{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:37:38Z","timestamp":1787027858660,"version":"build-2736575974"},"reference-count":115,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T00:00:00Z","timestamp":1786924800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Research and Innovation Foundation of Zuyderland MC"},{"id":[{"id":"https:\/\/ror.org\/00en9ce74","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>The diagnosis and clinical management of myelodysplastic neoplasms are increasingly challenged by the disease\u2019s inherent heterogeneity, particularly with respect to the diagnosis of low-grade variants. While standardized flow cytometric protocols traditionally rely on static biomarkers for lineage assignment, these often fail to capture the dynamic biological behavior of the malignant clone. This review synthesizes studies on the integration of functional biomarkers, specifically the nuclear proliferation marker Ki-67 and the anti-apoptotic protein Bcl-2, into the diagnostic and prognostic workflow. By utilizing high-dimensional multiparameter flow cytometry (MFC) and software-based maturation continuum analysis, the survival and growth kinetics of the myeloid, erythroid, and monocytic lineages can be quantified. These findings redefine myelodysplastic syndromes (MDS) as characterized by a significant decrease in cell-cycle progression and an increase in anti-apoptotic activity during early stages of maturation. Recent studies demonstrate that integrating the erythroid Ki-67 proliferation index as a fifth parameter into the conventional Ogata score dramatically improves diagnostic sensitivity for detecting MDS from 66% to 90% while maintaining 100% specificity. In particular, the sensitivity for detecting low-grade MDS improved from 56% to 91%. Additionally, a reduced erythroid Ki-67 index (\u226428%) is a powerful independent predictor of transfusion dependence within 1 year. Beyond diagnostics, the introduction of the Bcl-2:Ki-67 ratio provides a superior metric for biological aggressiveness and a potential predictive tool for precision medicine. A high ratio identifies a quiescent, apoptosis-resistant cell population that is likely refractory to standard chemotherapy but is an ideal candidate for targeted Bcl-2 inhibition with Venetoclax. The integration of functional biomarkers bridges the gap between complex mutational landscapes and clinical manifestations. While digital imaging and artificial intelligence (AI) are beginning to automate blast enumeration and maturation analysis, functional kinetics may provide a necessary biological readout for personalized therapy.<\/jats:p>","DOI":"10.3390\/cancers18162648","type":"journal-article","created":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T10:04:36Z","timestamp":1786961076000},"page":"2648","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Functional Characterization of Myelodysplastic Syndrome by Multiparameter Flow Cytometry: The Clinical Synergy Between Ki-67 and Bcl-2 and Their Potential Role in Diagnostics and Personalized Therapy"],"prefix":"10.3390","volume":"18","author":[{"given":"Sixuan J.","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Clinical Chemistry & Hematology, Zuyderland Medical Center, 6162 BG Sittard-Geleen, The Netherlands"},{"name":"NUTRIM-Institute for Nutrition and Translational Research in Metabolism, Maastricht University Medical Center, 6229 HX Maastricht, The Netherlands"},{"name":"Central Diagnostic Laboratory (CDL), Maastricht University Medical Center, 6229 HX Maastricht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-2440-4640","authenticated-orcid":false,"given":"Rinaldo A. J. N. van","family":"Meel","sequence":"additional","affiliation":[{"name":"Department of Clinical Chemistry & Hematology, Zuyderland Medical Center, 6162 BG Sittard-Geleen, The Netherlands"},{"name":"Department of Biotechnology, CHILL b.v., 6167 RD Sittard-Geleen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan G. C.","family":"Mestrum","sequence":"additional","affiliation":[{"name":"Department of Clinical Chemistry & Hematology, Zuyderland Medical Center, 6162 BG Sittard-Geleen, The Netherlands"},{"name":"Department of Genetics & Cell Biology, GROW Research Institute for Oncology and Reproduction, Maastricht University Medical Center, 6229 HX Maastricht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas H. P. M.","family":"Habets","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology (Maastro), GROW Research Institute for Oncology and Reproduction, Maastricht University Medical Center, 6229 HX Maastricht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anton H. N.","family":"Hopman","sequence":"additional","affiliation":[{"name":"Department of Genetics & Cell Biology, GROW Research Institute for Oncology and Reproduction, Maastricht University Medical Center, 6229 HX Maastricht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frans C. S.","family":"Ramaekers","sequence":"additional","affiliation":[{"name":"Department of Genetics & Cell Biology, GROW Research Institute for Oncology and Reproduction, Maastricht University Medical Center, 6229 HX Maastricht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yvonne M. C.","family":"Henskens","sequence":"additional","affiliation":[{"name":"Central Diagnostic Laboratory (CDL), Maastricht University Medical Center, 6229 HX Maastricht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2902-2927","authenticated-orcid":false,"given":"Otto","family":"Bekers","sequence":"additional","affiliation":[{"name":"Central Diagnostic Laboratory (CDL), Maastricht University Medical Center, 6229 HX Maastricht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5186-5600","authenticated-orcid":false,"given":"Mathie P. G.","family":"Leers","sequence":"additional","affiliation":[{"name":"Department of Clinical Chemistry & Hematology, Zuyderland Medical Center, 6162 BG Sittard-Geleen, The Netherlands"},{"name":"Department of Environmental Sciences, Faculty of Science, Open Universiteit, 6419 AT Heerlen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1038\/s41408-023-00894-8","article-title":"Validation of the molecular international prognostic scoring system in patients with myelodysplastic syndromes defined by international consensus classification","volume":"13","author":"Lee","year":"2023","journal-title":"Blood Cancer J."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1002\/cyto.b.22110","article-title":"Where diagnosis for myelodysplastic neoplasms (MDS) stands today and where it will go: The role of flow cytometry in evaluation of MDS","volume":"104","author":"Wang","year":"2023","journal-title":"Cytom. 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