Pharma Strategy Blog

Commentary on Pharma & Biotech Oncology / Hematology New Product Development

According to a paper in the New England Journal of Medicine, a gene, DNA methyltransferase 3A (DNMT3A), has been found to be frequently mutated in a subset of patients (~22%) who have Acute Myeloid Leukemia (AML).  The gene has previously been associated with both foetal development and also formation of adult blood cells.  Not surprisingly, these patients often have significantly worse outcomes than patients who have normal copies of the gene.

Many of you will remember Döhner’s breakdown at ASH last year of some AML phenotypes based on a Blood paper from 2009, which illustrates both the simplicity and complexity of the underlying situation.  What’s particularly interesting is that it was clear they had no idea yet which were relevant drivers and which were passengers of the disease.

In the current research, an attempt was made to link the mutation to outcomes:

“Using massively parallel DNA sequencing, we identified a somatic mutation in DNMT3A, encoding a DNA methyltransferase, in the genome of cells from a patient with AML with a normal karyotype. We sequenced the exons of DNMT3A in 280 additional patients with de novo AML to define recurring mutations…

After discovering a frameshift mutation in DNMT3A with whole-genome sequencing, we conducted a study to determine whether DNMT3A is recurrently mutated in AML samples and whether DNMT3A mutations are associated with poor survival.”

This is important, because the authors concluded:

“DNMT3A mutations are recurrent in patients with AML and are associated with poor event-free and overall survival, independently of age and the presence of FLT3 or NPM1 mutations and regardless of the type of mutation or genetic location. This finding strongly suggests that DNMT3A mutations are probably relevant to the pathogenesis of AML.”

Impact of the findings:

The overall frequency of the DNMT3A mutation was approx. 22% in the study, particularly amongst those people with an intermediate risk profile (none were in the favourable risk category), making it a sizeable target from a potential therapeutic standpoint.

In the short term, the clinical consequence of the data means that people with AML who have the mutated DNMT3A gene are more likely to be selected for more intensive therapy earlier in treatment or for intensive clinical trials, until a more viable therapy option emerges.


ResearchBlogging.orgLey, T., Ding, L., Walter, M., McLellan, M., Lamprecht, T., Larson, D., Kandoth, C., Payton, J., Baty, J., Welch, J., Harris, C., Lichti, C., Townsend, R., Fulton, R., Dooling, D., Koboldt, D., Schmidt, H., Zhang, Q., Osborne, J., Lin, L., O’Laughlin, M., McMichael, J., Delehaunty, K., McGrath, S., Fulton, L., Magrini, V., Vickery, T., Hundal, J., Cook, L., Conyers, J., Swift, G., Reed, J., Alldredge, P., Wylie, T., Walker, J., Kalicki, J., Watson, M., Heath, S., Shannon, W., Varghese, N., Nagarajan, R., Westervelt, P., Tomasson, M., Link, D., Graubert, T., DiPersio, J., Mardis, E., & Wilson, R. (2010).
Mutations in Acute Myeloid Leukemia New England Journal of Medicine DOI: 10.1056/NEJMoa1005143

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