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Single-cell analysis based dissection of clonality in myelofibrosis

Single-cell analysis based dissection of clonality in myelofibrosis
Single-cell analysis based dissection of clonality in myelofibrosis
Cancer development is an evolutionary genomic process with parallels to Darwinian selection. It requires acquisition of multiple somatic mutations that collectively cause a malignant phenotype and continuous clonal evolution is often linked to tumor progression. Here, we show the clonal evolution structure in 15 myelofibrosis (MF) patients while receiving treatment with JAK inhibitors (mean follow-up 3.9 years). Whole-exome sequencing at multiple time points reveal acquisition of somatic mutations and copy number aberrations over time. While JAK inhibition therapy does not seem to create a clear evolutionary bottleneck, we observe a more complex clonal architecture over time, and appearance of unrelated clones. Disease progression associates with increased genetic heterogeneity and gain of RAS/RTK pathway mutations. Clonal diversity results in clone-specific expansion within different myeloid cell lineages. Single-cell genotyping of circulating CD34 + progenitor cells allows the reconstruction of MF phylogeny demonstrating loss of heterozygosity and parallel evolution as recurrent events.
2041-1723
Mylonas, Elena
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Yoshida, Kenichi
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Frick, Mareike
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Hoyer, Kaja
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Christen, Friederike
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Kaeda, Jaspal
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Obenaus, Matthias
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Noerenberg, Daniel
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Hennch, Cornelius
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Chan, Willy
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Ochi, Yotaro
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Shiraishi, Yuichi
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Shiozawa, Yusuke
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Zenz, Thorsten
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Oakes, Christopher C.
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Sawitzki, Birgit
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Schwarz, Michaela
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Bullinger, Lars
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le Coutre, Philipp
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Rose-Zerilli, Matthew J.J.
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Ogawa, Seishi
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Damm, Frederik
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Mylonas, Elena
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Yoshida, Kenichi
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Frick, Mareike
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Hoyer, Kaja
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Christen, Friederike
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Kaeda, Jaspal
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Obenaus, Matthias
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Noerenberg, Daniel
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Hennch, Cornelius
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Chan, Willy
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Ochi, Yotaro
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Shiraishi, Yuichi
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Shiozawa, Yusuke
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Zenz, Thorsten
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Oakes, Christopher C.
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Sawitzki, Birgit
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Schwarz, Michaela
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Bullinger, Lars
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le Coutre, Philipp
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Rose-Zerilli, Matthew J.J.
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Ogawa, Seishi
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Damm, Frederik
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Mylonas, Elena, Yoshida, Kenichi, Frick, Mareike, Hoyer, Kaja, Christen, Friederike, Kaeda, Jaspal, Obenaus, Matthias, Noerenberg, Daniel, Hennch, Cornelius, Chan, Willy, Ochi, Yotaro, Shiraishi, Yuichi, Shiozawa, Yusuke, Zenz, Thorsten, Oakes, Christopher C., Sawitzki, Birgit, Schwarz, Michaela, Bullinger, Lars, le Coutre, Philipp, Rose-Zerilli, Matthew J.J., Ogawa, Seishi and Damm, Frederik (2020) Single-cell analysis based dissection of clonality in myelofibrosis. Nature Communications, 11 (1), [73]. (doi:10.1038/s41467-019-13892-x).

Record type: Article

Abstract

Cancer development is an evolutionary genomic process with parallels to Darwinian selection. It requires acquisition of multiple somatic mutations that collectively cause a malignant phenotype and continuous clonal evolution is often linked to tumor progression. Here, we show the clonal evolution structure in 15 myelofibrosis (MF) patients while receiving treatment with JAK inhibitors (mean follow-up 3.9 years). Whole-exome sequencing at multiple time points reveal acquisition of somatic mutations and copy number aberrations over time. While JAK inhibition therapy does not seem to create a clear evolutionary bottleneck, we observe a more complex clonal architecture over time, and appearance of unrelated clones. Disease progression associates with increased genetic heterogeneity and gain of RAS/RTK pathway mutations. Clonal diversity results in clone-specific expansion within different myeloid cell lineages. Single-cell genotyping of circulating CD34 + progenitor cells allows the reconstruction of MF phylogeny demonstrating loss of heterozygosity and parallel evolution as recurrent events.

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Accepted/In Press date: 28 November 2019
e-pub ahead of print date: 7 January 2020
Published date: 2020

Identifiers

Local EPrints ID: 437067
URI: http://eprints.soton.ac.uk/id/eprint/437067
ISSN: 2041-1723
PURE UUID: f5e129a6-c158-4178-b3f7-4c08f1eae0e6
ORCID for Matthew J.J. Rose-Zerilli: ORCID iD orcid.org/0000-0002-1064-5350

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Date deposited: 16 Jan 2020 17:31
Last modified: 13 Nov 2021 02:48

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Contributors

Author: Elena Mylonas
Author: Kenichi Yoshida
Author: Mareike Frick
Author: Kaja Hoyer
Author: Friederike Christen
Author: Jaspal Kaeda
Author: Matthias Obenaus
Author: Daniel Noerenberg
Author: Cornelius Hennch
Author: Willy Chan
Author: Yotaro Ochi
Author: Yuichi Shiraishi
Author: Yusuke Shiozawa
Author: Thorsten Zenz
Author: Christopher C. Oakes
Author: Birgit Sawitzki
Author: Michaela Schwarz
Author: Lars Bullinger
Author: Philipp le Coutre
Author: Seishi Ogawa
Author: Frederik Damm

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