Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2014 Oct 4:7:74.
doi: 10.1186/s13045-014-0074-4.

Clinical features of de novo acute myeloid leukemia with concurrent DNMT3A, FLT3 and NPM1 mutations

Sanam Loghavi, Zhuang Zuo, Farhad Ravandi, Hagop M Kantarjian, Carlos Bueso-Ramos, Liping Zhang, Rajesh R Singh, Keyur P Patel, L Jeffrey Medeiros, Francesco Stingo, Mark Routbort, Jorge Cortes, Rajyalakshmi Luthra, Joseph D Khoury

Clinical features of de novo acute myeloid leukemia with concurrent DNMT3A, FLT3 and NPM1 mutations

Sanam Loghavi et al. J Hematol Oncol. .

Abstract

Background: De novo acute myeloid leukemia (AML) with concurrent DNMT3A, FLT3 and NPM1 mutations (AML DNMT3A/FLT3/NPM1 ) has been suggested to represent a unique AML subset on the basis of integrative genomic analysis, but the clinical features of such patients have not been characterized systematically.

Methods: We assessed the features of patients (n = 178) harboring mutations in DNMT3A, FLT3 and/or NPM1, including an index group of AML DNMT3A/FLT3/NPM1 patients.

Results: Patients with AML DNMT3A/FLT3/NPM1 (n = 35) were significantly younger (median, 56.0 vs. 62.0 years; p = 0.025), mostly women (65.7% vs. 46.9%; p = 0.045), and presented with a higher percentage of bone marrow blasts (p < 0.001) and normal cytogenetics (p = 0.024) in comparison to patients within other mutation groups in this study. Among patients <60 years old, those with AML DNMT3A/FLT3/NPM1 had a shorter event-free survival (EFS) (p = 0.047). DNMT3A mutations and not FLT3 or NPM1 mutations were independently associated with overall survival (OS) (p = 0.026). Within mutation subgroups, patients with AML DNMT3A/NPM1 had a significantly shorter OS compared to those with AML FLT3-ITD/NPM1 (p = 0.047) suggesting that the adverse impact of DNMT3A mutations is more pronounced than that of FLT3-ITD among patients with NPM1 mutation.

Conclusions: DNMT3A has a significant dominant effect on the clinical features and outcomes of de novo AML patients with concurrent DNMT3A, FLT3 and NPM1 mutations.

PubMed Disclaimer

Figures

Figure 1
Figure 1
Mutation subgroups of de novo acute myeloid leukemia included in the study.
Figure 2
Figure 2
Schematic representation of mutations. (a) Mutation status of genes assessed in all patients in the study group. Each column represents an individual case. The bottom rows represent, respectively, the cytogenetic risk group (CG) and mutation group (MG) per corresponding color designation. Assessed genes in which mutations were not detected are not included in this diagram. Mutation detection techniques in the MDACC and TCGA groups were different (see Methods section). (b) Distribution of genomic variants within DNMT3A detected in the study group. PWWP represents a region encoding for a highly conserved proline-tryptophan-tryptophan-proline motif. ZNF represents the ADD (ATRX, DNMT3, and DNMT3L)-type zinc finger domain.
Figure 3
Figure 3
Estimated DNMT3A, FLT3 , and NPM1 variant (allelic) frequencies in a subset of de novo acute myeloid leukemia samples harboring all three mutations.
Figure 4
Figure 4
Survival analysis by mutation status. Overall survival (a) and event-free survival (b) of de novo acute myeloid leukemia patients younger than 60 years of age with concomitant mutations in DNMT3A, FLT3, and NPM1 (AMLDNMT3A/FLT3/NPM1) in comparison to those within other mutation subgroups in this study. Overall survival (c) and event-free survival (d) of patients with AML harboring NPM1 mutation in conjunction with wild-type DNMT3A (NPM1 group) or mutant DNMT3A (NPM1/DNMT3A group). Overall survival (e) of patients with CN-AML harboring NPM1 mutations with concomitant FLT3 (NPM1/FLT3 group) or DNMT3A (NPM1/DNMT3A group).
See this image and copyright information in PMC

References

    1. Ley TJ, Miller C, Ding L, Raphael BJ, Mungall AJ, Robertson A, Hoadley K, Triche TJ, Jr, Laird PW, Baty JD, Fulton LL, Fulton R, Heath SE, Kalicki-Veizer J, Kandoth C, Klco JM, Koboldt DC, Kanchi KL, Kulkarni S, Lamprecht TL, Larson DE, Lin L, Lu C, McLellan MD, McMichael JF, Payton J, Schmidt H, Spencer DH, Tomasson MH, Wallis JW, et al. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N Engl J Med. 2013;368:2059–2074. doi: 10.1056/NEJMoa1301689. - DOI - PMC - PubMed
    1. Patel JP, Gonen M, Figueroa ME, Fernandez H, Sun Z, Racevskis J, Van Vlierberghe P, Dolgalev I, Thomas S, Aminova O, Huberman K, Cheng J, Viale A, Socci ND, Heguy A, Cherry A, Vance G, Higgins RR, Ketterling RP, Gallagher RE, Litzow M, van den Brink MR, Lazarus HM, Rowe JM, Luger S, Ferrando A, Paietta E, Tallman MS, Melnick A, Abdel-Wahab O, et al. Prognostic relevance of integrated genetic profiling in acute myeloid leukemia. N Engl J Med. 2012;366:1079–1089. doi: 10.1056/NEJMoa1112304. - DOI - PMC - PubMed
    1. Ley TJ, Ding L, Walter MJ, McLellan MD, Lamprecht T, Larson DE, Kandoth C, Payton JE, Baty J, Welch J, Harris CC, Lichti CF, Townsend RR, Fulton RS, Dooling DJ, Koboldt DC, Schmidt H, Zhang Q, Osborne JR, Lin L, O'Laughlin M, McMichael JF, Delehaunty KD, McGrath SD, Fulton LA, Magrini VJ, Vickery TL, Hundal J, Cook LL, Conyers JJ, et al. DNMT3A mutations in acute myeloid leukemia. N Engl J Med. 2010;363:2424–2433. doi: 10.1056/NEJMoa1005143. - DOI - PMC - PubMed
    1. Thol F, Damm F, Ludeking A, Winschel C, Wagner K, Morgan M, Yun H, Gohring G, Schlegelberger B, Hoelzer D, Lubbert M, Kanz L, Fiedler W, Kirchner H, Heil G, Krauter J, Ganser A, Heuser M. Incidence and prognostic influence of DNMT3A mutations in acute myeloid leukemia. J Clin Oncol. 2011;29:2889–2896. doi: 10.1200/JCO.2011.35.4894. - DOI - PubMed
    1. Frohling S, Schlenk RF, Breitruck J, Benner A, Kreitmeier S, Tobis K, Dohner H, Dohner K, leukemia AMLSGUAm Prognostic significance of activating FLT3 mutations in younger adults (16 to 60 years) with acute myeloid leukemia and normal cytogenetics: a study of the AML Study Group Ulm. Blood. 2002;100:4372–4380. doi: 10.1182/blood-2002-05-1440. - DOI - PubMed

Publication types

MeSH terms