PXD058286

PXD058286 is an original dataset announced via ProteomeXchange.

Title	The Histone Acetyltransferase MOZ is a Molecular Dependency and Therapeutic Target in NUP98-Rearranged Acute Myeloid Leukemia
Description	NUP98 fusion oncoproteins (FOs) are a hallmark of childhood acute myeloid leukemia (AML), and drive leukemogenesis through liquid-liquid phase separation-mediated nuclear condensate formation. However, the composition and consequences of NUP98 FO-associated condensates are incompletely understood. Here we show that histone acetyltransferase (HAT) complex proteins including MOZ associate with NUP98 FOs, and that BRPF1, an epigenetic writer that associates with MOZ is a molecular dependency in NUP98::KDM5A AML. Inactivation of Brpf1 as well as HAT complex member Moz, Hbo1, Brd1 or Meaf6 in Nup98::Kdm5a;Vav-Cre cells impaired fitness of NUP98-rearranged cells. MOZ inhibition decreased global H3K23ac levels, displaced FO from chromatin at the Meis1 locus, and led to myeloid cell differentiation. Additionally, MOZ inhibition decreased leukemic burden in multiple NUP98-rearranged leukemia xenograft models, synergized with Menin inhibitor treatment, and was efficacious in Menin inhibitor-resistant cells. In summary, we show that MOZ is a potentially targetable dependency in NUP98-rearranged AMLs. SIGNIFICANCE STATEMENT MOZ is a member of NUP98 FO condensates with key roles in leukemia phenotypes. MOZ inhibition is effective in multiple preclinical models, including those non-responsive to Menin inhibition. MOZ and Menin inhibition are synergistic in some NUP98-rearranged models, supporting clinical translation to improve outcomes of NUP98 FO-driven leukemias.
HostingRepository	PRIDE
AnnounceDate	2025-06-03
AnnouncementXML	Submission_2025-06-03_08:28:08.048.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Valar Nila Roamio Franklin
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	monohydroxylated residue; deaminated residue
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2024-11-26 04:53:17	ID requested
⏵ 1	2025-06-03 08:28:08	announced

Dataset with its publication pending

submitter keyword: histone acetyltransferase, gene fusion, leukemia,NUP98

Clive D'santos
contact affiliation	Head of the Department, Proteomics Core
contact email	clivesdsantos@gmail.com
lab head
Valar Nila Roamio Franklin
contact affiliation	Principal Scientific Associate
contact email	Valar.Franklin@cruk.cam.ac.uk
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD058286
     1. Label: PRIDE project
     2. Name: The Histone Acetyltransferase MOZ is a Molecular Dependency and Therapeutic Target in NUP98-Rearranged Acute Myeloid Leukemia