Acute T-cell lymphoblastic leukemia (T-ALL) is a severe hematologic malignancy with limited treatment options and poor long-term survival. This study explores the role of IKZF1 in regulating BCL-2 expression in T-ALL.
CUT&Tag and CUT&Run assays were employed to assess IKZF1 binding to the BCL-2 promoter. IKZF1 overexpression and knockdown experiments were performed in T-ALL cell lines. The effects of CX-4945 and venetoclax, alone and in combination, were evaluated in vitro and in vivo T-ALL models.
CUT&Tag sequencing identified IKZF1 binding to the BCL-2 promoter, establishing it as a transcriptional repressor. Functional assays demonstrated that IKZF1 overexpression reduced BCL-2 mRNA levels and increased repressive histone marks at the BCL-2 promoter, while IKZF1 knockdown led to elevated BCL-2 expression. CX-4945, a CK2 inhibitor, could reduced BCL-2 levels in T-ALL cells. Notably, knockdown of IKZF1 partially rescued the CX-4945-induced repression of BCL-2. These results underscore the CK2-IKZF1 signaling axis as a key regulator of BCL-2 expression. In vitro, CX-4945 enhanced the cytotoxicity of venetoclax, with the combination showing significant synergistic effects and increased apoptosis in T-ALL cell lines. In vivo studies with cell line-derived xenograft (CDX) and patient-derived xenograft (PDX) models demonstrated that CX-4945 and venetoclax combined therapy provided superior therapeutic efficacy, reducing tumor burden and prolonging survival compared to single-agent treatments.
IKZF1 represses BCL-2 in T-ALL, and targeting the CK2-IKZF1 axis with CX-4945 and venetoclax offers a promising therapeutic strategy, showing enhanced efficacy and potential as a novel treatment approach for T-ALL.

The lack of curative therapies for acute myeloid leukaemia (AML) remains an ongoing challenge despite recent advances in the understanding of the molecular basis of the disease. Here we identify the WNK1-OXSR1/STK39 pathway as a previously uncharacterised dependency in AML. We show that genetic depletion and pharmacological inhibition of WNK1 or its downstream phosphorylation targets OXSR1 and STK39 strongly reduce cell proliferation and induce apoptosis in leukaemia cells in vitro and in vivo. Furthermore, we show that the WNK1-OXSR1/STK39 pathway controls mTORC1 signalling via regulating amino acid uptake through a mechanism involving the phosphorylation of amino acid transporters, such as SLC38A2. Our findings underscore an important role of the WNK1-OXSR1/STK39 pathway in regulating amino acid uptake and driving AML progression.
© 2025. The Author(s).

The CEBPA transcription factor is frequently mutated in acute myeloid leukemia (AML). Mutations in the CEBPA gene, which are typically biallelic, result in the production of a shorter isoform known as p30. Both the canonical 42-kDa isoform (p42) and the AML-associated p30 isoform bind chromatin and activate transcription, but the specific transcriptional programs controlled by each protein and how they are linked to a selective advantage in AML is not well understood. Here, we show that cells expressing the AML-associated p30 have reduced baseline inflammatory gene expression and display altered dynamics of transcriptional induction in response to LPS, consequently impacting cytokine secretion. This confers p30-expressing cells an increased resistance to the adverse effects of prolonged exposure to inflammatory signals. Mechanistically, we show that these differences primarily arise from the differential regulation of AP-1 family proteins. In addition, we find that the impaired function of the AP-1 member ATF4 in p30-expressing cells alters their response to ER stress. Collectively, these findings uncover a link between mutant CEBPA, inflammation and the stress response, potentially revealing a vulnerability in AML.
© 2025. The Author(s).

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with a poor prognosis, frequently driven by oncogenic KRAS mutations. Among these, KRAS G12D is the most prevalent, contributing to chemoresistance and limiting the efficacy of current therapeutic strategies. This study investigates the therapeutic potential of jorunnamycin A (JA), a bioactive compound derived from the marine sponge Xestospongia, in PDAC. Molecular docking analyses were performed to assess JA's binding affinity for various KRAS protein variants. The synergistic effects of JA in combination with standard chemotherapeutic agents were evaluated using the Bliss independence model in pancreatic cancer cell lines and patient-derived PDAC organoids harboring distinct KRAS mutations. Furthermore, western blot analysis was performed to examine the impact the molecular mechanisms underlying JA's anticancer activity. JA demonstrated potent anticancer activity against PDAC cells, irrespective of their KRAS mutation status. In silico molecular docking and protein suppression studies indicated a strong binding affinity between JA and KRAS G12D. Synergistic interactions between JA and various PDAC chemotherapeutic agents, including oxaliplatin, SN-38, paclitaxel, 5-fluorouracil, and gemcitabine, were observed using the Bliss independence model. Notably, co-treatment with JA at a 10-fold lower concentration significantly enhanced the cytotoxicity of oxaliplatin, reducing its IC50 values around tenfold. This synergistic impact was further validated in both KRAS G12D spheroids and patient-derived PDAC organoids harboring KRAS G12D and other KRAS variants. Mechanistically, the JA-oxaliplatin combination enhanced caspase-3/7 activation, suppressed key KRAS-mediated survival pathways (STAT3, B/C-RAF, AKT, and ERK), and led to the downregulation of anti-apoptotic proteins (MCL-1 and BCL-2). These findings highlight JA as a promising therapeutic candidate for PDAC, particularly in the context of KRAS G12D-driven tumors. Further investigations into its pharmacokinetics and clinical feasibility are warranted to explore its full potential in PDAC treatment.
© 2025. The Author(s).

Abstract In addition to small extracellular vesicles known as exosomes, cells release large extracellular vesicles containing mitochondria (EVMs). The molecular and functional characteristics of EVMs, as well as the impact of EVMs on the spreading of mitochondrial dysfunction between cells, remain unknown in the context of Alzheimer’s Disease (AD). Here, we provide an ultrastructural, biochemical, and functional characterization of EVMs isolated from neuroblastoma cells expressing the amyloid precursor protein with the familial Swedish mutations (APPswe). We identify differential proteomic and lipidomic signatures in APPswe-derived EVMs compared to control EVMs and revealed a specific proteomic profile in EVMs derived from fibroblasts of AD patients at the prodromal stage of the disease. Our findings show that the pathogenic accumulation of APP-C terminal fragments (APP-CTFs) potentiates the secretion of EVMs through plasma membrane budding. We demonstrate that APP-CTFs loaded EVMs are active carriers of dysfunctional mitochondria mediating the transfer of mitochondrial pathology between cells.