{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T14:23:15Z","timestamp":1787840595912,"version":"build-2784847793"},"reference-count":32,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T00:00:00Z","timestamp":1786060800000},"content-version":"vor","delay-in-days":6,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,8,1]],"date-time":"2026-08-01T00:00:00Z","timestamp":1785542400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Genes Chromosomes & Cancer"],"published-print":{"date-parts":[[2026,8]]},"abstract":"ABSTRACT<\/jats:title>\n \n Background<\/jats:title>\n \n Myelodysplastic syndromes (MDS) and acute myeloid leukemias (AML) harboring\n TP53<\/jats:italic>\n mutations are defined by extreme genomic instability, complex karyotypes (CK), and poor prognosis. While large\u2010scale chromosomal imbalances are common in CK\u2010MDS\/AML, the synergy between focal amplifications of signaling drivers and the disruption of transcriptional regulators remains poorly elucidated.\n <\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n We performed a comprehensive clinical, cytogenetic (GTG\u2010banding, M\u2010FISH, M\u2010Band), and molecular (targeted FISH, NGS) analysis of seven patients with MDS and AML characterized by a recurrent and distinct genomic signature.<\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n All cases exhibited highly complex karyotypes on a\n TP53<\/jats:italic>\n \u2010mutated background. We identified high\u2010level focal amplifications of\n EPOR<\/jats:italic>\n (19p13.2) and\n JAK2<\/jats:italic>\n (9p24.1), predominantly manifesting as homogeneously staining regions (HSRs) or complex \u201csandwich\u2010like\u201d derivative chromosomes. Notably, these signaling alterations consistently co\u2010occurred with monoallelic deletions of the\n TCF3<\/jats:italic>\n (\n E2A<\/jats:italic>\n ) tumor suppressor (19p13.3) and copy number gains of the\n ERG<\/jats:italic>\n transcription factor (21q22). Detailed structural analysis indicates that\n TCF3<\/jats:italic>\n loss likely arises as a structural consequence of chromosome 19 rearrangements driving\n EPOR<\/jats:italic>\n amplification. Based on this data, we propose a conceptual model of leukemogenesis where\n EPOR\/JAK2<\/jats:italic>\n co\u2010amplification potentially drives constitutive JAK2\/STAT5 signaling, while concurrent\n ERG<\/jats:italic>\n gain and\n TCF3<\/jats:italic>\n haploinsufficiency contribute to maturation delay.\n TP53<\/jats:italic>\n deficiency appears to be the primary permissive factor enabling the stabilization of these massive structural rearrangements.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n \n Our findings outline a recurrent and biologically coherent genomic pattern within the spectrum of\n TP53<\/jats:italic>\n \u2010mutated myeloid neoplasms, demonstrating significant phenotypic overlap with erythroid leukemia features in a subset of cases. Given the small cohort size, these findings are hypothesis\u2010generating. However, this convergence of predicted JAK2\/STAT5 pathway hyperactivation and transcriptional disinhibition points to a theoretical therapeutic vulnerability that warrants prospective validation in larger collaborative studies.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1002\/gcc.70159","type":"journal-article","created":{"date-parts":[[2026,8,8]],"date-time":"2026-08-08T03:22:49Z","timestamp":1786159369000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Complex Genomic Alterations in\n TP53<\/i>\n \u2010Mutated Myelodysplastic Syndrome and Acute Myeloid Leukemia Involving\n EPOR<\/i>\n \/\n JAK2<\/i>\n Amplification,\n ERG<\/i>\n Copy Gains, and\n TCF3<\/i>\n Deletion"],"prefix":"10.1002","volume":"65","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1302-3311","authenticated-orcid":false,"given":"T. L.","family":"Gindina","sequence":"first","affiliation":[{"name":"R.M. Gorbacheva Research Institute Pavlov University Saint\u2010Petersburg Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3152-3333","authenticated-orcid":false,"given":"S. S.","family":"Riumin","sequence":"additional","affiliation":[{"name":"R.M. Gorbacheva Research Institute Pavlov University Saint\u2010Petersburg Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8000-3652","authenticated-orcid":false,"given":"I. M.","family":"Barkhatov","sequence":"additional","affiliation":[{"name":"R.M. Gorbacheva Research Institute Pavlov University Saint\u2010Petersburg Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-0222-6763","authenticated-orcid":false,"given":"T. Yu","family":"Gracheva","sequence":"additional","affiliation":[{"name":"R.M. Gorbacheva Research Institute Pavlov University Saint\u2010Petersburg Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5849-1311","authenticated-orcid":false,"given":"D. S.","family":"Bug","sequence":"additional","affiliation":[{"name":"R.M. Gorbacheva Research Institute Pavlov University Saint\u2010Petersburg Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1959-9063","authenticated-orcid":false,"given":"E. V.","family":"Babenko","sequence":"additional","affiliation":[{"name":"R.M. Gorbacheva Research Institute Pavlov University Saint\u2010Petersburg Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9605-485X","authenticated-orcid":false,"given":"E. V.","family":"Morozova","sequence":"additional","affiliation":[{"name":"R.M. Gorbacheva Research Institute Pavlov University Saint\u2010Petersburg Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8401-0817","authenticated-orcid":false,"given":"N. Yu","family":"Tsvetkov","sequence":"additional","affiliation":[{"name":"R.M. Gorbacheva Research Institute Pavlov University Saint\u2010Petersburg Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4978-3467","authenticated-orcid":false,"given":"N. N.","family":"Mamaev","sequence":"additional","affiliation":[{"name":"R.M. Gorbacheva Research Institute Pavlov University Saint\u2010Petersburg Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9589-4136","authenticated-orcid":false,"given":"A. D.","family":"Kulagin","sequence":"additional","affiliation":[{"name":"R.M. Gorbacheva Research Institute Pavlov University Saint\u2010Petersburg Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,8,7]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood\u20102012\u201003\u2010420489"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1182\/bloodadvances.2021006239"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2022015850"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41375\u2010022\u201001613\u20101"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41591\u2010020\u20101008\u2010z"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1516192"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2022.976961"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood\u20102014\u201011\u2010575357"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0808866106"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20101785"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1186\/1471\u20102407\u201012\u2010194"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.bjc.6604220"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1158\/2643\u20103230.BCD\u201021\u20100192"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biocel.2011.05.014"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1002\/gcc.23027"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cancergen.2023.01.004"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2022.844794"},{"issue":"8","key":"e_1_2_10_19_1","first-page":"61","article-title":"Complex Chromosome Damages in Patients With Recurrent Acute Leukemias After Allogeneic Hematopoietic Stem Cell Transplantations","volume":"84","author":"Gindina T. 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