{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T10:35:31Z","timestamp":1777631731455,"version":"3.51.4"},"reference-count":40,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2023,11,26]],"date-time":"2023-11-26T00:00:00Z","timestamp":1700956800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100005677","name":"Jos\u00e9-Carreras Foundation","doi-asserted-by":"publisher","award":["DJCLS 10R\/2020"],"award-info":[{"award-number":["DJCLS 10R\/2020"]}],"id":[{"id":"10.13039\/501100005677","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005677","name":"Jos\u00e9-Carreras Foundation","doi-asserted-by":"publisher","award":["01GM1911A"],"award-info":[{"award-number":["01GM1911A"]}],"id":[{"id":"10.13039\/501100005677","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005677","name":"Jos\u00e9-Carreras Foundation","doi-asserted-by":"publisher","award":["01GM2207A"],"award-info":[{"award-number":["01GM2207A"]}],"id":[{"id":"10.13039\/501100005677","id-type":"DOI","asserted-by":"publisher"}]},{"name":"German Federal Ministry of Education and Research (BMBF)","award":["DJCLS 10R\/2020"],"award-info":[{"award-number":["DJCLS 10R\/2020"]}]},{"name":"German Federal Ministry of Education and Research (BMBF)","award":["01GM1911A"],"award-info":[{"award-number":["01GM1911A"]}]},{"name":"German Federal Ministry of Education and Research (BMBF)","award":["01GM2207A"],"award-info":[{"award-number":["01GM2207A"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>GATA2 deficiency is a heterogeneous, multisystem disorder associated with a high risk of developing myelodysplastic syndrome (MDS) and the progression to acute myeloid leukemia. The mechanisms underlying malignant transformation in GATA2 deficiency remain poorly understood, necessitating predictive markers to assess an individual\u2019s risk of progression and guide therapeutic decisions. In this study, we performed a systematic analysis of bone marrow biopsies from 57 pediatric MDS patients. Focusing on hematopoiesis and the hematopoietic niche, including its microenvironment, we used multiplex immunofluorescence combined with multispectral imaging, gene expression profiling, and multiplex RNA in situ hybridization. Patients with a GATA2 deficiency exhibited a dysregulated GATA2 transcriptional network. Disease progression (GATA2-EB, n = 6) was associated with increased GATA2 mRNA levels, restored expression of the GATA2 target EZH2, and increased H3K27me3. GATA2-EB was further characterized by the high expression of the anti-apoptotic protein BCL2, a feature absent in children with a GATA2 deficiency and refractory cytopenia of childhood (GATA2-RCC, n = 24) or other pediatric MDS subgroups (RCC, n = 17; MDS-EB, n = 10). The multispectral imaging analysis of additional BCL2 family members revealed significantly elevated Mediators of Apoptosis Combinatorial (MAC) scores in GATA2-EB patients. Taken together, our findings highlight the potential drivers of disease progression in GATA2 deficiency, particularly increased histone trimethylation and dysregulated apoptosis. Furthermore, upregulated BCL2 and EZH2 and increased MAC scores provide a strong rationale for the use of venetoclax and azacitidine in therapeutic regimens for GATA2-EB.<\/jats:p>","DOI":"10.3390\/cancers15235594","type":"journal-article","created":{"date-parts":[[2023,11,27]],"date-time":"2023-11-27T03:35:06Z","timestamp":1701056106000},"page":"5594","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Development of MDS in Pediatric Patients with GATA2 Deficiency: Increased Histone Trimethylation and Deregulated Apoptosis as Potential Drivers of Transformation"],"prefix":"10.3390","volume":"15","author":[{"given":"Franziska","family":"Schreiber","sequence":"first","affiliation":[{"name":"Institute of Pathology, Ludwig-Maximilians-University Munich, 80337 Munich, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Guido","family":"Piontek","sequence":"additional","affiliation":[{"name":"Institute of Pathology, Ludwig-Maximilians-University Munich, 80337 Munich, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuki","family":"Schneider-Kimoto","sequence":"additional","affiliation":[{"name":"Institute of Pathology, Ludwig-Maximilians-University Munich, 80337 Munich, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephan","family":"Schwarz-Furlan","sequence":"additional","affiliation":[{"name":"Institute of Pathology, Klinikum Kaufbeuren-Ravensburg, 87600 Kaufbeuren, Germany"},{"name":"Institute of Pathology, University Hospital Erlangen, 91054 Erlangen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rita","family":"De Vito","sequence":"additional","affiliation":[{"name":"Department of Pathology, Bambino Gesu Children\u2019s Hospital, IRCCS, 00165 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7976-3654","authenticated-orcid":false,"given":"Franco","family":"Locatelli","sequence":"additional","affiliation":[{"name":"Department of Pediatric Hematology and Oncology, Cell and Gene Therapy, Bambino Gesu Children\u2019s Hospital, IRCCS, 00165 Rome, Italy"},{"name":"Department of Life Sciences and Public Health, Catholic University of the Sacred Heart, 00168 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carole","family":"Gengler","sequence":"additional","affiliation":[{"name":"Institute of Pathology, Department of Laboratory Medicine and Pathology, Lausanne University Hospital, Lausanne University, CH-1011 Lausanne, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ayami","family":"Yoshimi","sequence":"additional","affiliation":[{"name":"Department of Pediatrics and Adolescent Medicine, Division of Pediatric Hematology and Oncology, Medical Center, Faculty of Medicine, University of Freiburg, 79110 Freiburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andreas","family":"Jung","sequence":"additional","affiliation":[{"name":"Institute of Pathology, Ludwig-Maximilians-University Munich, 80337 Munich, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Frederick","family":"Klauschen","sequence":"additional","affiliation":[{"name":"Institute of Pathology, Ludwig-Maximilians-University Munich, 80337 Munich, Germany"},{"name":"German Cancer Consortium (DKTK), Partner Site Munich, and German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3856-7937","authenticated-orcid":false,"given":"Charlotte M.","family":"Niemeyer","sequence":"additional","affiliation":[{"name":"Department of Pediatrics and Adolescent Medicine, Division of Pediatric Hematology and Oncology, Medical Center, Faculty of Medicine, University of Freiburg, 79110 Freiburg, Germany"},{"name":"German Cancer Consortium (DKTK), Heidelberg and Freiburg, 79106 Freiburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Miriam","family":"Erlacher","sequence":"additional","affiliation":[{"name":"Department of Pediatrics and Adolescent Medicine, Division of Pediatric Hematology and Oncology, Medical Center, Faculty of Medicine, University of Freiburg, 79110 Freiburg, Germany"},{"name":"German Cancer Consortium (DKTK), Heidelberg and Freiburg, 79106 Freiburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Martina","family":"Rudelius","sequence":"additional","affiliation":[{"name":"Institute of Pathology, Ludwig-Maximilians-University Munich, 80337 Munich, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,11,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"929","DOI":"10.1038\/ng.923","article-title":"Mutations in GATA2 cause primary lymphedema associated with a predisposition to acute myeloid leukemia (Emberger syndrome)","volume":"43","author":"Ostergaard","year":"2011","journal-title":"Nat. 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