Can DNMT3AR882H be used as a marker for MRD monitoring?

It has been reported that the recurrently mutated DNMT3A can be detected in cells of Acute Myeloid Leukemia (AML) patients in long-lasting Complete Remission (CR).1 In order to investigate whether DNMT3A could be used as a marker for Measurable Residual Disease (MRD) monitoring, Tiziana Ottone from Tor Vergata University, Rome, IT, and colleagues performed a sequential monitoring of DNMT3AR882H in AML patients and compared it to NPM1-mutation (mutation A) levels. The results of the study were reported in a Correspondence to the American Journal of Hematology.2

Mutational analysis of the most common alteration found in mutated DNMT3A gene, located at residue R882 of the methyltransferase domain (DNMT3AR882), NPM1 and FLT3 (ITD/TKD) was assessed at diagnosis in 556 patients with de novo AML (median age = 49 years, range 16–89 years) who were enrolled in clinical trials conducted by the Gruppo Italiano Malattie EMatologiche dell’Adulto (GIMEMA) between 2012–2015.

Quantitative assessment of DNMT3AR882H, NPM1mutA and patient-specific FLT3-ITD was performed on bone marrow (BM) samples collected at diagnosis, during follow-up and at the time of relapse

Key findings:
  • NPM1mut transcript levels in patients (n = 51) were significantly different at diagnosis, post-induction and post-consolidation therapy and was independent from DNMT3AR882 and FLT3 status
  • DNMT3AR882H expression levels, analyzed longitudinally in patients (n = 21) significantly decreased only after induction, but not after consolidation therapy regardless of the presence of FLT3 mutations
  • Compared to NPM1mut, DNMT3AR882H did not significantly increase at relapse, P = 0.09
  • In CR patients, there was no significant difference in DNMT3AR882H expression between multiparametric flow cytometry (MPFC) MRD positive and negative BM samples
  • Compared to NPM1mut, DNMT3AR882H expression levels in patient cells at relapse were higher in total BM-mononuclear cells than in the leukemia associated immunophenotype positive cells

The authors concluded by stating that their study “indicates that DNMT3AR882H quantification is an unreliable tool for MRD monitoring since it does not reflect disease status in AML”. They further added that “DNMT3AR882H mutation is likely present in pre-leukemic clonal myeloid and lymphoid populations persisting at the time of CR”.

  1. Pløen G. G. et al. Persistence of DNMT3A mutations at long-term remission in adult patients with AML. Br J Haematol. 2014; 167(4): 478–486. DOI: 10.1111/bjh.13062.
  2. Ottone T. et al. Longitudinal detection of DNMT3AR882H transcripts in patients with acute myeloid leukemia. Am J Hematol. 2018 Feb 8. DOI: 10.1002/ajh.25061. [Epub ahead of print].