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CDK4/6 Inhibitor, Palbociclib, overcomes Venetoclax resistance mechanisms and outperforms single agents in Acute Myeloid Leukemia [RNA-Seq]

ABSTRACT: Venetoclax (ven) combined with the hypomethylating agent azacytidine (aza) is a widely used therapy for Acute Myeloid Leukemia (AML), however, most patients develop resistance. Using RNASeq, we identified loss of Ikaros (IKZF1) as a potential resistance mechanism to ven+palbo. Examination of cells with IKZF1-loss revealed upregulation of the receptor, AXL, with concordant AXL inhibitor sensitivity in AML tumors harboring IKZF1 mutations. This work suggests that the combination of ven+palbo is a potential novel therapy for AML for potential subpopulations that may benefit the most from this treatment, as well as targeting translation as a means to overcome ven resistance.

ORGANISM(S): Homo sapiens

PROVIDER: GSE291339 | GEO | 2025/11/11

REPOSITORIES: GEO

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CDK4/6 Inhibitor, Palbociclib, overcomes Venetoclax resistance mechanisms and outperforms single agents in Acute Myeloid Leukemia [CRISPR Screen]

Project description:Venetoclax (ven) combined with the hypomethylating agent azacytidine (aza) is a widely used therapy for Acute Myeloid Leukemia (AML), however, most patients develop resistance. A genome-wide CRISPR screen showed that loss of genes involved in translation conferred sensitivity to ven but not ven+palbo. Accordingly, we show that increased translation occurs after AML cells are challenged with ven, and ven+palbo blocks this increase. We also found that loss of BAX, which leads to ven resistance, was overcome by combination with CDK4/6 inhibitors. Conversely, loss of RB1, a known mechanism of resistance to CDK4/6 inhibitors, was mitigated by ven+palbo. This work suggests that the combination of ven+palbo is a potential novel therapy for AML for potential subpopulations that may benefit the most from this treatment, as well as targeting translation as a means to overcome ven resistance.

2025-11-11 | GSE291338 | GEO

Targeting SUMOylation sensitizes Acute myeloid leukemia to Venetoclax treatment

Project description:Acute myeloid leukemia (AML) is a hematopoietic cancer characterized by the proliferation and accumulation of aberrant immature myeloid progenitor blasts in bone marrow and peripheral blood. Venetoclax (VEN), a selective B-cell lymphoma 2 (BCL-2) inhibitor, has received FDA approval for AML treatment in combination with hypomethylating agents (HMA). However, treatment failure and therapy resistance present an urgent need for new therapies to overcome VEN resistance and enhance VEN efficacy. We propose inhibition of SUMOylation as a novel therapy with the potential to address this need. SUMOylation regulates protein function by covalently attaching Small Ubiquitin-like MOdifier (SUMO) proteins to target proteins via an enzymatic cascade. Our study aims to evaluate the effects of SUMOylation inhibition on anti-AML activity of VEN and dissert the underlying mechanism.

2024-05-27 | GSE267885 | GEO

AML patients for in vivo study of venetoclax plus AraC treatment

Project description:Therapy resistance represents a major clinical challenge in acute myeloid leukemia (AML). Here we define a “MitoScore” signature that identifies high mitochondrial oxidative phosphorylation (OxPHOS) in vivo and in AML patients. Primary AML cells with cytarabine (AraC) resistance and high MitoScore relied on mitochondrial Bcl2 and were highly sensitive to venetoclax (VEN) plus AraC (but not to VEN plus azacytidine, AZA). Single-cell transcriptomics of VEN+AraC-residual cell populations revealed adaptive resistance associated with changes in OxPHOS, electron transport chain complex (ETC) and the TP53 pathway.

2021-11-12 | GSE183329 | GEO

Fatty acid metabolism mediates venetoclax resistance in acute myeloid leukemia stem cells

Project description:The combination of venetoclax with azacitidine (ven/aza) has recently emerged as a promising regimen for acute myeloid leukemia (AML), with approximately 70% of newly diagnosed patients achieving complete remission (CR). However, 30% of newly diagnosed and nearly all relapsed patients do not achieve CR with ven/aza. Mechanistically, we previously reported that ven/aza efficacy is based on eradication of AML stem cells through a mechanism involving inhibition of amino acid metabolism, a process which is required in primitive AML cells to drive oxidative phosphorylation. In the present study we demonstrate that resistance to ven/aza occurs as a consequence of up-regulated fatty acid oxidation (FAO), which occurs either as an intrinsic property of RAS pathway mutations, or as a compensatory adaptation in relapsed disease. Utilization of FAO obviates the need for amino acid metabolism into the TCA cycle, thereby rendering ven/aza ineffective. Importantly, we show that pharmacological inhibition of FAO via use of MCL-1 or CPT1 inhibitor drugs restores targeting of ven/aza resistant AML stem cells. Based on these findings we propose that inhibition of FAO is a potential therapeutic strategy to address ven/aza resistance.

2020-08-31 | GSE155431 | GEO

Fatty acid metabolism mediates venetoclax resistance in acute myeloid leukemia stem cells

2020-08-17 | GSE156008 | GEO

Gene epression analyses on pre- and post-treatment samples obtained from AML patients who respond or failed to respond to Venetoclax/Decitabine treatment

Project description:To elucidate the underlying mechanisms of resistance to venetoclax and dexitabine combination therapy, we performed transcriptomic analysis of VEN/DEC pre- and post-treatment samples from AML patients enrolled in the DEC10-VEN clinical trial (NCT03404193). We have reported that AML cells from non-responders show a significant upregulation of the mRNA expression of the fatty acid metabolism activator PPARG (Peroxisome Proliferator-Activated Receptor γ) after VEN/DEC treatment.

2025-08-06 | GSE270621 | GEO

Overexpression of the fructose transporter SLC2A5 (GLUT5) in association with PHGDH splicing dynamics is a venetoclax resistance mechanism in acute myeloid leukemia

Project description:Background: The combination of hypomethylating agents (HMA) with the Bcl-2 inhibitor venetoclax (VEN) has significantly advanced acute myeloid leukemia (AML) treatment. This therapy is approved for older patients and those with comorbidities. Objectives: We aimed to identify resistance mechanisms to HMA-VEN therapy using scRNA-Seq on primary AML samples. GLUT5 expression on AML progenitors from resistant and non-resistant patients was evaluated through immunoblotting and immunofluorescence. Seahorse and CRISPR experiments were conducted to validate the phenotype in the THP-1 AML monocyte cell line. Findings: scRNA-Seq revealed an upregulation of Leukemia Stem Cell (LSC) 17 scores in pre-treatment samples compared to HMA-VEN relapse samples. RNA velocity analysis indicated that LSCs in pre-treatment samples were the root cell population, while HMA-VEN relapse cells, specifically AML Blast 1, showed preferential splicing of PHGDH, a key serine synthesis pathway member, resulting in the overexpression of SLC2A5. GLUT5 was more frequently and intensely expressed on the cell surface in patients resistant to HMA-VEN. Seahorse assays demonstrated that fructose uptake via GLUT5 suppressed oxygen consumption in THP-1 cells following siRNA-mediated knockdown. Conclusions: Aberrant GLUT5 expression by leukemia progenitors represents a metabolic adaptation contributing to VEN resistance in AML.

2025-09-20 | GSE277678 | GEO

RAS-mutant AML stem cells acquire resistance to BH3 mimetics through altered BCL-2 family expression

Project description:Venetoclax (VEN) has transformed the therapy of acute myeloid leukemia (AML), but resistance and relapse are a major challenge. Monocytic differentiation was proposed as a cause of VEN resistance, but clinical and laboratory evidence is conflicting. Here we harness AML patientderived induced pluripotent stem cells (iPSCs) and Genotyping of Transcriptomes (GoT) to interrogate how mutational status and differentiation stage affect VEN sensitivity independently of one another. Findings in primary and iPSC-derived AML stem cells (LSCs) and monocytic blasts, together with clinical trial data, reveal that monocytic blasts are resistant to VEN, in contrast to LSCs, which express high levels of BCL2 and are sensitive, and that it is the latter, but not the former, that determines the clinical outcome. Crucially, N/KRAS-mutant LSCs produce more monocytic blasts, downregulate BCL2 and are resistant to VEN, driving clinical resistance or relapse. We thus provide a unifying mechanistic model of VEN resistance in AML.

2024-08-09 | GSE235206 | GEO

Targeting the metabolic vulnerability of acute myeloid leukemia blasts with a combination of venetoclax and 8-chloro-adenosine

Project description:Purpose: To show that 8-Cl-Ado can target FAO and synergizes with VEN to significantly decrease the oxygen consumption rate (OCR) and in turn OXPHOS in CD34-enriched AML cells. Methods: Using AML cell lines and LSC-enriched blast cells from pre-treatment AML patients, we evaluated the effects of 8-Cl-Ado, VEN and the 8-Cl-Ado/VEN combination on fatty acid metabolism, glycolysis and OXPHOS using liquid scintillation counting, a Seahorse XF Analyzer and gene set enrichment analysis (GSEA). Results: We here report that VEN and 8-Cl-Ado synergistically inhibited in vitro growth of AML cells. Furthermore, immunodeficient mice engrafted with MV4-11-Luc AML cells and treated with the combination of VEN plus 8-Cl-Ado had a significantly longer survival than mice treated with either drugs alone (p≤0.006). Conclusion: Taken together, the results suggest that 8-Cl-Ado enhances the antileukemic activity of VEN and that this combination represents a promising therapeutic regimen for treatment of AML.

2021-04-07 | GSE171552 | GEO

8-Cl-Ado and 8-NH2-Ado Synergize with Venetoclax to Target the Methionine-MAT2A-SAM Axis in Acute Myeloid Leukemia

Project description:Background: Targeting the metabolic dependencies of acute myeloid leukemia (AML) cells is a promising therapeutical strategy. In particular, the cysteine and methionine metabolism pathway (C/M) is significantly altered in AML cells compared to healthy blood cells. Moreover, methionine has been identified as one of the dominant amino acid dependencies of AML cells. Methods: Through RNA-seq, we found that the two nucleoside analogs 8-chloro-adenosine (8CA) and 8-amino-adenosine (8AA) significantly suppress the C/M pathway in AML cells, and methionine-adenosyltransferase-2A (MAT2A) is one of most significantly downregulated genes. Additionally, mass spectrometry analysis revealed that Venetoclax (VEN), a BCL-2 inhibitor recently approved by the FDA for AML treatment, significantly decreases the intracellular level of methionine in AML cells. Based on these findings, we hypothesized that combining 8CA or 8AA with VEN can efficiently target the Methionine-MAT2A-S-adenosyl-methionine (SAM) axis in AML. Results: Our results demonstrate that VEN and 8CA/8AA synergistically decrease the SAM biosynthesis and effectively target AML cells both in vivo and in vitro. Conclusions: These findings suggest the promising potential of combining 8CA/8AA and VEN for AML treatment by inhibiting Methionine-MAT2A-SAM axis and provide a strong rationale for our recently activated clinical trial.

2023-11-09 | GSE247025 | GEO

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