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. 2015 Nov;100(11):e438-42.
doi: 10.3324/haematol.2015.129510. Epub 2015 Aug 6.

DNMT3A mutations occur early or late in patients with myeloproliferative neoplasms and mutation order influences phenotype

Jyoti Nangalia  1 , Francesca L Nice  2 , David C Wedge  3 , Anna L Godfrey  4 , Jacob Grinfeld  1 , Clare Thakker  2 , Charlie E Massie  2 , Joanna Baxter  5 , David Sewell  5 , Yvonne Silber  2 , Peter J Campbell  1 , Anthony R Green  6
Affiliations

DNMT3A mutations occur early or late in patients with myeloproliferative neoplasms and mutation order influences phenotype

Jyoti Nangalia et al. Haematologica. 2015 Nov.
No abstract available

Keywords: DNMT3A mutation; mutation order; myeloproliferative neoplasms.

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Figures

Figure 1.
Figure 1.
Timing of acquisition of DNMT3A mutations. Single cell-derived hematopoietic erythroid colonies (BFU-E) were grown in vitro from peripheral blood-derived mononuclear cells and individually genotyped for mutations using Sanger sequencing. Plots in (A), (B), (C) and (D) show colony genotyping results for mutations in DNMT3A and JAK2, MPL or CALR for each patient and the order of mutation acquisition. Within each plot, each dot represents a single colony and its quadrant placement shows the corresponding genotype of DNMT3A (vertical axis) and JAK2/MPL/CALR (horizontal axis). Solid red arrows within quadrants show the confirmed path of clonal evolution. Wt, wild-type; het, heterozygous mutation; hom, homozygous mutation; PV, polycythemia vera; ET, essential thrombocythemia; PMF, primary myelofibrosis; PPV-MF, post-PV myelofibrosis (A) DNMT3A-first patients: four patients in whom mutated DNMT3A occurred prior to the acquisition of JAK2V617F. (B) Biclonal patients: three patients in whom DNMT3Amut and JAK2V617F were in separate clones. (C) JAK2/MPL-first patients: three patients in whom mutated JAK2 or MPL occurred prior to the acquisition of mutated DNMT3A. (D) Order unknown: three patients in whom the order of mutation acquisition of DNMT3A and JAK2/MPL/CALR could not be delineated as only wild-type colonies and/or double mutant colonies were detected.
Figure 2.
Figure 2.
Clonal structures of DNMT3A-mutated MPN. Individual single cell-derived hematopoietic erythroid colonies (BFU-E) from six patients were genotyped using Sanger sequencing or Fluidigm single nucleotide polymorphism genotyping for their respective somatic variants identified previously by whole exome sequencing. Genotyping results from individual colonies were then used to construct phylogenetic trees. Circles represent the subclones; wild-type (white); mutated (brown). The earliest detectable clone is represented at the top of each structure, with subsequent subclones shown below. Somatic mutations acquired in each subclone are indicated beside respective circles, and represent those that are acquired in addition to mutations present in earlier clones. Numbers of colonies identified for each subclone are shown inside circles. Mutations in JAK2, MPL, CALR and DNMT3A are highlighted in red. Additional mutations in genes known to be recurrently mutated in myeloid malignancies are highlighted in green. ET: essential thrombocythemia; PMF: primary myelofibrosis; PV: polycythemia vera; het: heterozygous mutation; hom: homozygous mutation.
Figure 3.
Figure 3.
Evolution of subclones in DNMT3A-mutated MPN. (A) Colonies grown from paired samples obtained at different time-points (median separation 35 months; range, 6–179 months) in ten patients. Vertical axis shows the percentage of total colonies and columns are shaded to represent the proportions of the different genotypes (red, JAK2/MPL-only; blue, DNMT3A-only; purple, double mutant). Numbers of colonies genotyped per patient are shown above columns and the timings of sample acquisition (months from diagnosis) are shown below. (B) Changes in subclonal proportions over time for the ten patients in (A) for a total of 19 subclones. red, JAK2/MPL-only; blue, DNMT3A-only; purple, double mutant; T1 and T2 represent the earliest and latest time-points sampled for the patients. The median interval between T1 and T2 did not differ significantly between the different subclones (one-way analysis of variance). * <0.05 Wilcoxon ranked sum test.
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References

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