Biology subjects

Valensi, H.

Publications and source records attributed to Valensi, H..

4 recordsLinked to original sources

bioRxiv2026

Lineage-specific CK2α deletion reshapes the transcriptome of hematopoietic stem cells toward an immune-primed state

Casein Kinase 2 (CK2) is a constitutively active kinase regulating proliferation and immune signaling and is frequently dysregulated in cancer, including acute myeloid leukemia (AML), making it a therapeutic target. CK2 comprises two catalytic subunits, CK2 or CK2, with two regulatory {beta} subunits. The role of CK2, the predominant catalytic subunit and principal mediator of CK2 kinase activity in hematopoietic cells, in steady-state hematopoiesis remains undefined. To define how CK2 shapes hematopoietic cells, we used bone marrow and spleen tissue samples of wild type control and conditional knock out (KO) of CK2 (Csnk2a1) in the hematopoietic compartment of transgenic mice. Using single-cell RNA sequencing, we profiled the transcriptomic changes associated with CK2 loss. Although HSC abundance was comparable between the control and CK2-deficient samples, HSCs experienced the largest transcriptional response to CK2 loss among all cell types. CK2-deficient HSCs displayed transcriptional remodeling for inflammatory and immune-associated programs, interferon signaling, and antigen presentation. Expression of inflammatory genes such as S100a8 and S100a9, changed in opposite directions in bone marrow and spleen HSCs, demonstrating the transcriptional consequences of CK2 loss shaped by tissue context. Using a network-based approach, we identified immune-associated transcription factors Nfkb1, Rfx5, Hes1, and AP-1 family members as regulatory hubs driving these inflammatory transcriptional states in CK2-deficient HSCs. Cell-cell communication profiling revealed multiple gains and losses in ligand-receptor communication between the HSCs and their immune microenvironment in KO. Our findings identify CK2 as a regulator of immune transcriptional programs in HSCs and suggest that disruption of CK2 signaling influences stem cell behavior and immune activation in contexts relevant to hematologic malignancies and CK2-targeted cancer therapies. Statement of significanceThis study reveals that inhibiting the protein CK2 forces blood stem cells into a stressed, immune-primed state. These tissue-specific findings highlight potential side effects for cancer therapies targeting this essential regulatory kinase.

genomics↗

bioRxiv2025

BNIP3-mTOR Signaling Mediates Resistance to MET Inhibition in Glioblastoma

Glioblastoma (GBM) is an aggressive primary brain malignancy with poor prognosis due to rapid progression, extensive invasiveness, and intrinsic resistance to standard therapies. Aberrant activation of receptor tyrosine kinases (RTKs), particularly MET, drives tumor proliferation, invasion, and therapy resistance. Here, we show that MET inhibition with crizotinib induces senescence and mitochondrial dysfunction in glioma-initiating cells (GICs), in part via downregulation of the mitochondrial protein BNIP3. However, BNIP3 downregulation activates mTOR signaling, enabling adaptive resistance. Targeting mTOR with everolimus in combination with crizotinib synergistically enhances anti-tumor effects, inducing apoptosis, senescence, and necroptosis, and significantly reducing cell viability and sphere-forming capacity. In orthotopic GBM xenograft models, this combination, particularly in a sequential regimen, markedly prolongs survival without overt toxicity. Our findings identify a BNIP3-mTOR signaling axis as a critical mediator of resistance to MET inhibition and provide a mechanistic rationale for combined MET and mTOR targeting as a promising therapeutic strategy in GBM. Statement of Translational RelevanceGlioblastoma (GBM) remains a highly aggressive and treatment-resistant brain tumor with limited therapeutic options. Our study identifies a BNIP3-mTOR signaling axis as a key mediator of resistance to MET inhibition. We show for the first time that combined MET and mTOR inhibition exhibits synergistic effects against GBM in vitro and in vivo. This combination prolongs survival without overt toxicity, providing a strong preclinical rationale for clinical evaluation in GBM patients with high MET expression and offering a promising strategy to overcome adaptive resistance.

cancer biology↗

bioRxiv2025

CK2 inhibitor, CX-4945, enhances BH3 priming and promotes apoptosis of venetoclax-resistant AML by targeting antiapoptotic proteins

Acute myeloid leukemia (AML), the most common hematologic malignancy, generally has a poor prognosis. Despite initial favorable responses to the BCL2 inhibitor venetoclax (VEN), remission is transient, and AML is eventually fatal. Resistance to VEN is primarily due to the overexpression of anti-apoptotic proteins, including MCL-1, BCL2L1 (BCL-XL), and BCL2A1. Casein kinase II (CK2) is a serine-threonine kinase and a known suppressor of apoptosis. We and others have reported that protein kinase CK2 activity is high in leukemic stem cells (LSCs) and associated with resistance to chemotherapy. We have shown that the selective CK2 inhibitor, CX-4945, suppresses BCL-XL and has a significant anti-tumor effect in AML preclinical models. CK2 expression and activity are high in venetoclax-resistant AML (VR-AML) cell lines. Genetic and pharmacological inhibition of CK2 significantly altered VR-AML gene signature, decreased MCL-1 protein level, increased BH3 priming and sensitized VR-AML cells to apoptosis. More importantly, CX-4945 selectively targeted LSCs (CD34+CD38-) and chemoresistant (CD123+CD47+) subpopulation in VR-AML. CX-4945 combined with VEN decreased leukemia burden and prolonged the survival of VR-AML cell line-derived and patient-derived xenografts compared to either drug alone. The combinatorial treatment was well tolerated in mice without additional myelosuppression or organ toxicity. CX-4945 (silmitasertib) is being tested in several early-phase clinical trials against adult and pediatric cancers. These preclinical results support the use of CX-4945 in combination with VEN to overcome resistance to apoptosis and re-sensitize VR-AML to chemotherapy. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=135 SRC="FIGDIR/small/696284v1_ufig1.gif" ALT="Figure 1"> View larger version (43K): org.highwire.dtl.DTLVardef@6a902forg.highwire.dtl.DTLVardef@2028f5org.highwire.dtl.DTLVardef@160fd4dorg.highwire.dtl.DTLVardef@95da53_HPS_FORMAT_FIGEXP M_FIG C_FIG

pharmacology and toxicology↗

bioRxiv2025

CK2 inhibitor CX-4945 targets EWS-FLI1 protein abundance and shows anti-tumor activity in metastatic mouse models of Ewing Sarcoma

Ewing sarcoma (ES) is an aggressive bone tumor that primarily affects children, adolescents, and young adults. EWS-FLI1 oncogenic fusion protein is indispensable for ES tumor survival and progression. Casein kinase II (CK2) is a serine/threonine kinase that plays an essential role in apoptosis, DNA damage repair, and the cell cycle. CK2 is highly expressed in ES and associated with metastatic disease and poor 5-year overall survival. Here, we show that CK2 inhibitor CX-4945 (silmitasertib) induced K48-specific ubiquitination and subsequent proteasomal degradation of EWS-FLI1. CK2 inhibition effectively altered fusion protein abundance and disrupted the ES oncogenic signaling, specifically repressing metastasis-associated gene programs. Phenotypically, CK2-depleted ES cells showed decreased migration and invasion in vitro. In the metastatic ES xenograft model, CX-4945 significantly suppressed tumor growth, reduced tumor burden in the lungs, and extended overall survival. CK2 genetic depletion phenocopied CX-4945 effects both in vitro and in vivo. Molecular analysis of treated tumors confirmed robust target engagement, characterized by significant decrease in CK2 substrate phosphorylation levels. CX-4945 showed synergistic cytotoxicity with Irinotecan, a commonly used chemotherapy for the treatment of relapsed ES. Our findings establish CK2 as a novel therapeutic target in ES and provide a mechanistic rationale for combining CK2 inhibitor with chemotherapy regimens. Given the established safety profile of CX-4945, these results support clinical testing of the CK2 inhibitor fusion for treatment of metastatic ES. A Phase 1/2 trial (NCT06541262) is currently evaluating CX-4945 in combination with chemotherapy for pediatric and young adults with relapsed or refractory solid tumors, including ES. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=133 SRC="FIGDIR/small/677357v2_ufig1.gif" ALT="Figure 1"> View larger version (41K): org.highwire.dtl.DTLVardef@2b590dorg.highwire.dtl.DTLVardef@1e38250org.highwire.dtl.DTLVardef@1808da0org.highwire.dtl.DTLVardef@d23355_HPS_FORMAT_FIGEXP M_FIG C_FIG Statement of Translational RelevanceOur study identifies Casein Kinase 2 (CK2) as a novel therapeutic target in Ewing Sarcoma (ES). We demonstrate that CK2 inhibition triggers K48-specific ubiquitination and subsequent proteasomal degradation of EWS-FLI1 oncoprotein. Additionally, CX-4945 simultaneously targets multiple oncogenic signaling pathways and EWS-FLI1 regulators, resulting in sustained suppression of proliferation and metastasis. In metastatic ES models, oral CX-4945 showed robust efficacy, significantly reducing tumor volume and lung metastasis while extending survival. These findings provide the mechanistic rationale for integrating CK2 inhibition into current chemotherapy regimens. The translational impact is immediate: CX-4945 has an established clinical development pathway, and its safety in combination with chemotherapy is currently being evaluated in an ongoing Phase 1 multicenter trial (NCT06541262), offering a novel targeted strategy for patients with metastatic Ewing Sarcoma.

cancer biology↗