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Clonal evolution revealed by whole genome sequencing in a case of primary myelofibrosis transformed to secondary acute myeloid leukemia.

Engle EK, Fisher DA, Miller CA, McLellan MD, Fulton RS, Moore DM, Wilson RK, Ley TJ, Oh ST - Leukemia (2014)

Bottom Line: The third group (including ASXL1) contained mutations with low frequency in PMF and high frequency in subsequent samples, indicating evolution of the dominant clone with disease progression.The fourth clonal group (including IDH1 and RUNX1) was acquired at sAML transformation and was predominantly absent at sAML remission/relapsed PMF.Taken together, these findings illustrate the complex clonal dynamics associated with disease evolution in MPNs and sAML.

View Article: PubMed Central - PubMed

Affiliation: Division of Hematology, Washington University School of Medicine, St Louis, MO, USA.

ABSTRACT
Clonal architecture in myeloproliferative neoplasms (MPNs) is poorly understood. Here we report genomic analyses of a patient with primary myelofibrosis (PMF) transformed to secondary acute myeloid leukemia (sAML). Whole genome sequencing (WGS) was performed on PMF and sAML diagnosis samples, with skin included as a germline surrogate. Deep sequencing validation was performed on the WGS samples and an additional sample obtained during sAML remission/relapsed PMF. Clustering analysis of 649 validated somatic single-nucleotide variants revealed four distinct clonal groups, each including putative driver mutations. The first group (including JAK2 and U2AF1), representing the founding clone, included mutations with high frequency at all three disease stages. The second clonal group (including MYB) was present only in PMF, suggesting the presence of a clone that was dispensable for transformation. The third group (including ASXL1) contained mutations with low frequency in PMF and high frequency in subsequent samples, indicating evolution of the dominant clone with disease progression. The fourth clonal group (including IDH1 and RUNX1) was acquired at sAML transformation and was predominantly absent at sAML remission/relapsed PMF. Taken together, these findings illustrate the complex clonal dynamics associated with disease evolution in MPNs and sAML.

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Clustering and clonal evolution across disease progressionUnsupervised clustering of 649 SNVs identified clusters of mutations with similar variant allele frequencies corresponding to the founding clone (green), subclone 1 (light blue), subclone 2 (red), and subclone 3 (dark blue). (A) Frequency of mutations in PMF versus sAML. (B) Frequency of mutations in sAML remission/relapsed PMF versus sAML. (C) A model of clonal evolution based on the median values for the VAFs in each of the four clusters at each stage of progression in (A) and (B) as shown below the plot. Abbreviations: PMF, primary myelofibrosis; sAML, secondary acute myeloid leukemia; sAML REM, secondary acute myeloid leukemia remission/relapsed PMF.
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Figure 3: Clustering and clonal evolution across disease progressionUnsupervised clustering of 649 SNVs identified clusters of mutations with similar variant allele frequencies corresponding to the founding clone (green), subclone 1 (light blue), subclone 2 (red), and subclone 3 (dark blue). (A) Frequency of mutations in PMF versus sAML. (B) Frequency of mutations in sAML remission/relapsed PMF versus sAML. (C) A model of clonal evolution based on the median values for the VAFs in each of the four clusters at each stage of progression in (A) and (B) as shown below the plot. Abbreviations: PMF, primary myelofibrosis; sAML, secondary acute myeloid leukemia; sAML REM, secondary acute myeloid leukemia remission/relapsed PMF.

Mentions: Using the assumption that mutations with similar VAFs represented a clonal group and traveled together, clonal groups were identified based on clusters of VAFs. Unsupervised clustering of the VAFs from the PMF and sAML sample identified a founding clone and two subclones (Figure 3A). The frequency of variants in the sAML remission/relapsed PMF sample provided a third timepoint to resolve clonal groups and showed that there was a founding clone and three subclones (Figure 3B). The sAML remission/relapsed PMF sample distinguished between a sAML-only clonal group and a clonal group that had a high VAF at both sAML and sAML remission/relapsed PMF. Based on the clustering results, a model of clonal progression was developed demonstrating the dynamics of clonal evolution across disease progression (Figure 3C).


Clonal evolution revealed by whole genome sequencing in a case of primary myelofibrosis transformed to secondary acute myeloid leukemia.

Engle EK, Fisher DA, Miller CA, McLellan MD, Fulton RS, Moore DM, Wilson RK, Ley TJ, Oh ST - Leukemia (2014)

Clustering and clonal evolution across disease progressionUnsupervised clustering of 649 SNVs identified clusters of mutations with similar variant allele frequencies corresponding to the founding clone (green), subclone 1 (light blue), subclone 2 (red), and subclone 3 (dark blue). (A) Frequency of mutations in PMF versus sAML. (B) Frequency of mutations in sAML remission/relapsed PMF versus sAML. (C) A model of clonal evolution based on the median values for the VAFs in each of the four clusters at each stage of progression in (A) and (B) as shown below the plot. Abbreviations: PMF, primary myelofibrosis; sAML, secondary acute myeloid leukemia; sAML REM, secondary acute myeloid leukemia remission/relapsed PMF.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4374044&req=5

Figure 3: Clustering and clonal evolution across disease progressionUnsupervised clustering of 649 SNVs identified clusters of mutations with similar variant allele frequencies corresponding to the founding clone (green), subclone 1 (light blue), subclone 2 (red), and subclone 3 (dark blue). (A) Frequency of mutations in PMF versus sAML. (B) Frequency of mutations in sAML remission/relapsed PMF versus sAML. (C) A model of clonal evolution based on the median values for the VAFs in each of the four clusters at each stage of progression in (A) and (B) as shown below the plot. Abbreviations: PMF, primary myelofibrosis; sAML, secondary acute myeloid leukemia; sAML REM, secondary acute myeloid leukemia remission/relapsed PMF.
Mentions: Using the assumption that mutations with similar VAFs represented a clonal group and traveled together, clonal groups were identified based on clusters of VAFs. Unsupervised clustering of the VAFs from the PMF and sAML sample identified a founding clone and two subclones (Figure 3A). The frequency of variants in the sAML remission/relapsed PMF sample provided a third timepoint to resolve clonal groups and showed that there was a founding clone and three subclones (Figure 3B). The sAML remission/relapsed PMF sample distinguished between a sAML-only clonal group and a clonal group that had a high VAF at both sAML and sAML remission/relapsed PMF. Based on the clustering results, a model of clonal progression was developed demonstrating the dynamics of clonal evolution across disease progression (Figure 3C).

Bottom Line: The third group (including ASXL1) contained mutations with low frequency in PMF and high frequency in subsequent samples, indicating evolution of the dominant clone with disease progression.The fourth clonal group (including IDH1 and RUNX1) was acquired at sAML transformation and was predominantly absent at sAML remission/relapsed PMF.Taken together, these findings illustrate the complex clonal dynamics associated with disease evolution in MPNs and sAML.

View Article: PubMed Central - PubMed

Affiliation: Division of Hematology, Washington University School of Medicine, St Louis, MO, USA.

ABSTRACT
Clonal architecture in myeloproliferative neoplasms (MPNs) is poorly understood. Here we report genomic analyses of a patient with primary myelofibrosis (PMF) transformed to secondary acute myeloid leukemia (sAML). Whole genome sequencing (WGS) was performed on PMF and sAML diagnosis samples, with skin included as a germline surrogate. Deep sequencing validation was performed on the WGS samples and an additional sample obtained during sAML remission/relapsed PMF. Clustering analysis of 649 validated somatic single-nucleotide variants revealed four distinct clonal groups, each including putative driver mutations. The first group (including JAK2 and U2AF1), representing the founding clone, included mutations with high frequency at all three disease stages. The second clonal group (including MYB) was present only in PMF, suggesting the presence of a clone that was dispensable for transformation. The third group (including ASXL1) contained mutations with low frequency in PMF and high frequency in subsequent samples, indicating evolution of the dominant clone with disease progression. The fourth clonal group (including IDH1 and RUNX1) was acquired at sAML transformation and was predominantly absent at sAML remission/relapsed PMF. Taken together, these findings illustrate the complex clonal dynamics associated with disease evolution in MPNs and sAML.

Show MeSH
Related in: MedlinePlus