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ERK1/2 Inhibition Overcomes Resistance to Venetoclax in AML by Inhibiting Drp1-Dependent Mitochondrial Fission and Destabilizing Mcl-1 [scRNA-Seq 2]

ABSTRACT: ERK1/2-mediated phosphorylation of Drp1 drives mitochondrial fission, stemness, and therapy resistance in RAS-driven solid tumors; however, its role in acute myeloid leukemia (AML) remains unclear. We identified ERK1/2-mediated Drp1 phosphorylation as a mechanism of resistance to venetoclax in AML. ERK1/2 inhibition using Compound 27 (ERKi), an analog of the clinical ERK1/2 inhibitor ASTX029, reduced mitochondrial fission, induced ROS accumulation, mitochondrial depolarization, and apoptosis in venetoclax-resistant AML cells. ERKi sensitized resistant AML cells to venetoclax and depleted leukemia progenitor cells in primary AML samples. Conversely, overexpression of Drp1-phosphomimetic restored mitochondrial fission and reversed apoptosis induced by venetoclax alone and in combination with ERKi. In post-venetoclax/decitabine relapsed human AML PDX model, co-treatment with venetoclax and ASTX029 improved survival and reduced leukemia burden accompanied by decreased pDrp1-Ser616, Mcl-1, and pMcl-1-Thr163 expression in bone marrow-derived human leukemic cells. In conclusion, inhibiting the ERK1/2-Drp1 axis overcomes resistance to venetoclax in AML.

ORGANISM(S): Homo sapiens

PROVIDER: GSE349089 | GEO | 2026/09/30

REPOSITORIES: GEO

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ERK1/2 Inhibition Overcomes Resistance to Venetoclax in AML by Inhibiting Drp1-Dependent Mitochondrial Fission and Destabilizing Mcl-1 [scRNA-Seq 1]

Project description:ERK1/2-mediated phosphorylation of Drp1 drives mitochondrial fission, stemness, and therapy resistance in RAS-driven solid tumors; however, its role in acute myeloid leukemia (AML) remains unclear. We identified ERK1/2-mediated Drp1 phosphorylation as a mechanism of resistance to venetoclax in AML. ERK1/2 inhibition using Compound 27 (ERKi), an analog of the clinical ERK1/2 inhibitor ASTX029, reduced mitochondrial fission, induced ROS accumulation, mitochondrial depolarization, and apoptosis in venetoclax-resistant AML cells. ERKi sensitized resistant AML cells to venetoclax and depleted leukemia progenitor cells in primary AML samples. Conversely, overexpression of Drp1-phosphomimetic restored mitochondrial fission and reversed apoptosis induced by venetoclax alone and in combination with ERKi. In post-venetoclax/decitabine relapsed human AML PDX model, co-treatment with venetoclax and ASTX029 improved survival and reduced leukemia burden accompanied by decreased pDrp1-Ser616, Mcl-1, and pMcl-1-Thr163 expression in bone marrow-derived human leukemic cells. In conclusion, inhibiting the ERK1/2-Drp1 axis overcomes resistance to venetoclax in AML.

2026-09-30 | GSE349088 | GEO

ERK1/2 Inhibition Overcomes Resistance to Venetoclax in AML By Inhibiting Drp1 Dependent Mitochondrial Fission

Project description:Acute myeloid leukemia (AML) is a fatal hematological malignancy for most patients, and (MAPK) cascade is activated in 70%-80% of AML patients owing to activating/inactivating mutations in RAS and upstream proteins. Mutations in the RAS pathway are associated with secondary clinical resistance to venetoclax (ABT199) and hypomethylating agents. We found that ERK1/2 inhibition leads to increased mitochondrial length as well as overcomes resistance to venetoclax. To identify the factors that contribute to synergy and overcome resistance, we perfomed transcriptome profiling of AML cells treated with ABT199, ERK1/2 inhibitor or the combination treatment.Transcriptome analysis revealed downregulation of DRP1, a fission GTPase and a direct downstream target of ERK1/2, in response to ERKi +/-ABT199.

2026-06-23 | GSE270318 | GEO

ERK1/2 Inhibition Overcomes Resistance to Venetoclax in AML By Inhibiting Drp1 Dependent Mitochondrial Fission

Project description:ERK1/2 Inhibition Overcomes Resistance to Venetoclax in AML By Inhibiting Drp1 Dependent Mitochondrial Fission

| PRJNA1126190 | ENA

Project description:ERK1/2 Inhibition Overcomes Resistance to Venetoclax in AML by Inhibiting Drp1-Dependent Mitochondrial Fission and Destabilizing Mcl-1

| PRJNA1534923 | ENA

Drp1 regulates mitochondrial health and controls skeletal muscle mass through the Erk1/2-Nur77 pathway

Project description:The maintenance of skeletal muscle mass is critically dependent upon mitochondrial quality control, including balanced mitochondrial dynamics and mitophagy. Dynamin-related protein 1 (Drp1), a key mediator of mitochondrial fission, plays an important role in these processes. However, the precise mechanisms by which Drp1 regulates mitochondrial integrity and muscle mass remain inadequately understood. Here, we show that acute Drp1 deletion from skeletal muscle impairs mitochondrial activity, increases Parkin-mediated mitophagy, progressively reduces mitochondrial DNA (mtDNA) content, and ultimately causes severe muscle atrophy. Interestingly, dual deletion of Drp1 and Parkin from skeletal muscle restored mtDNA content, but did not prevent muscle loss. Mechanistically, Drp1 deletion disrupted mitochondrial respiratory chain activity, which suppressed extracellular signal-regulated kinase 1/2 (Erk1/2) signaling and downregulated the nuclear receptor subfamily 4 group member 1 (Nur77), a regulator of muscle quality. Finally, clenbuterol, a β2-adrenergic receptor agonist, activated Erk1/2 signaling, restored Nur77 expression, and rescued muscle atrophy. Collectively, our findings identify a Drp1-Erk1/2-Nur77 signaling axis that connects mitochondrial integrity to the preservation of skeletal muscle mass and represents a potential therapeutic avenue for muscle degeneration in mitochondrial and metabolic disorders.

2025-12-08 | GSE295479 | GEO

Paired single-cell RNA-seq pre- and post-venetoclax therapy of 8 AML patients

Project description:Acute myeloid leukemia (AML) remains a cancer with dismal prognosis, particularly in high-risk disease patients and those ineligible for allogeneic stem cell transplantation. BCL-2 inhibitor venetoclax, in combination with hypomethylating agents, has emerged as an effective therapy and forms the backbone of multiple combination therapies in clinical trials. However, venetoclax-based therapy is rarely curative. While multiple venetoclax resistance mechanisms have been discovered, most of these have been identified using cell line models that only partially reflect the heterogeneous composition of human AML. Using paired single-cell data from 8 AML patients with pre- and post-venetoclax therapy samples, we aimed to characterize mechanisms driving venetoclax resistance in a clinically relevant setting.

2025-12-31 | E-MTAB-14143 | biostudies-arrayexpress

Targeting mitochondrial structure sensitizes AML to Venetoclax

Project description:The BCL-2 family plays important roles in acute myeloid leukemia (AML) and Venetoclax, a selective BCL-2 inhibitor, has received FDA approval for treatment of AML. However, drug resistance ensues after prolonged treatment, highlighting the need for a greater understanding of the underlying mechanisms. Using a genome-wide CRISPR/Cas9 screen in human AML, we identified genes whose inactivation sensitizes AML blasts to Venetoclax. Genes involved in mitochondrial organization and function were significantly depleted throughout our screen, including the mitochondrial chaperonin CLPB. We demonstrated that CLPB is upregulated in human AML, it is further induced upon acquisition of Venetoclax resistance and its ablation sensitizes AML cells to Venetoclax. Mechanistically, CLPB maintains the mitochondrial cristae structure via its interaction with the cristae-shaping protein OPA1, whereas its loss promotes apoptosis by inducing cristae remodeling and mitochondrial stress responses. Overall, our data suggest that targeting mitochondrial architecture may provide a promising approach to circumvent Venetoclax resistance.

2019-05-03 | GSE125403 | GEO

Targeting UGCG sensitizes AML cells to Venetoclax through RAB32-mediated endoplasmic reticulum-mitochondria communication

Project description:UDP-glucose ceramide glucosyltransferase (UGCG) is an enzyme that glycosylates ceramide and blunts its pro-apoptotic activity in cancer cells. Targeting UGCG sensitizes solid cancer cells to chemotherapy. However, whether targeting UGCG can increase the sensitivity of AML cells to Venetoclax remains unclear. Here, we found that the inhibition of UGCG genetically or with its inhibitor Eliglustat efficiently suppressed growth and promoted apoptosis in AML cells. Moreover, Eliglustat in combination with Venetoclax increased apoptosis, reduced AML cell viability, and inhibited AML effectively both for primary AML cells and xenograft models. Mechanistically, the combination induced ceramide accumulation which activated the endoplasmic reticulum (ER) stress-GRP78/PERK/CHOP axis. Interestingly, combinatory treatment activated RAB32, which led to mitochondrial fission through ER-mitochondria communication and DRP1 activation. These findings demonstrate that targeting UGCG in combination with Venetoclax is a new combinatory strategy to treat AML, and provide new insights for ceramide-mediated cell death in anti-cancer therapies.

2026-01-09 | GSE315549 | GEO

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

Epigenetic dysregulation of the Drp1 binding partners MiD49 and MiD51 increases mitotic mitochondrial fission and promotes pulmonary arterial hypertension: mechanism and therapeutic implications

Project description:Mitotic fission is increased in hyperproliferative, apoptosis-resistant diseases, such as pulmonary arterial hypertension (PAH). PAH’s fissogenic phenotype includes activation of the fission mediator, dynamin related protein 1 (Drp1), which must complex with its adaptor proteins to cause fission. Drp1-induced fission has been therapeutically targeted in experimental PAH. Here we examine the role of two recently discovered, poorly understood, Drp1 adapter proteins, mitochondrial dynamics protein of 49 and 51 kDa (MiD49 and MiD51) in normal vascular cells and explore the role of their dysregulation in the pathogenesis of PAH. MiDs are increased in PAH PASMC. This accelerates Drp1-mediated mitotic fission, which increases cell proliferation and decreases apoptosis. Silencing MiDs (but not Fis1 or MFF) promotes mitochondrial fusion and G1-phase cell cycle arrest through an ERK1/2 and CDK4-dependent mechanism. Augmenting MiDs in normal cells causes fission and recapitulates the PAH phenotype. MiD upregulation results from decreased microRNA-34a-3p (miR-34a-3p) expression. Circulatory miR34a-3p expression is decreased in PAH patients as well as in preclinical models of PAH. Silencing MiDs or augmenting miR-34a-3p regresses experimental PAH. We used microarrays to identify differences in miR expression in pulmonary artery smooth muscle cells (PASMC) taken from either pulmonary arterial hypertension patients or healthy controls

2018-01-31 | GSE108707 | GEO

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