Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Targeting Y593-phosphorylated DDX5 triggers mitochondrial dysfunction and synergizes with BCL2 inhibition in acute myeloid leukemia

ABSTRACT: Acute myeloid leukemia (AML) remains a lethal malignancy with limited therapeutic durability. DEAD-box RNA helicase 5 (DDX5) is highly expressed in AML and associated with poor outcome, yet its mechanistic role and therapeutic tractability are incompletely defined. Here, we identify phosphorylation at tyrosine 593 (Y593) of DDX5 as a therapeutic vulnerability in AML. We show that DDX5 is constitutively phosphorylated at Y593 in AML cells independent of Src or c-Abl activity. While genetic depletion of DDX5 suppresses AML growth, phosphorylation-deficient Y593F knock-in mutants show that Y593 phosphorylation is dispensable for baseline proliferation but is required to maintain mitochondrial integrity and define the BCL-2 family–controlled apoptotic threshold. Targeting Y593-phosphorylated DDX5 with the small-molecule RX-5902 destabilizes β-catenin and, more importantly, triggers acute mitochondrial dysfunction characterized by impaired oxidative phosphorylation, permeabilizes mitochondrial outer membranes, and increases BCL-2 dependence. Accordingly, inhibition of Y593-phosphorylated DDX5 represents a mitochondrial sensitizer that creates vulnerability to BCL-2 blockade. Consistent with this mechanism, RX-5902 strongly synergizes with venetoclax across AML cell lines, primary patient samples, and xenograft models. Together, these findings establish Y593-phosphorylated DDX5 as an actionable regulator of mitochondrial apoptotic priming in AML and support combined targeting of DDX5 and BCL-2 as a rational therapeutic strategy.

ORGANISM(S): Homo sapiens

PROVIDER: GSE324645 | GEO | 2026/05/01

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Mitochondria inside acute myeloid leukemia cells hydrolyze ATP to resist chemotherapy

Project description:Despite early optimism, therapeutics targeting oxidative phosphorylation (OxPhos) have faced clinical setbacks, primarily stemming from their inability to distinguish healthy from cancerous mitochondria. Herein, we describe an actionable bioenergetic mechanism unique to cancerous mitochondria inside acute myeloid leukemia (AML) cells. Unlike healthy cells which couple respiration to the synthesis of ATP, AML mitochondria were discovered to support inner membrane polarization by consuming ATP. Because matrix ATP consumption allows cells to survive bioenergetic stress, we hypothesized that AML cells may resist cell death induced by OxPhos damaging chemotherapy by reversing the ATP synthase reaction. In support of our hypothesis, targeted inhibition of BCL-2 with venetoclax abolished OxPhos flux without impacting mitochondrial membrane potential. In surviving AML cells, sustained polarization of the mitochondrial inner membrane was dependent on matrix ATP consumption. Mitochondrial ATP consumption was further enhanced in AML cells made refractory venetoclax, consequential to downregulations in both the proton-pumping respiratory complexes, as well the endogenous F1-ATPase inhibitor ATP5IF1. In treatment-naive AML, ATP5IF1 knockdown was sufficient to drive venetoclax resistance, while ATP5IF1 overexpression impaired F1-ATPase activity and heightened sensitivity to venetoclax. Collectively, our data identify matrix ATP consumption as cancer-cell intrinsic bioenergetic vulnerability actionable in the context of mitochondrial damaging chemotherapy.

2025-04-02 | PXD051129 | JPOST Repository

SETD2 Deficiency Drives Mitochondrial DNA Leakage and Creates a Druggable Dependency on BCL-XL in Clear Cell Renal Cell Carcinoma

Project description:SETD2 is frequently mutated or deleted in clear cell renal cell carcinoma (ccRCC). Loss of SETD2 could create synthetic lethal dependencies that confer therapeutic vulnerabilities. Here, we demonstrated that SETD2 deficiency promotes cytoplasmic mitochondrial DNA (mtDNA) leakage, leading to basal activation of cGAS-STING inflammatory signaling and increased apoptotic priming. This inflammatory state upregulated the BH3-only protein NOXA, constrained MCL-1 function, and enforced a synthetic lethal dependency on the anti-apoptotic protein BCL-xL. Pharmacological inhibition of BCL-xL further amplified cGAS-STING signaling in SETD2-deficient cells through sublethal mitochondrial outer membrane permeabilization, resulting in increased mtDNA release and robust NOXA induction. Elevated NOXA neutralized the compensatory MCL-1-mediated survival signaling, triggering apoptosis. In contrast, SETD2 proficient ccRCC cells exhibited minimal cGAS-STING activation and failed to induce NOXA following BCL-xL inhibition, rendering them resistant. Genetic ablation of cGAS, STING, IRF3, or NOXA rescued sensitivity to BCL-xL inhibition, confirming that mtDNA-driven innate immune signaling is required for this dependency. In vivo, BCL-xL inhibition suppressed tumor growth and prolonged survival in SETD2-deficient xenograft models. Collectively, these findings establish a mechanistic link between SETD2 loss, mtDNA-driven innate immune activation, and enforced BCL-xL dependence in ccRCC, revealing a therapeutically targetable vulnerability in SETD2-deficient tumors.

2026-04-23 | GSE297044 | GEO

Supinoxin Blocks Small Cell Lung Cancer Progression by Inhibiting Mitochondrial Respiration through DDX5

Project description:DDX5 is a DEAD-box RNA helicase that is overexpressed and implicated in the progression of several cancers, including small cell lung cancer (SCLC). Our laboratory has demonstrated that DDX5 is essential for the invasive growth of SCLC and mitochondrial respiration. SCLC is an extremely lethal, recalcitrant tumor, and currently lacking effective treatments. Supinoxin (RX 5902), a compound having anti-cancer activity, is a known target of phosphor-DDX5. We now report that Supinoxin inhibits the proliferation of chemo-sensitive and chemo-resistant SCLC lines, H69 and H69AR respectively. Additionally, Supinoxin mitigates both the growth of H69AR xenograft tumors and SCLC PDX tumors in vivo. Finally, we find that Supinoxin inhibits expression of mitochondrial genes and effectively blocks respiration. These studies suggest that Supinoxin functions in anti-tumor progression by reducing cellular energy levels through DDX5.

2025-02-20 | GSE255741 | GEO

Targeting NLRP3 inhibits AML progression by inducing PERK/eIF2-mediated apoptosis

Project description:Hyperactivation of the NLRP3 inflammasome has been linked to disease progression in acute myeloid leukemia (AML). However, the precise mechanisms behind this pathology remain elusive. Here, we highlight not only a significant correlation between elevated NLRP3 expression and diminished overall survival in AML patients, but also a potential pathomechanism. We show that genetic deletion and pharmacological inhibition of NLRP3 leads to a reduction in AML cell survival by triggering apoptosis. Additionally, our proteomic analyses revealed NLRP3-dependent alterations in protein translation, substantiated by increased eIF2α phosphorylation in NLRP3-deficient AML cells. Furthermore, we show that inhibition of the eIF2α kinase PERK mitigates eIF2α phosphorylation and decreases apoptosis by reducing the expression of pro-apoptotic Bcl-2 family members to levels comparable to those of wild-type cells. Substantiating these observations, we found that deleting NLRP3 in engrafted AML cells led to reduced splenomegaly and AML cell infiltration into organs in mice. Taken together, our findings demonstrate that blocking NLRP3 induces apoptosis via PERK/eIF2, revealing a promising avenue for therapeutic intervention in AML.

2024-08-14 | PXD047745 | Pride

Identification of CD84 as a potent survival factor in acute myeloid leukemia

Project description:Acute myeloid leukemia (AML) is an aggressive and often deadly malignancy associated with proliferative immature myeloid blasts. Here, we identified CD84 as a critical survival regulator in AML. High levels of CD84 expression provide survival advantage to leukemia cells, whereas CD84 downregulation disrupts their proliferation, clonogenicity and engraftment capabilities in both human cell lines and patient derived xenograft cells. Critically, loss of CD84 also markedly blocks leukemia engraftment and clonogenicity in MLL-AF9 and inv(16) AML mouse models, highlighting its pivotal role as survival factor across species. Mechanistically, CD84 regulates leukemia cells’ energy metabolism and mitochondrial dynamics. Depletion of CD84 alters mitochondrial ultra-structure and function of leukemia cells, and it caused down-modulation of both oxidative phosphorylation and fatty acid oxidation pathways. CD84 knockdown induced a block of Akt phosphorylation and down-modulation of nuclear factor erythroid 2-related factor 2 (NRF2) impairing AML antioxidant defense. Conversely, CD84 over-expression stabilizes NRF2 and promotes its transcriptional activation, thereby supporting redox homeostasis and mitochondrial function in AML. Collectively, our findings indicate that AML cells depend on CD84 to support antioxidant pro-survival pathways, highlighting a previously unexplored therapeutic vulnerability of leukemia cells.

2025-05-01 | GSE288016 | GEO

Mitochondrial metabolism sustains DNMT3A-R882-mutant clonal haematopoiesis

Project description:Somatic DNMT3A R882 codon mutations drive the most common form of clonal haematopoiesis (CH) and are associated with increased acute myeloid leukaemia (AML) risk1,2. Preventing expansion of DNMT3A-R882-mutant haematopoietic stem/progenitor cells (HSPCs) may therefore avert progression to AML. To identify DNMT3A-R882-mutant-specific vulnerabilities, we conducted a genome-wide CRISPR screen on primary mouse Dnmt3aR882H/+ HSPCs. Amongst the 640 vulnerability genes identified, many were involved in mitochondrial metabolism and metabolic flux analysis confirmed enhanced oxidative phosphorylation usage in Dnmt3aR882H/+ vs Dnmt3a+/+ (WT) HSPCs. We selected citrate/malate transporter Slc25a1 and complex I component Ndufb11, for which pharmacological inhibitors are available, for downstream studies. In vivo administration of SLC25A1 inhibitor CTPI2 and complex I inhibitors IACS-010759 and metformin, suppressed post-transplantation clonal expansion of Dnmt3aR882H/+, but not WT, LT-HSCs. The effect of metformin was recapitulated using a primary human DNMT3A-R882 CH sample. Notably, analysis of 412,234 UK Biobank participants revealed that individuals taking metformin had markedly lower prevalence of DNMT3A-R882-mutant CH, after controlling for potential confounders including glycated haemoglobin, diabetes and body mass index. Collectively, our data propose that modulation of mitochondrial metabolism as a therapeutic strategy for prevention of DNMT3A-R882-mutant AML.

2025-02-06 | MTBLS12201 | MetaboLights

An effective therapy by co-targeting c-Myc and Bcl-2 for resistant acute myeloid leukemia.

Project description:We showed that genetically double-knockdown of c-Myc/Bcl-2 synergistically killed AML cells and inhibited the growth of AML cells in vivo. Mechanically, co-targeting c-Myc/Bcl-2 reciprocally abrogated over-proliferation and apoptosis resistance via synergistically impairing mitochondrial biogenesis.

2022-11-03 | GSE216977 | GEO

Toosendanin Suppresses Acute Myeloid Leukemia by Targeting DDX5/c-Myc Axis to inhibit Protein Synthesis

Project description:The treatment of acute myeloid leukemia (AML) continues to be challenged by relapse and resistance, necessitating the development of novel therapeutic strategies. Toosendanin (TSN), a natural product derived from traditional Chinese medicine, exhibits antitumor activity in solid tumors; however, its mechanism of action and direct molecular targets in AML remain undefined. Here, we demonstrate that TSN potently inhibits AML cell proliferation, induces dual G0/G1 and G2/M phase arrest, and triggers caspase-dependent apoptosis at nanomolar concentrations. Using an integrated approach, including affinity pull-down, cellular thermal shift assay (CETSA), and molecular docking, we identified RNA helicase DDX5 as a direct target of TSN. TSN binding promotes DDX5 degradation via both proteasomal and lysosomal pathways. Transcriptomic and functional analyses revealed that TSN downregulates the c-Myc transcriptional network via DDX5 targeting, leading to the suppression of ribosome biogenesis. Rescue experiments confirmed that DDX5 is the central mediator of this pathway. In an MLL-AF9-driven AML mouse model, TSN treatment significantly prolonged survival, without observable toxicity. Collectively, our study delineates a novel anti-leukemic mechanism wherein TSN targets DDX5 for degradation and consequently inhibits c-Myc signaling, providing a rationale for therapeutic targeting of the DDX5/c-Myc axis and further development of TSN in AML.

2026-02-03 | GSE317933 | GEO

ABT-737 treatment induces regulation and activation of pathways implicated in cell survival, proliferation and stem cells in treated AML mice survival, proliferation and stem cells in treated AML mice

Project description:Myelodysplastic syndrome (MDS) transforms into an acute myelogenous leukemia (AML) with associated increased bone marrow blast infiltration. Using a transgenic mouse model, MRP8[NRASD12/hBCL-2], in which the NRAS:BCL-2 complex at the mitochondria induces MDS progressing to AML with dysplastic features, we studied the therapeutic potential of a BCL-2 homology domain 3 (BH3) mimetic inhibitor, ABT-737. Treatment significantly extended lifespan, increased survival of lethally irradiated secondary recipients transplanted with treated cells compared with cells from untreated mice, with a reduction of bone marrow (BM) blasts, LSK and progenitor populations by increased apoptosis of infiltrating blasts of diseased mice assessed in vivo by Tc-99m-labeled Annexin V single photon emission computed tomography (SPECT) and ex vivo by Annexin V/7AAD flow cytometry, TUNEL, caspase 3 cleavage and re-localization of the NRAS:BCL-2 complex from mitochondria to plasma membrane. Phosphoprotein analysis showed restoration of wild-type AKT, ERK1/2 and MEK patterns in spleen cells after treatment, which show reduced mitochondrial membrane potential. Exon specific gene expression profiling corroborates the reduction of leukemic cells, with an increase in expression of genes coding for stem cell development and maintenance, myeloid differentiation and apoptosis. Myelodysplastic features persist underscoring targeting of BCL-2-mediated effects on MDS-AML transformation and survival of leukemic cells. NRASD12/BCL-2 double transgenic mice were analysed by enriching for primitive Sca1+ cells from splenocytes from untreated and ABT-737 treated mice. RNA was extracted analysed for gene expression profiles using exon specific arrays.

2013-11-06 | E-GEOD-48601 | biostudies-arrayexpress

CK2-mediated DEK Phosphorylation Drives PBX3 Overexpression: A Core Event in Hematopoietic Stem Cell-to-Leukemia Stem Cell Transformation [RNA-seq]

Project description:Leukemia stem cells (LSCs) possess self-renewal capacity and are largely refractory to conventional chemotherapy, thereby driving relapse and treatment failure in acute myeloid leukemia (AML). Here, we identify DEK as a crucial oncogenic factor aberrantly overexpressed in relapsed AML, with markedly increased phosphorylation by casein kinase 2 (CK2), correlating with poor patient prognosis. Using human AML cells and mouse models, we demonstrate that loss of DEK or phospho-mutants DEK, specifically at Ser306/Ser308/Ser311/Ser312 induces AML cells proliferation, differentiation, and weakened LSCs stemness. Mechanistically, phosphorylated DEK recruits GABPA to activate PBX3 transcription, thereby driving a leukemic transcriptional program. Importantly, targeting DEK or pharmacologic inhibition of CK2 using the specific inhibitor CX-4945 disrupts DEK phosphorylation and markedly sensitizes AML cells to venetoclax treatment, providing a rationale for a potential combination therapeutic strategy. Collectively, our findings uncover a unique and critical role of phosphorylated DEK as a transcriptional coactivator in AML and highlight the CK2-DEK/GABPA-PBX3 axis as a promising therapeutic target for AML.

2025-09-30 | GSE309176 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data