PXD030616-2

PXD030616 is an original dataset announced via ProteomeXchange.

Title	RUNX1 isoforms in leukemogenesis
Description	Aneuploidy and structural aberrations affecting chromosome 21 (Hsa21) are the most frequent in cytogentic events in acute myeloid leukemia. However, it remains unclear why leukemic blasts select for amplifications of Hsa21 or parts of it and why children with Down syndrome (i.e. trisomy 21) are at a high risk of developing leukemia. Here, we propose that disequilibrium of the RUNX1 isoforms and resultant RUNX1A dominance are key to trisomy 21-associated leukemogenesis. Using a Hsa21-focussed CRISPR-Cas9 screen, we uncovered a strong and specific RUNX1 dependency in myeloid leukemia associated with Down syndrome (ML-DS). High levels of RUNX1A – as seen in ML-DS – synergized with the pathognomonic Gata1s mutation in ML-DS pathogenesis, an effect that was reversed upon restoration of the normal RUNX1A:RUNX1C equilibrium. Mechanistically, RUNX1A displaces RUNX1C from its endogenous binding sites and recruits the MYC cofactor MAX to induce oncogenic programs and perturb normal differentiation. This presents a therapeutic vulnerability that can be exploited by interfering with MYC:MAX dimerization. Our study highlights the importance of alternative splicing in leukemogenesis, and paves the way for developing specific and targeted therapies for ML-DS as well as for other leukemias with Hsa21 aneuploidy or RUNX1 isoform disequilibrium.
HostingRepository	PRIDE
AnnounceDate	2023-11-14
AnnouncementXML	Submission_2023-11-14_08:46:47.698.xml
DigitalObjectIdentifier	https://dx.doi.org/10.6019/PXD030616
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	Christian Ihling
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	iodoacetamide derivatized residue
Instrument	Q Exactive; Orbitrap Fusion

Revision	Datetime	Status	ChangeLog Entry
0	2021-12-23 00:26:47	ID requested
1	2023-05-10 13:25:07	announced
⏵ 2	2023-11-14 08:46:50	announced	2023-11-14: Updated project metadata.

10.6019/PXD030616;

Gialesaki S, Br, ä, uer-Hartmann D, Issa H, Bhayadia R, Alejo-Valle O, Verboon L, Schmell AL, Laszig S, Reg, é, nyi E, Schuschel K, Labuhn M, Ng M, Winkler R, Ihling C, Sinz A, Gla, ß M, H, ü, ttelmaier S, Matzk S, Schmid L, Str, ü, we FJ, Kadel SK, Reinhardt D, Yaspo ML, Heckl D, Klusmann JH, leukemia. Blood, 141(10):1105-1118(2023) [pubmed]

submitter keyword: Down syndrome, RUNX1,Acute Myeloid Leukemia, GATA1, Transient Abnormal Myelopoiesis

Jan-Henning Klusmann
contact affiliation	Pediatric Hematology, Oncology and Hemostaseology, Hospital for Children and Adolescents, University Hospital of Frankfurt/Main, Goethe-University Frankfurt/Main, Frankfurt, Germany
contact email	jan-henning.klusmann@kgu.de
lab head
Christian Ihling
contact affiliation	MLU Halle, Inst. f. Pharmacy
contact email	christian.ihling@pharmazie.uni-halle.de
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2023/05/PXD030616

PRIDE project URI

• PRIDE
  1. PXD030616
     1. Label: PRIDE project
     2. Name: RUNX1 isoforms in leukemogenesis