Antagonistic regulation of HBZ splicing by hnRNPA1 and hnRNPH1 drives HTLV-1 leukemogenesis

A PTBP1–CDC42 splicing axis regulates leukemia growth and venetoclax sensitivity in acute myeloid leukemia

Acute myeloid leukemia (AML) is an aggressive blood cancer characterized by high rates of relapse and poor outcomes, especially in elderly or unfit patients, who cannot tolerate intensive chemotherapy. While the BCL2 inhibitor venetoclax has improved initial responses in this high-risk population, relapses remain nearly universal, highlighting the need for novel therapeutic strategies. Here, we identify the RNA-binding protein PTBP1 as a critical dependency in AML. PTBP1 depletion impairs leukemic growth in vitro and in vivo, and is associated with widespread splicing alterations and global disruption of protein synthesis. Integrative transcriptomic and iCLIP analyses reveal that PTBP1 orchestrates a splicing program centered on Rho GTPase signaling, with CDC42 as a key downstream effector. Mechanistically, PTBP1 loss triggers a splicing switch from CDC42-v1 to CDC42-v2, leading to reduced GTPase activity and impaired protein synthesis. Pharmacological inhibition of CDC42 selectively induces cytotoxicity in AML cells, while sparing healthy hematopoietic cells. Importantly, CDC42 inhibition markedly enhances venetoclax anti-leukemic efficacy. These findings establish PTBP1 as a critical regulator of AML cell fitness and identify a clinically actionable therapeutic combination that exploits AML dependency on PTBP1-CDC42 signaling to enhance the efficacy of venetoclax-based regimens.

Splicing-mediated control of hnRNPD isoform switching by SRSF2 drives PD-L1-dependent immune evasion in gallbladder cancer

A specific protein (SRSF2) acts like a rogue editor, altering the genetic instructions of another molecule (hnRNPD) and creates a “shield” (PD-L1) on the surface of the cancer cell, effectively blinding the immune system and allowing the tumor to grow unchecked.

Splicing factor HNRNPD and alternative splicing of MAP4K4 are associated with cell apoptosis and immune microenvironment features in Wilms’ tumor

Background As the most common malignant renal tumor in children, the progression of Wilms’ tumor is frequently driven by abnormal alternative splicing (AS), cell death imbalance, and an immunosuppressive microenvironment. However, the precise regulatory chain connecting these three critical elements remains largely unexplored. This study aimed to systematically construct and characterize an “AS-cell death-immunity” regulatory network in Wilms’ tumor. Methods We performed a comprehensive in silico analysis using matched paired Wilms’ tumor and adjacent normal RNA-seq data from the GSE138869 cohort. The SUVA algorithm was employed to identify cell death-related regulated alternative splicing events (RASEs). A tripartite regulatory network was constructed via correlation analysis to link these RASEs with upstream differentially expressed splicing factors (DESFs). Immune cell infiltration was quantified using CIBERSORT. Finally, the HNRNPD knockout and FLASH-seq multi-omics dataset (GSE212767) was utilized to computationally validate the predicted regulatory axis. Results Our analysis identified 118 cell death-related host genes undergoing significant alternative splicing in Wilms’ tumor. Network integration highlighted a critical regulatory axis where the overexpressed splicing factor HNRNPD is strongly correlated with an aberrant AS event (clualt5p51764) in the apoptosis-related kinase MAP4K4. Further immune deconvolution demonstrated that both HNRNPD upregulation and the MAP4K4 splicing shift were significantly correlated with increased monocyte infiltration in the tumor microenvironment. Moreover, cross-validation utilizing the GSE212767 dataset confirmed that HNRNPD perturbation directly alters MAP4K4 splicing. Conclusions Our computational framework proposes that the HNRNPD-MAP4K4 splicing axis links apoptotic dysregulation to immune microenvironment remodeling in Wilms’ tumor. These correlative in silico findings provide a robust, hypothesis-generating basis for discovering novel prognostic biomarkers and developing targeted therapeutic strategies directed at the splicing machinery.

TRDMT1 Slows Lung Cancer Growth by Stabilizing TFRC mRNA and Triggering Ferroptosis Cell Death.

Lung adenocarcinoma (LUAD), the most common subtype of non-small cell lung cancer, remains a significant therapeutic challenge due to its high mortality rates, driven by both inherent and acquired resistance to standard therapies. Emerging evidence highlights the role of epitranscriptomic regulation, particularly RNA modifications such as 5-methylcytosine (m5C), in the pathogenesis of cancer. This study identifies TRDMT1 (DNMT2), an m5C methyltransferase, as a tumor suppressor in LUAD. It was found that TRDMT1 expression is significantly lower in LUAD tissues, and this reduction is associated with poor prognosis in patients. Functional assays indicated that TRDMT1 inhibits the proliferation, migration, and invasion of LUAD cells in vitro. Mechanistically, transcriptomic profiling and subsequent investigation revealed that TRDMT1 enhances the stability of transferrin receptor (TFRC) mRNA in an m5C-dependent manner. This post-transcriptional regulation leads to TFRC upregulation, which subsequently disrupts intracellular iron homeostasis, culminating in increased susceptibility to ferroptosis-an iron-dependent form of regulated cell death. Rescue experiments confirmed that the tumor-suppressive and pro-ferroptotic effects of TRDMT1 are mediated through TFRC. This study unveils a novel TRDMT1-TFRC regulatory axis that suppresses LUAD progression through the modulation of ferroptosis, highlighting this pathway as a promising therapeutic target for future interventions.

EIF4A3-dependent nonsense-mediated decay buffers AML1-ETO9a dosage and modulates outcome in t(8;21) acute myeloid leukemia

can modulate TAL1 transcriptional activity through interaction with LMO2