Case report: biallelic DNMT3A mutations in acute myeloid leukemia

Frontiers in Oncology

Oncology

Francesco Albano¹  Crescenzio Francesco Minervini¹  Francesco Tarantini¹  Immacolata Redavid¹  Paola Orsini¹  Paola Carluccio¹  Antonella Zagaria¹  Cosimo Cumbo¹  Luisa Anelli¹  Angela Minervini¹  Giuseppina Tota¹  Elisa Parciante¹  Maria Rosa Conserva¹  Nicoletta Coccaro¹  Pellegrino Musto¹  Maria Federica Iannò²  Anna De Grassi³  Ciro Leonardo Pierri³  Loris De Cecco⁴  Giorgina Specchia⁵ 

[1] Department of Precision and Regenerative Medicine and Ionian Area (DiMePRe-J), Hematology and Stem Cell Transplantation Unit, University of Bari “Aldo Moro”, Bari, Italy;Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy;Laboratory of Biochemistry, Molecular and Computational Biology, Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, Bari, Italy;Molecular Mechanisms Unit, Department of Research Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy;School of Medicine, University of Bari “Aldo Moro”, Bari, Italy;

关键词: DNMT3A;    biallelic mutations;    acute myeloid leukemia;    hypermethylation;    cell differentiation;   

DOI  :  10.3389/fonc.2023.1205220

 received in 2023-04-13, accepted in 2023-06-09,  发布年份 2023

来源: Frontiers

【 摘 要 】

DNMT3A gene mutations, detected in 20-25% of de novo acute myeloid leukemia (AML) patients, are typically heterozygous. Biallelic variants are uncommon, affecting ~3% of cases and identifying a worse prognosis. Indeed, two concomitant DNMT3A mutations were recently associated with shorter event-free survival and overall survival in AML. We present an AML case bearing an unusual DNMT3A molecular status, strongly affecting its function and strangely impacting the global genomic methylation profile. A 56-year-old Caucasian male with a diagnosis of AML not otherwise specified (NOS) presented a complex DNMT3A molecular profile consisting of four different somatic variants mapping on different alleles (in trans). 3D modelling analysis predicted the effect of the DNMT3A mutational status, showing that all the investigated mutations decreased or abolished DNMT3A activity. Although unexpected, DNMT3A’s severe loss of function resulted in a global genomic hypermethylation in genes generally involved in cell differentiation. The mechanisms through which DNMT3A contributes to AML remain elusive. We present a unique AML case bearing multiple biallelic DNMT3A variants abolishing its activity and resulting in an unexpected global hypermethylation. The unusual DNMT3A behavior described requires a reflection on its role in AML development and persistence, highlighting the heterogeneity of its deregulation.

【 授权许可】

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Copyright © 2023 Cumbo, Orsini, Anelli, Zagaria, Iannò, De Cecco, Minervini, Coccaro, Tota, Parciante, Conserva, Redavid, Tarantini, Minervini, Carluccio, De Grassi, Pierri, Specchia, Musto and Albano