The findings suggest that targeting GSK3β may represent a therapeutic vulnerability in this model of chronic myeloid leukemia, and CDH2 exhibits context-dependent expression across malignancies.
Abstract
Chronic myeloid leukemia (CML) is driven by uncontrolled myeloid proliferation, yet underlying molecular mechanisms remain incompletely understood. This study investigated the pan-cancer expression profile of N-cadherin (CDH2) and its potential role in suppressing proliferation in K562 CML cells, with an exploratory focus on the GSK3β/β-catenin axis. We combined in silico analyses (TCGA/GEO datasets) with functional assays in K562 cells. CDH2 expression was assessed across 31 cancer types. In K562 cells, we evaluated the effects of CDH2 overexpression on proliferation, cell cycle, apoptosis, and several proteins within the β-catenin/GSK3β network. CDH2 was significantly upregulated in 18 malignancies and downregulated in 10. It was associated with adverse overall survival in five solid tumors but favorable in KIRC. In acute myeloid leukemia (AML), higher CDH2 expression correlated with poor-prognosis cytogenetic risk (P = 0.008). CDH2 expression also correlated with macrophage/NK cell infiltration in some solid tumors. In K562 cells, CDH2 overexpression suppressed proliferation, induced cell cycle arrest and early apoptosis. This was accompanied by increased total β-catenin protein but a reduced nuclear-to-cytoplasmic β-catenin ratio, without consistent changes in canonical Wnt target gene expression. Notably, the GSK3 inhibitor CHIR-99,021 reversed the anti-proliferative effect of CDH2, whereas the β-catenin degrader MSAB did not rescue it. CDH2 exhibits context-dependent expression across malignancies. In K562 CML cells, CDH2 overexpression suppresses proliferation through a GSK3β-sensitive mechanism. However, the precise molecular mechanism remains unresolved. Our findings suggest that targeting GSK3β may represent a therapeutic vulnerability in this model.
B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is characterized by impaired B-cell maturation and poor prognosis in relapsed/refractory (R/R) cases. While CD20-targeted immunotherapies offer clinical benefit, their efficacy is limited by low and heterogeneous CD20 expression on BCP-ALL cells. In this study, we demonstrate that overexpression of wild-type IKZF1, a tumor suppressor frequently mutated in high-risk BCP-ALL, upregulates CD20 and promotes leukemic B cell maturation. Using a transcriptional mimicry approach, we identified mTORC1 inhibitors as compounds showing similarity to selected IKZF1-induced transcriptional signatures, including convergence on B-cell maturation and induction of CD20 expression both in vitro and in vivo. mTORC1 inhibition enhanced the antitumor efficacy of anti-CD20 monoclonal antibodies and promoted B-lineage antigen expression, while downregulating immature markers. Mechanistically, CD20 upregulation was mediated via the AKT-FOXO1 axis, with AKT phosphorylation being essential for this effect. Importantly, this phenotypic shift was observed in BCP-ALL models with IKZF1 deletions, highlighting the relevance to high-risk disease. Our findings support the use of mTORC1 inhibitors to sensitize BCP-ALL cells to CD20-directed immunotherapies and provide a strong rationale for their clinical evaluation as adjuncts to anti-CD20 immunotherapy in BCP-ALL.
KANSL2, a core component of the NSL histone acetyltransferase complex, has been implicated in tumorigenesis. However, its pan-cancer relevance and functional role in liver hepatocellular carcinoma (LIHC) remain unclear. Multi-omics data from TCGA, GEO, and HPA were integrated to systematically evaluate KANSL2 expression, clinical significance, genomic alterations, and immune associations across cancers. Functional enrichment, immune infiltration analyses, and single-cell transcriptomics were performed. In vitro assays were conducted to validate the biological effects of KANSL2 in LIHC cells. KANSL2 is broadly upregulated across cancers and exhibits strong diagnostic performance. Elevated KANSL2 expression correlates with unfavorable prognosis, particularly in LIHC. Mechanistically, KANSL2 and its co-expressed genes are enriched in cell-cycle progression. KANSL2 expression is also closely associated with immune infiltration and immunoregulatory signaling within the tumor microenvironment, with single-cell data indicating preferential expression in proliferative T-cell subsets. Functional experiments demonstrate that KANSL2 silencing suppresses proliferation, migration, and invasion, and induces G2/M phase arrest in LIHC cells. Notably, its effects on apoptosis are limited, suggesting that KANSL2 primarily drives tumor progression through cell-cycle-dependent mechanisms. This study identifies KANSL2 as a key regulator of tumor progression and immune remodeling in LIHC. By promoting malignancy predominantly via cell-cycle control, KANSL2 represents a promising biomarker for diagnosis and prognosis, and a potential therapeutic target.
Nan-Bin Liu, Kun Li, Jun-Qiao Feng et al.· Clinical and Experimental Me...· 0 citations
Background: Death-associated protein kinase 1 (DAPK1) is a key regulator of apoptosis and immune responses; however, its prognostic significance in oral cancer remains insufficiently characterized. This study investigated the prognostic relevance of DAPK1 in oral squamous cell carcinoma (OSCC) and examined its associations with immune infiltration and apoptosis-related signaling pathways. Methods: A retrospective translational study design was employed, integrating TCGA-based expression and methylation analyses of 528 head and neck squamous cell carcinoma (HNSCC) tumors, UALCAN epigenetic profiling, GeneMANIA protein–protein interaction mapping, TIMER 2.0 immune correlation analyses in 422 HPV-negative HNSCC patients, and multiplex immunofluorescence validation using a tissue microarray cohort of 82 patients with histologically confirmed OSCC, of whom 75 were eligible for the final analysis at Kaohsiung Veterans General Hospital, Taiwan. Results: In vitro validation using Western blot analysis in FaDu cells showed that epidermal growth factor receptor (EGFR) inhibition with gefitinib induced upregulation of DAPK1 protein expression at 10 μM and increased total caspase-3 expression. Higher DAPK1 signal in whole-field quantification was associated with increased CD4+ and CD8+ T-cell infiltration and enrichment of apoptosis-related pathways. Patients with high DAPK1 expression demonstrated a consistent protective trend for overall survival in a pre-specified fully adjusted primary model (adjusted HR = 0.51, 95% CI: 0.21–1.21, p = 0.126), and exhibited significantly improved survival in a secondary parsimonious model (adjusted HR = 0.41, 95% CI: 0.18–0.91, p = 0.029). Multiplex immunofluorescence further confirmed stronger DAPK1 and caspase-3 staining, along with denser lymphocytic infiltration within the tumor microenvironment. Conclusions: Collectively, these findings suggest that DAPK1 is associated with apoptosis-related signaling, increased immune-cell infiltration, and favorable clinical outcomes in OSCC, although its independent prognostic value requires validation in larger cohorts.
A GSTT1HighCD133High stem-like subpopulation in metastatic PDA is identified and an FGFR-dependent signaling axis that sustains this state is identified, representing a potential therapeutic vulnerability.
Delgado Herrera Deborah de la Caridad, Alejandro Arroyo Roman, Riyan N. Campbell et al.· Cancer Letters· 0 citations
Background/Objectives: Revolutionary small molecule, targeted, tyrosine kinase inhibitors (TKIs) in the clinic have engendered the perception that optimal treatment has already been established for diseases like chronic myeloid leukemia (CML). Addressing BCR::ABL1 oncokinase domain mutations in CML is unlikely to redress disease recrudescence owing to persistent leukemia stem cells (LSCs). Therefore, it is necessary to consider an alternative strategic approach: disrupting LSC interactions with the protective microenvironment and/or immune system. The interaction of the TNF-α superfamily member, CD27, with its upregulated ligand, CD70, initiates survival signaling specifically in CML cells when BCR::ABL1 is inhibited by TKIs and thus represents an attractive target. Previous studies modulating the expression of CD27 on LSCs in a mouse model of advanced phase CML were encouraging. In our study, we explored the CD70/CD27 axis as a therapeutic target in early-phase disease. Methods: Primitive CD34+ cells from treatment-naïve chronic phase (CP) CML patients were drug-exposed in an in vitro co-culture system; combination drug treatments of the therapeutic anti-CD70 antibody and TKIs, nilotinib, were assessed in our CP CML murine model. Results: The blockade of the CD70/CD27 axis in combination with TKIs did not result in greater LSC elimination than with nilotinib as a single agent in our CP CML models. Nonetheless, there was an observed reduction in CD70+ cells with combination treatment. Conclusion: Further preclinical study of the antibody as an adjunct in CD70-expressing hematological malignancy is perhaps warranted.
Jennifer E. Cassels, M. Drotar, Alyson MacNeil et al.· Hematology Reports· 0 citations
