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Landscape of biallelic DNMT3A mutant myeloid neoplasms.
- Source :
-
Journal of hematology & oncology [J Hematol Oncol] 2024 Sep 27; Vol. 17 (1), pp. 87. Date of Electronic Publication: 2024 Sep 27. - Publication Year :
- 2024
-
Abstract
- DNA methyltransferase 3 A mutations (DNMT3A <superscript>MT</superscript> ) are frequent in myeloid neoplasia (MN) and mostly heterozygous. However, cases with multiple DNMT3A <superscript>MT</superscript> can be also encountered but their clinical and genetic landscape remains unexplored. We retrospectively analyzed 533 cases with DNMT3A <superscript>MT</superscript> identified out of 5,603 consecutive MNs, of whom 8.4% had multiple DNMT3A <superscript>MT</superscript> hits. They were most frequent in acute myeloid leukemia (AML) with R882 variant accounting for 13.3% of the multi-hits. Multiple DNMT3A <superscript>MT</superscript> more likely coincided with IDH2 (P = 0.005) and ETV6 (P = 0.044) mutations compared to patients with single DNMT3A <superscript>MT</superscript> . When the sum of variant allele frequencies (VAFs) for multiple DNMT3A <superscript>MT</superscript> exceeded 60%, we found a significant positive clonal burden correlation of the two DNMT3A variants (P < 0.0001) suggesting that they occurred in biallelic configuration. AML patients with biallelic DNMT3A inactivation (n = 52) presented with older age (P = 0.029), higher leukocytes (P < 0.0001) and peripheral blast counts (P = 0.0001) and significantly poorer survival rate (5.6% vs. 47.6% at 2 years; P = 0.002) than monoallelic DNMT3A <superscript>MT</superscript> . Multivariate analysis identified biallelic DNMT3A <superscript>MT</superscript> (HR 2.65; P = 0.001), male gender (HR 2.05; P = 0.014) and adverse genetic alteration according to the European LeukemiaNet 2022 classification (HR 1.84; P = 0.028) as independent adverse factors for survival, whereas intensive chemotherapy (HR 0.47; P = 0.011) favorably influenced outcomes. Longitudinal molecular analysis of 12 cases with biallelic DNMT3A <superscript>MT</superscript> demonstrated that such clones persisted or expanded in 9 relapsed or transformed cases (75%) suggesting the early origin of biallelic hits with strong leukemogenic potential. Our study describes the likelihood that biallelic DNMT3A <superscript>MT</superscript> , while rare, are indeed compatible with clonal expansion and thus questions the applicability of synthetic lethality strategies.<br /> (© 2024. The Author(s).)
- Subjects :
- Humans
Male
Female
Retrospective Studies
Middle Aged
Adult
Aged
Alleles
Young Adult
Aged, 80 and over
Adolescent
Myeloproliferative Disorders genetics
Gene Frequency
DNA Methyltransferase 3A
DNA (Cytosine-5-)-Methyltransferases genetics
Mutation
Leukemia, Myeloid, Acute genetics
Leukemia, Myeloid, Acute mortality
Subjects
Details
- Language :
- English
- ISSN :
- 1756-8722
- Volume :
- 17
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Journal of hematology & oncology
- Publication Type :
- Academic Journal
- Accession number :
- 39334207
- Full Text :
- https://doi.org/10.1186/s13045-024-01607-9