PXD050539

PXD050539 is an original dataset announced via ProteomeXchange.

Title	Genome-Wide CRISPR-Cas9 Screening Identifies a Synergy between Hypomethylating Agents and SUMOylation Blockade in Myelodysplastic Syndromes and Acute Myeloid Leukemia
Description	Hypomethylating agents (HMAs) are frontline therapies effective at altering the natural course of Myelodysplastic Neoplasms (MDS). However, acquired resistance and treatment failure are hallmarks of HMA therapy. Developing effective and rational HMA-focused combinatorial therapies is challenging as the underlying mechanisms driving HMA efficacy are complex. To address this clinical need, we performed a genome-wide CRISPR-Cas9 screen in a human MDS-derived cell line, MDS-L, and characterized TOPORS as a highly ranked target that synergizes with HMAs to reduce leukemic burden and improve survival in xenograft models. We demonstrated that the depletion of TOPORS mediates sensitivity to HMAs by predisposing leukemic blasts to an impaired DNA damage response (DDR) accompanied by an accumulation of SUMOylated DNMT1 in HMA-treated TOPORS-depleted cells. Importantly, the combination of HMAs with targeting of TOPORS did not functionally impair healthy hematopoiesis. While inhibitors of TOPORS are currently unavailable, we show that inhibition of SUMOylation (upstream of TOPORS functions) with TAK-981 partially phenocopies HMA-sensitivity and DDR impairment. Overall, our data suggest that the combination of HMAs with the inhibition of SUMOylation demonstrates a favourable therapeutic index and represents a rational framework towards the treatment of High-Risk MDS (HR-MDS) or Acute Myeloid Leukemia (AML).
HostingRepository	PRIDE
AnnounceDate	2024-07-25
AnnouncementXML	Submission_2024-07-25_09:49:07.064.xml
DigitalObjectIdentifier	https://dx.doi.org/10.6019/PXD050539
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	Mark Raftery
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	sumoylated lysine; monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2024-03-11 14:53:54	ID requested
⏵ 1	2024-07-25 09:49:07	announced

10.6019/PXD050539;

submitter keyword: Myelodysplastic Neoplasms, proteomics, genome-wide CRISPR-Cas9 screen, SUMO

Professor John Pimanda
contact affiliation	Lowy Cancer Research Centre School of Medical Sciences UNSW SYDNEY NSW 2052 AUSTRALIA
contact email	jpimanda@unsw.edu.au
lab head
Mark Raftery
contact affiliation	University of New South Wales
contact email	m.raftery@unsw.edu.au
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD050539
     1. Label: PRIDE project
     2. Name: Genome-Wide CRISPR-Cas9 Screening Identifies a Synergy between Hypomethylating Agents and SUMOylation Blockade in Myelodysplastic Syndromes and Acute Myeloid Leukemia