Charlotte Brierley
@ckbrierley.bsky.social
Academic Clinical Lecturer in Haematology, Oxford. Interested in all things myeloid disease and cellular therapy.
And - above all - we remain indebted to the patients who contributed samples and inspired this work. FIN.
June 10, 2025 at 3:26 PM
And - above all - we remain indebted to the patients who contributed samples and inspired this work. FIN.
We are grateful for fantastic support from institutions and funders, critical to enabling this work:
@cancerresearchuk.org @leukaemiauk.bsky.social
@wellcometrust.bsky.social @imm.ox.ac.uk
@rdm.ox.ac.uk @mskcancercenter.bsky.social @stjuderesearch.bsky.social
@cancerresearchuk.org @leukaemiauk.bsky.social
@wellcometrust.bsky.social @imm.ox.ac.uk
@rdm.ox.ac.uk @mskcancercenter.bsky.social @stjuderesearch.bsky.social
June 10, 2025 at 3:26 PM
We are grateful for fantastic support from institutions and funders, critical to enabling this work:
@cancerresearchuk.org @leukaemiauk.bsky.social
@wellcometrust.bsky.social @imm.ox.ac.uk
@rdm.ox.ac.uk @mskcancercenter.bsky.social @stjuderesearch.bsky.social
@cancerresearchuk.org @leukaemiauk.bsky.social
@wellcometrust.bsky.social @imm.ox.ac.uk
@rdm.ox.ac.uk @mskcancercenter.bsky.social @stjuderesearch.bsky.social
Thank you to reviewers for committing their time and thoughtful comments to the manuscript, and to Safia Danovi for a smooth editorial process.
June 10, 2025 at 3:26 PM
Thank you to reviewers for committing their time and thoughtful comments to the manuscript, and to Safia Danovi for a smooth editorial process.
It truly took a village to deliver this project, and would not have been possible without so many wonderful colleagues and collaborators,
@giuliaorlandogo.bsky.social Bon Ham Yip, Jeremy Wen,
@anton-henssen.bsky.social @antoniorromera.bsky.social and so many others not (yet!) on 🦋
@giuliaorlandogo.bsky.social Bon Ham Yip, Jeremy Wen,
@anton-henssen.bsky.social @antoniorromera.bsky.social and so many others not (yet!) on 🦋
June 10, 2025 at 3:26 PM
It truly took a village to deliver this project, and would not have been possible without so many wonderful colleagues and collaborators,
@giuliaorlandogo.bsky.social Bon Ham Yip, Jeremy Wen,
@anton-henssen.bsky.social @antoniorromera.bsky.social and so many others not (yet!) on 🦋
@giuliaorlandogo.bsky.social Bon Ham Yip, Jeremy Wen,
@anton-henssen.bsky.social @antoniorromera.bsky.social and so many others not (yet!) on 🦋
With huge thanks to my supervisors and mentors for their boundless enthusiasm and support: Adam Mead, @bethpsaila.bsky.social, Elli Papaemmanuil and John Crispino.
June 10, 2025 at 3:26 PM
With huge thanks to my supervisors and mentors for their boundless enthusiasm and support: Adam Mead, @bethpsaila.bsky.social, Elli Papaemmanuil and John Crispino.
Please do check out the full paper for all the detail:
shorturl.at/94s5S @natgenet.nature.com
We hope the insights generated from this study will pave the way to clinical trials of DYRK1A inhibitors - and ultimately improve outcomes for patients with this devastating disease. 15/n
shorturl.at/94s5S @natgenet.nature.com
We hope the insights generated from this study will pave the way to clinical trials of DYRK1A inhibitors - and ultimately improve outcomes for patients with this devastating disease. 15/n
Chromothripsis-associated chromosome 21 amplification orchestrates transformation to blast-phase MPN through targetable overexpression of DYRK1A - Nature Genetics
Multiomic analysis of blast-phase myeloproliferative neoplasms identifies a chromosome 21 amplicon harboring DYRK1A as a clonal and therapeutically targetable event in around a quarter of cases.
shorturl.at
June 10, 2025 at 3:26 PM
Please do check out the full paper for all the detail:
shorturl.at/94s5S @natgenet.nature.com
We hope the insights generated from this study will pave the way to clinical trials of DYRK1A inhibitors - and ultimately improve outcomes for patients with this devastating disease. 15/n
shorturl.at/94s5S @natgenet.nature.com
We hope the insights generated from this study will pave the way to clinical trials of DYRK1A inhibitors - and ultimately improve outcomes for patients with this devastating disease. 15/n
How might DYRK1A drive disease transformation in BP-MPN? Through a series of functional and mechanistic assays, we show that DYRK1A downregulates DNA repair, while concomitantly promoting cell survival by amplifying JAK STAT signaling - and that this axis is targetable. 14/n
June 10, 2025 at 3:26 PM
How might DYRK1A drive disease transformation in BP-MPN? Through a series of functional and mechanistic assays, we show that DYRK1A downregulates DNA repair, while concomitantly promoting cell survival by amplifying JAK STAT signaling - and that this axis is targetable. 14/n
DYRK1A is a serine threonine kinase with roles in cell proliferation and DNA repair. We demonstrate that genetic or pharmacological downregulation of DYRK1A reduces BPMPN cell line and primary patient cell viability and proliferation in vitro and in vivo. 13/n
June 10, 2025 at 3:26 PM
DYRK1A is a serine threonine kinase with roles in cell proliferation and DNA repair. We demonstrate that genetic or pharmacological downregulation of DYRK1A reduces BPMPN cell line and primary patient cell viability and proliferation in vitro and in vivo. 13/n
But which gene(s) in the 2.7Mb minimally amplified region might be mediating the effect? Multiomic analyses in single cell and bulk comparing chr21amp with non-chr21amp demonstrated that of the 24 genes, only one was differentially expressed and differentially accessible -DYRK1A! 12/n
June 10, 2025 at 3:26 PM
But which gene(s) in the 2.7Mb minimally amplified region might be mediating the effect? Multiomic analyses in single cell and bulk comparing chr21amp with non-chr21amp demonstrated that of the 24 genes, only one was differentially expressed and differentially accessible -DYRK1A! 12/n
- which was nicely corroborated by timing the chr21amp event on WGS against somatic mutations in the amplified segments - confirming that chr21amp occurred after JAK2 or TP53 as the final clonal event prior to disease transformation and sample collection. 11/n
June 10, 2025 at 3:26 PM
- which was nicely corroborated by timing the chr21amp event on WGS against somatic mutations in the amplified segments - confirming that chr21amp occurred after JAK2 or TP53 as the final clonal event prior to disease transformation and sample collection. 11/n
Leveraging TARGET-seq, an allele-specific resolution approach to single cell genotyping in conjunction with the single cell copy number calling algorithm numbat (developed by @gaoteng.bsky.social), enabled inference of clonal phylogeny - 10/n
June 10, 2025 at 3:26 PM
Leveraging TARGET-seq, an allele-specific resolution approach to single cell genotyping in conjunction with the single cell copy number calling algorithm numbat (developed by @gaoteng.bsky.social), enabled inference of clonal phylogeny - 10/n
..., while metaphase FISH validated the event as intrachromosomal. 9/n
June 10, 2025 at 3:26 PM
..., while metaphase FISH validated the event as intrachromosomal. 9/n
With help from a fantastic collaboration with
@isabl_io we analysed tumour-only whole genome sequencing to demonstrate that each case demonstrated a unique pattern of genomic arrangement with a shared region of maximal amplification, and features of chromothripsis 8/n
@isabl_io we analysed tumour-only whole genome sequencing to demonstrate that each case demonstrated a unique pattern of genomic arrangement with a shared region of maximal amplification, and features of chromothripsis 8/n
June 10, 2025 at 3:26 PM
With help from a fantastic collaboration with
@isabl_io we analysed tumour-only whole genome sequencing to demonstrate that each case demonstrated a unique pattern of genomic arrangement with a shared region of maximal amplification, and features of chromothripsis 8/n
@isabl_io we analysed tumour-only whole genome sequencing to demonstrate that each case demonstrated a unique pattern of genomic arrangement with a shared region of maximal amplification, and features of chromothripsis 8/n
Chr21amp was a highly adverse biomarker, with not a single patient surviving to a year, and was associated with genomic instability across the genome. 7/n
June 10, 2025 at 3:26 PM
Chr21amp was a highly adverse biomarker, with not a single patient surviving to a year, and was associated with genomic instability across the genome. 7/n
To our surprise, in a subset of chr21amp, the event was characterised by oscillating copy number with regions of high amplification - features in keeping with chromothripsis! 6/n
June 10, 2025 at 3:26 PM
To our surprise, in a subset of chr21amp, the event was characterised by oscillating copy number with regions of high amplification - features in keeping with chromothripsis! 6/n
See beautiful work by
@isidrolauscher.bsky.social and @peterlylab.bsky.social outlining incidence, causes, and molecular dependencies.
go.nature.com/3No51B6 5/n
@isidrolauscher.bsky.social and @peterlylab.bsky.social outlining incidence, causes, and molecular dependencies.
go.nature.com/3No51B6 5/n
June 10, 2025 at 3:26 PM
See beautiful work by
@isidrolauscher.bsky.social and @peterlylab.bsky.social outlining incidence, causes, and molecular dependencies.
go.nature.com/3No51B6 5/n
@isidrolauscher.bsky.social and @peterlylab.bsky.social outlining incidence, causes, and molecular dependencies.
go.nature.com/3No51B6 5/n
Chromothripsis, the shattering and haphazard repair of a chromosome after mitotic error, is a driver of somatic evolution and found in ~35% of all human cancers, but has not to date been shown to be a major player in myeloid malignancy. 4/n
June 10, 2025 at 3:26 PM
Chromothripsis, the shattering and haphazard repair of a chromosome after mitotic error, is a driver of somatic evolution and found in ~35% of all human cancers, but has not to date been shown to be a major player in myeloid malignancy. 4/n
We set out to comprehensively profile diagnostic samples from 64 blast phase MPN patients. Deploying a high density SNP array alongside next generation sequencing, we found that cases were mutationally diverse, but identified recurrent chr21q amplification ('chr21amp') in 25%. 3/n
June 10, 2025 at 3:26 PM
We set out to comprehensively profile diagnostic samples from 64 blast phase MPN patients. Deploying a high density SNP array alongside next generation sequencing, we found that cases were mutationally diverse, but identified recurrent chr21q amplification ('chr21amp') in 25%. 3/n
Leukaemic transformation in myeloproliferative neoplasms is the most feared complication of the MPNs. Here, a slow-growing clonal, chronic disorder transforms into a highly aggressive malignancy, characterised by genetic instability and a very poor response to treatment. 2/n
June 10, 2025 at 3:26 PM
Leukaemic transformation in myeloproliferative neoplasms is the most feared complication of the MPNs. Here, a slow-growing clonal, chronic disorder transforms into a highly aggressive malignancy, characterised by genetic instability and a very poor response to treatment. 2/n
Just survived this process to get to #ASH24! I feel you - a minor miracle I made it, along with remembering the school Xmas jumper day and a 1000 other bits. Failure to Out-of-office here too 😂
December 11, 2024 at 12:38 PM
Just survived this process to get to #ASH24! I feel you - a minor miracle I made it, along with remembering the school Xmas jumper day and a 1000 other bits. Failure to Out-of-office here too 😂