PXD054797

PXD054797 is an original dataset announced via ProteomeXchange.

Title	Mechanisms of Chemotherapy Failure in Refractory/Relapsed Acute Myeloid Leukemia: The Role of Cytarabine Resistance and Mitochondrial Metabolism
Description	Acute myeloid leukemia (AML) originates from malignant, immature myeloid progenitor cells that differentiate into dysfunctional myeloblasts. While cytarabine (Ara-C) and daunorubicin (DNR)-based chemotherapy regimens are the standard treatments, approximately 10-40% of AML patients under the age of 60 and 40-60% over 60 do not respond, leading to refractory or relapsed (R/R) AML. Targeted chemotherapy for FLT3-ITD mutated R/R AML cells improves response rates and survival outcomes in FLT3-ITD mutated R/R AML patients. However, patients with wild-type FLT3 R/R AML remain therapeutically challenged, with persistent difficulty in finding effective treatments. Better insights on the fundamental understanding of treatment failure in wild-type FLT3 AML cells are needed to enhance therapeutic outcomes. However, precise mechanisms behind the treatment failure remain unclear. This study investigates the mechanisms underlying the failure of Ara-C and DNR-based chemotherapy in wild-type FLT3 R/R AML. Using RHI-1 cells, a wild-type FLT3 AML cell line with Ara-C resistance, we demonstrated that Ara-C resistance-mediated DNR tolerance did not result from reducing the concentration of DNR in RHI-1 cells, but rather from interrupting the cytotoxic mechanisms of DNR through the Ara-C resistance of RHI-1. The down-regulated deoxycytidine kinase (DCK) in RHI-1 cells interrupted mechanisms of Ara-C cytotoxic action. Also, the down-regulation of DCK enhanced mitochondrial metabolic pathways, DNA repair process, and ROS detoxification. Through these pathways, RHI-1 cells exhibit tolerance under DNR treatment. Among these enhanced processes, targeting mitochondrial metabolism, particularly OXPHOS complex I proteins, improved the efficacy of both Ara-C and DNR. Our findings shed light on a potential mechanism underlying the treatment failure and the role of mitochondrial metabolism in wild-type FLT3 R/R AML cells.
HostingRepository	PRIDE
AnnounceDate	2025-05-07
AnnouncementXML	Submission_2025-05-07_00:27:37.353.xml
DigitalObjectIdentifier	https://dx.doi.org/10.6019/PXD054797
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	Jong-Seo Kim
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	phosphorylated residue
Instrument	Orbitrap Eclipse

Revision	Datetime	Status	ChangeLog Entry
0	2024-08-11 20:25:20	ID requested
⏵ 1	2025-05-07 00:27:38	announced

10.6019/PXD054797;

10.1038/s41419-025-07653-6;

Yeon Chae S, Jang SY, Kim J, Hwang S, Malani D, Kallioniemi O, Yun SG, Kim JS, Kim HI, Mechanisms of chemotherapy failure in refractory/relapsed acute myeloid leukemia: the role of cytarabine resistance and mitochondrial metabolism. Cell Death Dis, 16(1):331(2025) [pubmed]

submitter keyword: Mitochondrial metabolism,Acute myeloid leukemia, Cytrabine

Jong-Seo Kim
contact affiliation	Assistant professor, School of Biological Sciences, Seoul National University
contact email	jongseokim@snu.ac.kr
lab head
Jong-Seo Kim
contact affiliation	School of Biological Sciences, Seoul National University
contact email	jongseokim@snu.ac.kr
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/2025/05/PXD054797

PRIDE project URI

• PRIDE
  1. PXD054797
     1. Label: PRIDE project
     2. Name: Mechanisms of Chemotherapy Failure in Refractory/Relapsed Acute Myeloid Leukemia: The Role of Cytarabine Resistance and Mitochondrial Metabolism