Res."},{"key":"ref_83","doi-asserted-by":"crossref","unstructured":"Thiecke, M.J., Wutz, G., Muhar, M., Tang, W., Bevan, S., Malysheva, V., Stocsits, R., Neumann, T., Zuber, J., and Fraser, P. (2020). Cohesin-Dependent and -Independent Mechanisms Mediate Chromosomal Contacts between Promoters and Enhancers. Cell Rep., 32.","DOI":"10.1101\/2020.02.10.941989"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1016\/j.cell.2017.09.026","article-title":"Cohesin Loss Eliminates All Loop Domains","volume":"171","author":"Rao","year":"2017","journal-title":"Cell"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"2066","DOI":"10.1101\/gr.161620.113","article-title":"Cohesin-based chromatin interactions enable regulated gene expression within preexisting architectural compartments","volume":"23","author":"Seitan","year":"2013","journal-title":"Genome Res."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"930","DOI":"10.1016\/j.cell.2017.05.004","article-title":"Targeted Degradation of CTCF Decouples Local Insulation of Chromosome Domains from Genomic Compartmentalization","volume":"169","author":"Nora","year":"2017","journal-title":"Cell"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"655","DOI":"10.1038\/s41588-020-0643-0","article-title":"CTCF is dispensable for immune cell transdifferentiation but facilitates an acute inflammatory response","volume":"52","author":"Stik","year":"2020","journal-title":"Nat. Genet."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1084\/jem.20181505","article-title":"Cohesin-mediated NF-\u03baB signaling limits hematopoietic stem cell self-renewal in aging and inflammation","volume":"216","author":"Chen","year":"2019","journal-title":"J. Exp. Med."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"607","DOI":"10.1038\/ncb3346","article-title":"Chronic interleukin-1 exposure drives haematopoietic stem cells towards precocious myeloid differentiation at the expense of self-renewal","volume":"18","author":"Pietras","year":"2016","journal-title":"Nat. Cell Biol."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"904","DOI":"10.1038\/nature07815","article-title":"IFN\u03b1 activates dormant haematopoietic stem cells in vivo","volume":"458","author":"Essers","year":"2009","journal-title":"Nature"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"793","DOI":"10.1038\/nature09135","article-title":"Quiescent haematopoietic stem cells are activated by IFN-\u03b3 in response to chronic infection","volume":"465","author":"Baldridge","year":"2010","journal-title":"Nature"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"836","DOI":"10.1158\/2159-8290.CD-19-0982","article-title":"Combined Cohesin\u2013RUNX1 deficiency synergistically perturbs chromatin looping and causes myelodysplastic syndromes","volume":"10","author":"Ochi","year":"2020","journal-title":"Cancer Discov."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"2195","DOI":"10.1182\/blood.2019001553","article-title":"Cohesin-dependent regulation of gene expression during differentiation is lost in cohesin-mutated myeloid malignancies","volume":"134","author":"Sasca","year":"2019","journal-title":"Blood"},{"key":"ref_94","doi-asserted-by":"crossref","unstructured":"Antony, J., Chin, C.V., and Horsfield, J.A. (2021). Cohesin Mutations in Cancer: Emerging Therapeutic Targets. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22136788"},{"key":"ref_95","doi-asserted-by":"crossref","unstructured":"Tothova, Z., Valton, A.L., Gorelov, R.A., Vallurupalli, M., Krill-Burger, J.M., Holmes, A., Landers, C.C., Haydu, J.E., Malolepsza, E., and Hartigan, C. (2021). Cohesin mutations alter DNA damage repair and chromatin structure and create therapeutic vulnerabilities in MDS\/AML. JCI Insight, 6.","DOI":"10.1172\/jci.insight.142149"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"1","DOI":"10.7554\/eLife.61405","article-title":"Cohesin mutations are synthetic lethal with stimulation of WNT signaling","volume":"9","author":"Chin","year":"2020","journal-title":"Elife"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"4100","DOI":"10.1038\/onc.2017.25","article-title":"CTCF genetic alterations in endometrial carcinoma are pro-tumorigenic","volume":"36","author":"Marshal","year":"2017","journal-title":"Oncogene"},{"key":"ref_98","doi-asserted-by":"crossref","unstructured":"Bailey, C.G., Gupta, S., Metierre, C., Amarasekera, P.M., O\u2019young, P., Kyaw, W., Laletin, T., Francis, H., Semaan1, C., and Singh, K.P. (2021). Somatic mutations in CTCF zinc fingers produce cellular phenotypes explained by structure-function relationships. bioRxiv.","DOI":"10.1101\/2021.01.08.425848"},{"key":"ref_99","doi-asserted-by":"crossref","unstructured":"Dolnik, A., Engelmann, J.C., Scharfenberger-Schmeer, M., Mauch, J., Kelkenberg-Schade, S., Haldemann, B., Fries, T., Kr\u00f6nke, J., K\u00fchn, M.W.M., and Paschka, P. (2012). Commonly altered genomic regions in acute myeloid leukemia are enriched for somatic mutations involved in chromatin remodeling and splicing. Blood, 120.","DOI":"10.1182\/blood-2011-12-401471"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"390","DOI":"10.1158\/0008-5472.CAN-16-1303","article-title":"Mutational landscape of pediatric acute lymphoblastic leukemia","volume":"77","author":"Ding","year":"2017","journal-title":"Cancer Res."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1038\/nature25795","article-title":"Pan-cancer genome and transcriptome analyses of 1,699 paediatric leukaemias and solid tumours","volume":"555","author":"Ma","year":"2018","journal-title":"Nature"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"1301","DOI":"10.3324\/haematol.2015.130179","article-title":"Targeted sequencing identifies associations between IL7R-JAK mutations and epigenetic modulators in T-cell acute lymphoblastic leukemia","volume":"100","author":"Vicente","year":"2015","journal-title":"Haematologica"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"1211","DOI":"10.1038\/ng.3909","article-title":"The genomic landscape of pediatric and young adult T-lineage acute lymphoblastic leukemia","volume":"49","author":"Liu","year":"2017","journal-title":"Nat. Genet."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"376","DOI":"10.1038\/nature11082","article-title":"Topological domains in mammalian genomes identified by analysis of chromatin interactions","volume":"485","author":"Dixon","year":"2012","journal-title":"Nature"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"1285","DOI":"10.1016\/j.cell.2013.02.029","article-title":"CTCF and cohesin: Linking gene regulatory elements with their targets","volume":"152","author":"Merkenschlager","year":"2013","journal-title":"Cell"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"1194","DOI":"10.1016\/j.cell.2009.06.001","article-title":"CTCF: Master Weaver of the Genome","volume":"137","author":"Phillips","year":"2009","journal-title":"Cell"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"1665","DOI":"10.1016\/j.cell.2014.11.021","article-title":"A 3D map of the human genome at kilobase resolution reveals principles of chromatin looping","volume":"159","author":"Rao","year":"2014","journal-title":"Cell"},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"28152","DOI":"10.1074\/jbc.M501481200","article-title":"CTCF regulates growth and erythroid differentiation of human myeloid leukemia cells","volume":"280","author":"Torrano","year":"2005","journal-title":"J. Biol. Chem."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"1327","DOI":"10.1182\/blood.2020005780","article-title":"Dynamic CTCF binding directly mediates interactions among cis-regulatory elements essential for hematopoiesis","volume":"137","author":"Qi","year":"2021","journal-title":"Blood"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"952","DOI":"10.1038\/ncb3573","article-title":"Tissue-specific CTCF-cohesin-mediated chromatin architecture delimits enhancer interactions and function in vivo","volume":"19","author":"Hanssen","year":"2017","journal-title":"Nat. Cell Biol."},{"key":"ref_111","doi-asserted-by":"crossref","unstructured":"Kim, T.G., Kim, S., Jung, S., Kim, M., Yang, B., Lee, M.G., and Kim, H.P. (2017). CCCTC-binding factor is essential to the maintenance and quiescence of hematopoietic stem cells in mice. Exp. Mol. Med., 49.","DOI":"10.1038\/emm.2017.124"},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1182\/blood.2019002326","article-title":"AML Displays Increased CTCF Occupancy Associated to Aberrant Gene Expression and Transcription Factor Binding","volume":"136","author":"Mujahed","year":"2020","journal-title":"Blood"},{"key":"ref_113","doi-asserted-by":"crossref","unstructured":"Aitken, S.J., Ibarra-Soria, X., Kentepozidou, E., Flicek, P., Feig, C., Marioni, J.C., and Odom, D.T. (2018). CTCF maintains regulatory homeostasis of cancer pathways. Genome Biol., 19.","DOI":"10.1186\/s13059-018-1484-3"},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"1020","DOI":"10.1016\/j.celrep.2014.04.004","article-title":"CTCF haploinsufficiency destabilizes DNA methylation and predisposes to cancer","volume":"7","author":"Kemp","year":"2014","journal-title":"Cell Rep."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"1603","DOI":"10.1002\/ijc.28184","article-title":"The cancer-testis antigen BORIS phenocopies the tumor suppressor CTCF in normal and neoplastic cells","volume":"133","author":"Tiffen","year":"2013","journal-title":"Int. J. Cancer"},{"key":"ref_116","doi-asserted-by":"crossref","unstructured":"Bailey, C.G., Metierre, C., Feng, Y., Baidya, K., Filippova, G.N., Loukinov, D.I., Lobanenkov, V.V., Semaan, C., and Rasko, J.E.J. (2018). CTCF expression is essential for somatic cell viability and protection against cancer. Int. J. Mol. Sci., 19.","DOI":"10.20944\/preprints201810.0451.v1"},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1023\/A:1024930404629","article-title":"CTCF gene mutations in invasive ductal breast cancer","volume":"80","author":"Aulmann","year":"2003","journal-title":"Breast Cancer Res. Treat."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1002\/humu.22463","article-title":"High Frequency Strand Slippage Mutations in CTCF in MSI-Positive Endometrial Cancers","volume":"35","author":"Zighelboim","year":"2014","journal-title":"Hum. Mutat."},{"key":"ref_119","doi-asserted-by":"crossref","unstructured":"Walker, C.J., Miranda, M.A., O\u2019Hern, M.J., McElroy, J.P., Coombes, K.R., Bundschuh, R., Cohn, D.E., Mutch, D.G., and Goodfellow, P.J. (2015). Patterns of CTCF and ZFHX3 mutation and associated outcomes in endometrial cancer. J. Natl. Cancer Inst., 107.","DOI":"10.1093\/jnci\/djv249"},{"key":"ref_120","doi-asserted-by":"crossref","unstructured":"Zhou, X.L., Werelius, B., and Lindblom, A. (2004). A screen for germline mutations in the gene encoding CCCTC-binding factor (CTCF) in familial non-BRCA1\/BRCA2 breast cancer. Breast Cancer Res., 6.","DOI":"10.1186\/bcr774"},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"607","DOI":"10.1016\/j.jsps.2020.03.013","article-title":"Association of mutation and low expression of the CTCF gene with breast cancer progression","volume":"28","author":"Akhtar","year":"2020","journal-title":"Saudi Pharm. J."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1038\/nature12912","article-title":"Discovery and saturation analysis of cancer genes across 21 tumour types","volume":"505","author":"Lawrence","year":"2014","journal-title":"Nature"},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1016\/j.cell.2017.08.002","article-title":"Genome Regulation by Polycomb and Trithorax: 70 Years and Counting","volume":"171","author":"Schuettengruber","year":"2017","journal-title":"Cell"},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1200\/JCO.2005.01.5180","article-title":"EZH2 expression is associated with high proliferation rate and aggressive tumor subgroups in cutaneous melanoma and cancers of the endometrium, prostate, and breast","volume":"24","author":"Bachmann","year":"2006","journal-title":"J. Clin. Oncol."},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"624","DOI":"10.1038\/nature01075","article-title":"The polycomb group protein EZH2 is involved in progression of prostate cancer","volume":"419","author":"Varambally","year":"2002","journal-title":"Nature"},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1038\/ng.518","article-title":"Somatic mutations altering EZH2 (Tyr641) in follicular and diffuse large B-cell lymphomas of germinal-center origin","volume":"42","author":"Morin","year":"2010","journal-title":"Nat. Genet."},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"722","DOI":"10.1038\/ng.621","article-title":"Inactivating mutations of the histone methyltransferase gene EZH2 in myeloid disorders","volume":"42","author":"Ernst","year":"2010","journal-title":"Nat. Genet."},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"665","DOI":"10.1038\/ng.620","article-title":"Somatic mutations of the histone methyltransferase gene EZH2 in myelodysplastic syndromes","volume":"42","author":"Nikoloski","year":"2010","journal-title":"Nat. Genet."},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"3376","DOI":"10.1200\/JCO.2011.40.7379","article-title":"Validation of a prognostic model and the impact of mutations in patients with lower-risk myelodysplastic syndromes","volume":"30","author":"Bejar","year":"2012","journal-title":"J. Clin. Oncol."},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1038\/nm.4247","article-title":"Loss of the histone methyltransferase EZH2 induces resistance to multiple drugs in acute myeloid leukemia","volume":"23","author":"Oellerich","year":"2017","journal-title":"Nat. Med."},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"731","DOI":"10.1182\/blood-2009-12-260760","article-title":"Opposing roles of polycomb repressive complexes in hematopoietic stem and progenitor cells","volume":"116","author":"Majewski","year":"2010","journal-title":"Blood"},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/ncomms5177","article-title":"Ezh2 loss promotes development of myelodysplastic syndrome but attenuates its predisposition to leukaemic transformation","volume":"5","author":"Sashida","year":"2014","journal-title":"Nat. Commun."},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"1228","DOI":"10.1158\/2159-8290.CD-19-0152","article-title":"Loss of EZH2 reprograms BCAA metabolism to drive leukemic transformation","volume":"9","author":"Gu","year":"2019","journal-title":"Cancer Discov."},{"key":"ref_134","doi-asserted-by":"crossref","unstructured":"Sullivan, K.D., Lewis, H.C., Hill, A.A., Pandey, A., Jackson, L.P., Cabral, J.M., Smith, K.P., Liggett, L.A., Gomez, E.B., and Galbraith, M.D. (2016). Trisomy 21 consistently activates the interferon response. Elife, 5.","DOI":"10.7554\/eLife.16220"},{"key":"ref_135","doi-asserted-by":"crossref","first-page":"3292","DOI":"10.1172\/JCI40609","article-title":"Developmental differences in IFN signaling affect GATA1s-induced megakaryocyte hyperproliferation","volume":"123","author":"Woo","year":"2013","journal-title":"J. Clin. Investig."},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"3205","DOI":"10.1182\/blood-2012-04-421172","article-title":"The calcineurin-NFAT pathway negatively regulates megakaryopoiesis","volume":"121","author":"Zaslavsky","year":"2013","journal-title":"Blood"},{"key":"ref_137","doi-asserted-by":"crossref","first-page":"1659","DOI":"10.1101\/gad.1903410","article-title":"Developmental stage-specific interplay of GATA1 and IGF signaling in fetal megakaryopoiesis and leukemogenesis","volume":"24","author":"Klusmann","year":"2010","journal-title":"Genes Dev."},{"key":"ref_138","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1146\/annurev.immunol.16.1.293","article-title":"Jaks and STATs: Biological implications","volume":"16","author":"Leonard","year":"1998","journal-title":"Annu. Rev. Immunol."},{"key":"ref_139","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1038\/nrd1441","article-title":"A new modality for immunosuppression: Targeting the JAK\/STAT pathway","volume":"3","author":"Pesu","year":"2004","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_140","doi-asserted-by":"crossref","unstructured":"Darnell, J.E., Kerr, I.M., and Stark, G.R. (1994). Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. Science.","DOI":"10.1126\/science.8197455"},{"key":"ref_141","doi-asserted-by":"crossref","first-page":"374","DOI":"10.1038\/ni.3691","article-title":"Mechanisms and consequences of Jak-STAT signaling in the immune system","volume":"18","author":"Villarino","year":"2017","journal-title":"Nat. Immunol."},{"key":"ref_142","doi-asserted-by":"crossref","first-page":"580","DOI":"10.15252\/embj.201592383","article-title":"Cytokine-induced megakaryocytic differentiation is regulated by genome-wide loss of a uSTAT transcriptional program","volume":"35","author":"Park","year":"2016","journal-title":"EMBO J."},{"key":"ref_143","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1016\/j.ccr.2005.03.023","article-title":"Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis","volume":"7","author":"Levine","year":"2005","journal-title":"Cancer Cell"},{"key":"ref_144","doi-asserted-by":"crossref","first-page":"1054","DOI":"10.1016\/S0140-6736(05)71142-9","article-title":"Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders","volume":"365","author":"Baxter","year":"2005","journal-title":"Lancet"},{"key":"ref_145","doi-asserted-by":"crossref","unstructured":"Kralovics, R., Passamonti, F., Buser, A.S., Teo, S.-S., Tiedt, R., Passweg, J.R., Tichelli, A., Cazzola, M., and Skoda, R.C. (2005). A Gain-of-Function Mutation of JAK2 in Myeloproliferative Disorders. N. Engl. J. Med.","DOI":"10.1056\/NEJMoa051113"},{"key":"ref_146","first-page":"669","article-title":"A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera","volume":"21","author":"Ugo","year":"2005","journal-title":"Med. Sci."},{"key":"ref_147","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1016\/j.cyto.2016.06.017","article-title":"JAK-STAT signaling in cancer: From cytokines to non-coding genome","volume":"87","author":"Pencik","year":"2016","journal-title":"Cytokine"},{"key":"ref_148","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1182\/asheducation.V2012.1.389.3798360","article-title":"The molecular genetic makeup of acute lymphoblastic leukemia","volume":"2012","author":"Mullighan","year":"2012","journal-title":"Hematol. Am. Soc. Hematol. Educ. Program"},{"key":"ref_149","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1038\/nature10725","article-title":"The genetic basis of early T-cell precursor acute lymphoblastic leukaemia","volume":"481","author":"Zhang","year":"2012","journal-title":"Nature"},{"key":"ref_150","doi-asserted-by":"crossref","first-page":"751","DOI":"10.1084\/jem.20072182","article-title":"Somatically acquired JAK1 mutations in adult acute lymphoblastic leukemia","volume":"205","author":"Flex","year":"2008","journal-title":"J. Exp. Med."},{"key":"ref_151","doi-asserted-by":"crossref","first-page":"3048","DOI":"10.1182\/blood-2012-06-435297","article-title":"STAT3 mutations unify the pathogenesis of chronic lymphoproliferative disorders of NK cells and T-cell large granular lymphocyte leukemia","volume":"120","author":"Jerez","year":"2012","journal-title":"Blood"},{"key":"ref_152","doi-asserted-by":"crossref","first-page":"1598","DOI":"10.1038\/leu.2012.350","article-title":"STAT3 mutations are highly specific for large granular lymphocytic leukemia","volume":"27","author":"Fasan","year":"2013","journal-title":"Leukemia"},{"key":"ref_153","doi-asserted-by":"crossref","first-page":"3198","DOI":"10.18632\/oncotarget.23226","article-title":"Systematic analysis of gene expression alterations and clinical outcomes of STAT3 in cancer","volume":"9","author":"Cui","year":"2018","journal-title":"Oncotarget"},{"key":"ref_154","doi-asserted-by":"crossref","first-page":"2770","DOI":"10.1182\/blood-2006-04-014712","article-title":"JAK2T875N is a novel activating mutation that results in myeloproliferative disease with features of megakaryoblastic leukemia in a murine bone marrow transplantation model","volume":"108","author":"Mercher","year":"2006","journal-title":"Blood"},{"key":"ref_155","doi-asserted-by":"crossref","first-page":"681","DOI":"10.1111\/j.1365-2141.2008.07081.x","article-title":"Functional analysis of JAK3 mutations in transient myeloproliferative disorder and acute megakaryoblastic leukaemia accompanying Down syndrome","volume":"141","author":"Sato","year":"2008","journal-title":"Br. J. Haematol."},{"key":"ref_156","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1111\/j.1365-2141.2007.06574.x","article-title":"Loss-of-function JAK3 mutations in TMD and AMKL of Down syndrome","volume":"137","author":"Mulligan","year":"2007","journal-title":"Br. J. Haematol."},{"key":"ref_157","doi-asserted-by":"crossref","first-page":"574","DOI":"10.1038\/sj.leu.2404527","article-title":"JAK3 mutations occur in acute megakaryoblastic leukemia both in Down syndrome children and non-Down syndrome adults","volume":"21","author":"Kiyoi","year":"2007","journal-title":"Leukemia"},{"key":"ref_158","doi-asserted-by":"crossref","first-page":"1584","DOI":"10.1038\/sj.leu.2404694","article-title":"Janus kinase mutations in the development of acute megakaryoblastic leukemia in children with and without Down\u2019s syndrome","volume":"21","author":"Klusmann","year":"2007","journal-title":"Leukemia"},{"key":"ref_159","doi-asserted-by":"crossref","first-page":"4220","DOI":"10.1182\/blood-2008-01-136366","article-title":"Activating mutations in human acute megakaryoblastic leukemia","volume":"112","author":"Malinge","year":"2008","journal-title":"Blood"},{"key":"ref_160","doi-asserted-by":"crossref","first-page":"1077","DOI":"10.1182\/blood-2007-03-080374","article-title":"Analysis of JAK3, JAK2, and C-MPL mutations in transient myeloproliferative disorder and myeloid leukemia of Down syndrome blasts in children with down syndrome","volume":"110","author":"Norton","year":"2007","journal-title":"Blood"},{"key":"ref_161","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/j.ccr.2006.06.002","article-title":"Activating alleles of JAK3 in acute megakaryoblastic leukemia","volume":"10","author":"Walters","year":"2006","journal-title":"Cancer Cell"},{"key":"ref_162","doi-asserted-by":"crossref","first-page":"2250","DOI":"10.1038\/sj.leu.2403121","article-title":"Comprehensive analysis of gene alterations in acute megakaryoblastic leukemia of Down\u2019s syndrome","volume":"17","author":"Hirose","year":"2003","journal-title":"Leukemia"},{"key":"ref_163","doi-asserted-by":"crossref","unstructured":"Ungureanu, D., Wu, J., Pekkala, T., Niranjan, Y., Young, C., Jensen, O.N., Xu, C.F., Neubert, T.A., Skoda, R.C., and Hubbard, S.R. (2011). The pseudokinase domain of JAK2 is a dual-specificity protein kinase that negatively regulates cytokine signaling. Nat. Struct. Mol. Biol.","DOI":"10.1038\/nsmb.2099"},{"key":"ref_164","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1016\/j.cyto.2015.02.005","article-title":"The \u03b2c receptor family\u2014Structural insights and their functional implications","volume":"74","author":"Broughton","year":"2015","journal-title":"Cytokine"},{"key":"ref_165","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1016\/j.cytogfr.2013.03.002","article-title":"Signalling by the \u03b2c family of cytokines","volume":"24","author":"Hercus","year":"2013","journal-title":"Cytokine Growth Factor Rev."},{"key":"ref_166","doi-asserted-by":"crossref","first-page":"5903","DOI":"10.1002\/jcp.29593","article-title":"Janus kinase inhibitors: A therapeutic strategy for cancer and autoimmune diseases","volume":"235","author":"Hosseini","year":"2020","journal-title":"J. Cell Physiol."},{"key":"ref_167","doi-asserted-by":"crossref","first-page":"1395","DOI":"10.1038\/sj.onc.1202174","article-title":"Increasing complexity of Ras signaling","volume":"17","author":"Campbell","year":"1998","journal-title":"Oncogene"},{"key":"ref_168","doi-asserted-by":"crossref","first-page":"6503","DOI":"10.1038\/sj.onc.1204036","article-title":"Signal transduction and the Ets family of transcription factors","volume":"19","author":"Yordy","year":"2000","journal-title":"Oncogene"},{"key":"ref_169","doi-asserted-by":"crossref","unstructured":"Rodriguez-Viciana, P., Warne, P.H., Dhand, R., Vanhaesebroeck, B., Gout, I., Fry, M.J., Waterfield, M.D., and Downward, J. (1994). Phosphatidylinositol-3-OH kinase direct target of Ras. Nature.","DOI":"10.1038\/370527a0"},{"key":"ref_170","doi-asserted-by":"crossref","unstructured":"Pacold, M.E., Suire, S., Perisic, O., Lara-Gonzalez, S., Davis, C.T., Walker, E.H., Hawkins, P.T., Stephens, L., Eccleston, J.F., and Williams, R.L. (2000). Crystal structure and functional analysis of Ras binding to its effector phosphoinositide 3-kinase \u03b3. Cell.","DOI":"10.1016\/S0092-8674(00)00196-3"},{"key":"ref_171","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1038\/nrc969","article-title":"Targeting RAS signalling pathways in cancer therapy","volume":"3","author":"Downward","year":"2003","journal-title":"Nat. Rev. Cancer"},{"key":"ref_172","doi-asserted-by":"crossref","unstructured":"Jones, S., Zhang, X., Parsons, D.W., Lin, J.C.H., Leary, R.J., Angenendt, P., Mankoo, P., Carter, H., Kamiyama, H., and Jimeno, A. (2008). Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science.","DOI":"10.1126\/science.1164368"},{"key":"ref_173","unstructured":"Muzny, D.M., Bainbridge, M.N., Chang, K., Dinh, H.H., Drummond, J.A., Fowler, G., Kovar, C.L., Lewis, L.R., Morgan, M.B., and Newsham, I.F. (2012). Comprehensive molecular characterization of human colon and rectal cancer. Nature."},{"key":"ref_174","unstructured":"Collisson, E.A., Campbell, J.D., Brooks, A.N., Berger, A.H., Lee, W., Chmielecki, J., Beer, D.G., Cope, L., Creighton, C.J., and Danilova, L. (2014). Comprehensive molecular profiling of lung adenocarcinoma: The cancer genome atlas research network. Nature."},{"key":"ref_175","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1038\/sj.leu.2400617","article-title":"Constitutive activation of mitogen-activated protein kinase pathway in acute leukemia cells","volume":"11","author":"Towatari","year":"1997","journal-title":"Leukemia"},{"key":"ref_176","doi-asserted-by":"crossref","first-page":"601","DOI":"10.2174\/092986707780059670","article-title":"Signaling Through RAS-RAF-MEK-ERK: From Basics to Bedside","volume":"14","author":"Zebisch","year":"2007","journal-title":"Curr. Med. Chem."},{"key":"ref_177","doi-asserted-by":"crossref","first-page":"2901","DOI":"10.1038\/s41467-021-23186-w","article-title":"RAS mutations drive proliferative chronic myelomonocytic leukemia via a KMT2A-PLK1 axis","volume":"12","author":"Carr","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_178","doi-asserted-by":"crossref","unstructured":"Hirai, H., Kobayashi, Y., Mano, H., Hagiwara, K., Maru, Y., Omine, M., Mizoguchi, H., Nishida, J., and Takaku, F. (1987). A point mutation at codon 13 of the N-ras oncogene in myelodysplastic syndrome. Nature.","DOI":"10.1038\/327430a0"},{"key":"ref_179","doi-asserted-by":"crossref","first-page":"828","DOI":"10.1038\/nrd4389","article-title":"Drugging the undruggable RAS: Mission Possible?","volume":"13","author":"Cox","year":"2014","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_180","doi-asserted-by":"crossref","first-page":"1207","DOI":"10.1056\/NEJMoa1917239","article-title":"KRASG12C Inhibition with Sotorasib in Advanced Solid Tumors","volume":"383","author":"Hong","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_181","doi-asserted-by":"crossref","unstructured":"Indini, A., Rijavec, E., Ghidini, M., Cortellini, A., and Grossi, F. (2021). Targeting KRAS in Solid Tumors: Current Challenges and Future Opportunities of Novel KRAS Inhibitors. Pharmaceutics, 13.","DOI":"10.3390\/pharmaceutics13050653"},{"key":"ref_182","doi-asserted-by":"crossref","first-page":"1521","DOI":"10.1038\/s41375-021-01161-0","article-title":"EZH2 inactivation in RAS-driven myeloid neoplasms hyperactivates RAS-signaling and increases MEK inhibitor sensitivity","volume":"35","author":"Berg","year":"2021","journal-title":"Leukemia"},{"key":"ref_183","doi-asserted-by":"crossref","first-page":"1635","DOI":"10.1038\/s41375-018-0368-6","article-title":"Sequentially inducible mouse models reveal that Npm1 mutation causes malignant transformation of Dnmt3a-mutant clonal hematopoiesis","volume":"33","author":"Loberg","year":"2019","journal-title":"Leukemia"},{"key":"ref_184","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1038\/s41586-020-2864-x","article-title":"Single-cell mutation analysis of clonal evolution in myeloid malignancies","volume":"587","author":"Miles","year":"2020","journal-title":"Nature"}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/13\/16\/4144\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:46:07Z","timestamp":1760165167000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/13\/16\/4144"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,8,18]]},"references-count":184,"journal-issue":{"issue":"16","published-online":{"date-parts":[[2021,8]]}},"alternative-id":["cancers13164144"],"URL":"https:\/\/doi.org\/10.3390\/cancers13164144","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,8,18]]}}}