Atypical 3q26/MECOM rearrangements genocopy inv(3)/t(3;3) in acute myeloid leukemia
| Autor: | Marije Havermans, Eric M.J. Bindels, Leonie Smeenk, Peter J. M. Valk, Stanley van Herk, Claudia Erpelinck, Roger Mulet-Lazaro, H. Berna Beverloo, Ruud Delwel, Robert van der Helm, Sophie Ottema, Torsten Haferlach, Claudia Haferlach, Tim Grob |
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| Přispěvatelé: | Hematology, Clinical Genetics |
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Male
Myeloid MECOM Immunology Chromosomal translocation Biology Biochemistry Translocation Genetic Genocopy hemic and lymphatic diseases medicine Humans Allele Gene Expression Regulation Leukemic GATA2 Myeloid leukemia Cell Biology Hematology medicine.disease MDS1 and EVI1 Complex Locus Protein Leukemia Leukemia Myeloid Acute medicine.anatomical_structure Enhancer Elements Genetic Chromosome Inversion Cancer research Female Chromosomes Human Pair 3 |
| Zdroj: | Blood, 136(2), 224-234. American Society of Hematology |
| ISSN: | 1528-0020 0006-4971 |
| Popis: | Acute myeloid leukemia (AML) with inv(3)/t(3;3)(q21q26) is a distinct World Health Organization recognized entity, characterized by its aggressive course and poor prognosis. In this subtype of AML, the translocation of a GATA2 enhancer (3q21) to MECOM (3q26) results in overexpression of the MECOM isoform EVI1 and monoallelic expression of GATA2 from the unaffected allele. The full-length MECOM transcript, MDS1-EVI1, is not expressed as the result of the 3q26 rearrangement. Besides the classical inv(3)/t(3;3), a number of other 3q26/MECOM rearrangements with poor treatment response have been reported in AML. Here, we demonstrate, in a group of 33 AML patients with atypical 3q26 rearrangements, MECOM involvement with EVI1 overexpression but no or low MDS1-EVI1 levels. Moreover, the 3q26 translocations in these AML patients often involve superenhancers of genes active in myeloid development (eg, CD164, PROM1, CDK6, or MYC). In >50% of these cases, allele-specific GATA2 expression was observed, either by copy-number loss or by an unexplained allelic imbalance. Altogether, atypical 3q26 recapitulate the main leukemic mechanism of inv(3)/t(3;3) AML, namely EVI1 overexpression driven by enhancer hijacking, absent MDS1-EVI1 expression and potential GATA2 involvement. Therefore, we conclude that both atypical 3q26/MECOM and inv(3)/t(3;3) can be classified as a single entity of 3q26-rearranged AMLs. Routine analyses determining MECOM rearrangements and EVI1 and MDS1-EVI1 expression are required to recognize 3q-rearranged AML cases. |
| Databáze: | OpenAIRE |
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