🚨🚨Paper out! 🚨🚨 Delighted to share our work, now published in @NatureGenet 🧬! https://t.co/7KJpQBsLWq We identified a targetable, chromothripsis-associated genetic event in blast phase (BP) MPN, a particularly poor prognostic subtype of acute leukaemia. 1/n 🧵👇

MEET THE FACULTY OF #ESHMPN2026! 11th Translational Research Conference Myeloproliferative Neoplasms April 24-26, 2026/Estoril, Portugal Chairs:@jjkiladjian @rosslevinemd @MullallyLab @jyoti_nangalia More information➡️ https://t.co/r6busR9sOn #ESHCONFERENCES #MPNsm

Understanding leukemic transformation: biology insights from @CKBrierley @VJHemOnc #iwMDS25 #iwMPN25 #LeukemicTransformation #MPN

Fantastic discussion from Adam Meade, @CKBrierley & Juan Carlos Hernandez-Boluda who covered novel ideas on blastic phase and transplantation #iwMDSMPN25 🩸 📷 Full discussion will be posted soon on https://t.co/O9p0vDBrzw 📷

And - above all - we are indebted to the patients, who contributed samples and inspired this work.

We are incredibly grateful for fantastic support from institutions and funders, critical to enabling this work: @CR_UK @LeukUK @wellcometrust @MRC_WIMM @RDMOxford @MSKCancerCenter @StJude

Thank you to reviewers for committing their time and energy to thoughtfully advance the manuscript, and to @SafiaDanovi for a smooth editorial process @NatureGenet

@AntonioRRomera @anton_gh @AlbaRMeira @josephhamley98 @jdavieslab @mada48422514 @jm_osullivan @Stefan_constan and others not on here.

It truly took a village to deliver this project, and would not have been possible without so many wonderful colleagues and collaborators: @GiuliaOrlandoGO #bonhamyip #jeremywen @davidcwedge @isabl_io #MariaJacobsdottir @stephen_knapper @MattBashton @Sean_Wen221 @Harshkvgoyal

With huge thanks to my supervisors and mentors for their boundless enthusiasm and support: @AdamMead_Oxford @beth_psaila @PapaemmanuilLab and the twitterless #johncrispino.

Please do check out the full paper for all the detail: https://t.co/7KJpQBsLWq 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. 13/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

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 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

Leveraging TARGET-seq, an allele-specific resolution approach to single cell genotyping (developed by @AlbaRMeira) in conjunction with the single cell copy number calling algorithm numbat (developed by @tGaoTeng), enabled inference of clonal phylogeny - 10/n

...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

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

See beautiful work by @isidrolauscherand @PeterLyLab outlining incidence, causes, and molecular dependencies. https://t.co/mdxSdukTpb 5/n