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 🦋

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 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

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

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
@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

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

🚨🚨Paper out! 🚨🚨

Delighted to share our work, now published in ‪@natgenet.nature.com‬ 🧬!
shorturl.at/94s5S

We identified a targetable, chromothripsis-associated genetic event in blast phase (BP) MPN, a particularly poor prognostic subtype of acute leukaemia. 1/n

Illustration: Hratch Arbach
🧵👇

The Splash @ASH! Stepping out of my comfort zone to flex a fledgling journalistic muscle. Many of the
#ASH24 community have been generous in giving time for interviews and discussion. Now looking fwd to meeting folks in person - and the fab editorial team
#ASHNewsDaily! @ash-hematology.bsky.social

Blue skies (perfect for a first post over here 🦋)and beautiful views over Greenland on a plane brimming with haematologists. A peaceful moment ahead of the tumult!
#ASH24