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The canonical hotspot K700E variant is generally associated with a favorable prognosis, whereas the impact of other recurrent variants is poorly defined. We investigated the clinical, transcriptomic, and functional consequences of distinct\n                      <jats:italic>SF3B1<\/jats:italic>\n                      mutations in MDS patients and isogenic cell models.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Clinical data from 121\n                      <jats:italic>SF3B1<\/jats:italic>\n                      -mutated MDS patients were analyzed. RNA sequencing was performed on CD34\u207a patient bone marrow cells and CRISPR-engineered NALM-6 lines harboring individual\n                      <jats:italic>SF3B1<\/jats:italic>\n                      variants. Comprehensive profiling of splicing, gene expression, and mitochondrial bioenergetic parameters was performed.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Compared with K700E, the K666 variant was associated with shorter progression-free survival, distinct splicing abnormalities, and a higher frequency of retained introns, showing partial overlap with the H662 variant. Mitochondria-related genes were frequently mis-spliced and differentially expressed in K666-variant cells. In isogenic models, reduced complex IV activity and marked OXPHOS impairment were observed, with the most pronounced effects seen in K666N. Overall,\n                      <jats:italic>SF3B1<\/jats:italic>\n                      variants confer heterogeneous biological and clinical effects. The K666N variant, in particular, is associated with adverse prognosis and profound bioenergetic dysfunction.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      These results support a refined view of\n                      <jats:italic>SF3B1<\/jats:italic>\n                      -mutated MDS as a biologically heterogeneous entity and suggest that variant-specific mitochondrial vulnerabilities may represent exploitable targets for precision-based therapeutic strategies.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s40246-026-01000-2","type":"journal-article","created":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T15:50:54Z","timestamp":1781797854000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Variant-specific SF3B1 mutations drive distinct splicing and mitochondrial dysfunction in myelodysplastic neoplasms"],"prefix":"10.1186","volume":"20","author":[{"given":"Andrea","family":"Hru\u0161tincov\u00e1","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iva","family":"Trsov\u00e1","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Kundr\u00e1t","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monika","family":"Beli\u010dkov\u00e1","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monika","family":"Kaisrl\u00edkov\u00e1","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jitka","family":"Vesel\u00e1","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zden\u011bk","family":"Krej\u010d\u00edk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Al\u017eb\u011bta","family":"Hlav\u00e1\u010dkov\u00e1","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ji\u0159\u00ed","family":"Suttnar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hana","family":"\u0160tufkov\u00e1","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nikol","family":"Volfov\u00e1","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hana","family":"Hans\u00edkov\u00e1","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tatiana","family":"Aghov\u00e1","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zuzana","family":"Zemanov\u00e1","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Jon\u00e1\u0161ov\u00e1","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jaroslav","family":"\u010cerm\u00e1k","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark\u00e9ta","family":"\u0160\u0165astn\u00e1 Markov\u00e1","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michaela","family":"Dost\u00e1lov\u00e1 Merkerov\u00e1","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,6,18]]},"reference":[{"key":"1000_CR1","doi-asserted-by":"publisher","first-page":"1307","DOI":"10.1002\/ajh.26984","volume":"98","author":"G Garcia-Manero","year":"2023","unstructured":"Garcia-Manero G. 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