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1853 Differential Impact of Domain Stratified Non-R882 DNMT3A Mutations in Myeloid Neoplasms

Program: Oral and Poster Abstracts
Session: 636. Myelodysplastic Syndromes – Basic and Translational: Poster I
Hematology Disease Topics & Pathways:
Research, Translational Research
Saturday, December 9, 2023, 5:30 PM-7:30 PM

Lakshmi Bhavani Potluri, MD1, Vikram Dhillon, DO, MBA2, Jeff Aguilar, MD, MBA3, Sushmitha Nanja Reddy, MD, MBBS4, Dakshin Padmanabhan, MBBS5, Gregory Dyson, PhD6*, Julie Boerner6*, Jaroslaw P. Maciejewski, M.D., Ph.D., FACP7 and Suresh Kumar Balasubramanian, MD6,7

1Wayne State University/Sinai-Grace Hospital, Farmington Hills, MI
2Department of Hematology/Oncology, Neal Cancer Center/Houston Methodist Hospital, Detroit, MI
3Department of Oncology, Karmanos Cancer Institute/Wayne State University, Windsor, ON, Canada
4Karmanos Cancer Institute/Department of Oncology, Wayne State University, Novi, MI
5St Joseph Mercy Oakland (Trinity Health) Hospital, Rochester Hills, MI
6Karmanos Cancer Institute/Department of Oncology, Wayne State University, Detroit, MI
7Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH


DNMT3A mutations are present in approximately 20% of acute myeloid leukemia (AML) patients and other myeloid neoplasms (MN) and are considered the earliest clonal event in leukemogenesis. In AML, 50-60% of DNMT3A mutations are heterozygous missense mutations affecting codon R882, which were shown to be dominant-negative in multiple studies. In contrast, there is still a complete lack of data related to the biological impact of a substantial number of widely dispersed non-R882 mutations and their clinical implications. It is possible that mutations in different DNMT3A domains are unique, leading to specific molecular characteristics and clinical phenotypes. Domain-based characterization and phenotypic effects of non-R882 mutations in more granularity is needed to understand the significance of DNMT3A mutations in MN.


We conducted a large retrospective analysis of 16,565 MN patients by screening publicly available databases of AACR GENIE (v 13.1, n=4167), cBioPortal (Cerami et al., 2012, n=3669) along with Karmanos Cancer Institute (n=800) and a previously published metanalytic cohort (Awada et al., Blood 2021 and Kewan et al., Nature Communications, 2023). Clinical characteristics and genomic data were extracted for DNMT3AMT patients to study associated mutational signatures with respect to various biological characteristics. Chi square test was used for analysis of various parameters and KM curves were used to estimate overall survival (OS).


DNMT3AMT was found in 17.5% (2903/16,565) of patients in the whole cohort. Of these, 1635 patients had one or more DNMT3A non-R882 mutations, with pAML in 920 (56.3%), sAML in 355 (21.7%), MDS in 259 (15.8%), MPN in 68 (4.2%) and MDS/MPN in 33(2.0%) patients.

Among 2088 non-R882 mutations, the most common type is missense (59%, n=1232), followed by frameshift (16.5%, n=345) and nonsense (12.3%, n=256) mutations. 78 (5%) patients had mutations in the N-terminal domain (NTD), 231 (14.1%) in Pro-Trp-Trp-Pro (PWWP) domain, 311 (19%) in ATRX-DNMT3-DNMT3L (ADD) domain and 777 (47.5%) in the methyltransferase (MTase) domain (p=0.0001). Patients with more than one domain or with splice site mutations were excluded. The median age of patients was 67.6 (59-74.8) ys. and male:female ratio showed no difference across domains (p=0.73 & p=0.64 resp.).

Patients with NTDMT were less frequently pAML when compared to the other three domains [38.5% vs. 56%, p=0.002]; however, there was no domain distribution pattern observed for sAML and MDS patients. NTD was enriched with abnormal cytogenetics [58% vs 37%, p=0.0034]. NTDMT patients had only numerically lower BM blast percentage, WBC, and platelet counts.

In domain-specific analysis, NTDMT had worse OS than non-NTDMT in pAML [8.2 vs. 15 mo., p=0.002], with no difference in sAML and MDS disease groups. PWWPMT had worse OS than non-PWWPMT in sAML alone [5.2 vs 10.6 mo., p=0.012]. ADDMT status was not related to prognostic outcome in any disease groups. MtaseMT had better OS than non-MtaseMT [11 vs 8 mo., p = 0.003] in sAML alone.

In NTDMT pAML patients with poor OS, frameshiftMT and abnormal karyotype were enriched than in the non-NTDMT group [31% vs 17.9%, p=0.04 and 57.9% vs 29.1%, p = 0.001, resp.]. PWWPMT sAML patients with worse OS had lower missense [43.2 vs 75.5, p=0.000006], higher nonsense [34.1 vs 9.7, p=0.00006] and abnormal karyotype [68.4% vs 49.1%, p= 0.0086] than in non-PWWPMT. MtaseMT sAML patients with better OS had higher missense [80.2% vs 59.2%, p= 0.002] and lower nonsense mutations [7.3% vs 20.8%, p=0.01]. CEBPA [10% vs 1.7%, p=0.02] and CSF3R [10% vs 2.9%, p=0.03] were mostly co-mutated in NTDMT pAML patients and NRAS [17% vs 7%, p=0.016] in PWWPMT sAML patients. MtaseMT sAML patients had less BCOR [6% vs 13%, p=0.03] and WT1 [1.8% vs 7%, p=0.04] than in non-MtaseMT group.


non-R882 DNMT3AMT conveys differential prognosis based on the locus. It conferred poor prognosis in pAML, with more frameshift mutations and abnormal cytogenetics. PWWPMT is associated with worse and MTaseMT with better outcomes in the sAML group. This is the first analysis to not only explore the non-R882 mutations at length but also reveal the significance of domain specific non-R882 DNMT3AMT in AML. Our study emphasizes the need to include the domain-based impact of DNMT3A mutational status in the prognostic schema for AML, which may help guide treatment plans and encourage further molecular analysis.

Disclosures: Maciejewski: Novartis: Honoraria, Speakers Bureau; Omeros: Consultancy; Regeneron: Consultancy, Honoraria; Alexion: Membership on an entity's Board of Directors or advisory committees. Balasubramanian: Kura Oncology: Research Funding; Karyopharm Therapeutics: Other: Drug supply for research.

*signifies non-member of ASH