Biology subjects

Vose, J. M.

Publications and source records attributed to Vose, J. M..

4 recordsLinked to original sources

bioRxiv2026

Proteome landscape of B-cell malignancies identifies mantle cell lymphoma protein signature

Mantle cell lymphoma (MCL) is one of the deadliest forms of Non-Hodgkins B-cell lymphoma. Typically, patients present with both overexpression of CyclinD1 and secondary mutations identified by genomic sequencing. Although MCL patients may initially respond to treatment, they eventually relapse and succumb to disease, highlighting the essential need to identify new targets for treatment. Here we performed proteomic profiling of healthy B cells and three different forms of B-cell malignancies, including MCL, to define the proteomic signature of MCL. We compared the proteome of each to MCL and identified 10 proteins that are specifically upregulated in MCL. Of these 10 proteins, seven of them show no transcriptional changes and have been overlooked by conventional RNA expression analysis. Further analysis of the proteomic signature reveals potential avenues for dual targeting in CAR T-cell therapy and provides guidance for personalized therapeutics based on protein expression. STATEMENT OF SIGNIFICANCEWe present a resource defining the protein landscape of MCL, CLL, and FL as compared to healthy b cells identified utilizing quantitative proteomics from primary patient samples. Applied to MCL, our results identify 10 proteins specifically upregulated in MCL that may prove to be therapeutic targets to treat the disease.

cancer biology↗

bioRxiv2025

Functional genomics and tumor microenvironment analysis reveal prognostic biological subtypes in Mantle cell lymphoma

Mantle cell lymphoma (MCL) is a genetically and clinically heterogeneous B-cell malignancy. We studied two MCL cohorts with differing treatment patterns: one enriched for immunochemotherapy, the other for chemotherapy alone. TP53 alterations were consistently associated with poor prognosis, whereas ATM mutations correlated with improved outcomes following rituximab-based chemotherapy. Based on recurrent genetic events, six clusters were identified and refined into three prognostic groups: high-risk (TP53 mutations and deletions at 17p13.3, 13q14.2, and 19p13.3), intermediate-risk (ATM and epigenetic regulator mutations, or gains at 8q/17q/15q), and low-risk (lacking TP53 alterations, rare ATM mutations without 11q deletions, gains at 3q, deletions at 6q). Transcriptomic analysis revealed enrichment of proliferation, metabolism-promoting gene signatures in high-risk; angiogenesis and NOTCH signaling in intermediate-risk; and proinflammatory-related (i.e., IFN, TNF) in low-risk MCLs. Multi-proteomic spatial profiling using imaging mass cytometry (IMC) demonstrated enrichment of CD8 T cells with high expression of exhaustion markers and dominant population of myeloid cells skewed toward an M2-like phenotype. Compared to ATM-perturbed tumors, TP53-perturbed tumors exhibited enriched SOX11 tumor cells and enhanced tumor-immune cell interactions. Functional analysis revealed that p53 represses BCR signaling through PTPN6 activation. Collectively, these findings highlight distinct molecular and immune landscapes and reveal therapeutic vulnerabilities in high-risk TP53-altered MCL.

cancer biology↗

bioRxiv2024

Novel spirocyclic dimer, SpiD3, targets chronic lymphocytic leukemia survival pathways with potent preclinical effects

Chronic lymphocytic leukemia (CLL) cell survival and growth is fueled by the induction of B-cell receptor (BCR) signaling within the tumor microenvironment (TME) driving activation of NF- {kappa}B signaling and the unfolded protein response (UPR). Malignant cells have higher basal levels of UPR posing a unique therapeutic window to combat CLL cell growth using pharmacological agents that induce accumulation of misfolded proteins. Frontline CLL therapeutics that directly target BCR signaling such as Bruton-tyrosine kinase (BTK) inhibitors (e.g., ibrutinib) have enhanced patient survival. However, resistance mechanisms wherein tumor cells bypass BTK inhibition through acquired BTK mutations, and/or activation of alternative survival mechanisms have rendered ibrutinib ineffective, imposing the need for novel therapeutics. We evaluated SpiD3, a novel spirocyclic dimer, in CLL cell lines, patient-derived CLL samples, ibrutinib-resistant CLL cells, and in the E{micro}-TCL1 mouse model. Our integrated multi-omics and functional analyses revealed BCR signaling, NF-{kappa}B signaling, and endoplasmic reticulum stress among the top pathways modulated by SpiD3. This was accompanied by marked upregulation of the UPR and inhibition of global protein synthesis in CLL cell lines and patient-derived CLL cells. In ibrutinib-resistant CLL cells, SpiD3 retained its anti-leukemic effects, mirrored in reduced activation of key proliferative pathways (e.g., PRAS, ERK, MYC). Translationally, we observed reduced tumor burden in SpiD3-treated E{micro}-TCL1 mice. Our findings reveal that SpiD3 exploits critical vulnerabilities in CLL cells including NF-{kappa}B signaling and the UPR, culminating in profound anti-tumor properties independent of TME stimuli. STATEMENT OF SIGNIFICANCESpiD3 demonstrates cytotoxicity in CLL partially through inhibition of NF-{kappa}B signaling independent of tumor-supportive stimuli. By inducing the accumulation of unfolded proteins, SpiD3 activates the UPR and hinders protein synthesis in CLL cells. Overall, SpiD3 exploits critical CLL vulnerabilities (i.e., the NF-{kappa}B pathway and UPR) highlighting its use in drug-resistant CLL. VISUAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=137 HEIGHT=200 SRC="FIGDIR/small/578283v1_ufig1.gif" ALT="Figure 1"> View larger version (27K): org.highwire.dtl.DTLVardef@1dd7a38org.highwire.dtl.DTLVardef@1831c85org.highwire.dtl.DTLVardef@c571f9org.highwire.dtl.DTLVardef@bdce53_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2022

A novel triple-action inhibitor targeting B-cell receptor signaling and BRD4 demonstrates preclinical activity in chronic lymphocytic leukemia

B-cell chronic lymphocytic leukemia (CLL) results from intrinsic genetic defects and complex microenvironment stimuli that fuel CLL cell growth through an array of survival-signaling pathways. Novel small-molecule agents targeting the B-cell receptor pathway and anti-apoptotic proteins alone or in combination have revolutionized the management of CLL, yet combination therapy carries significant toxicity and CLL still remains an incurable disease due to residual disease and relapse. Single-molecule inhibitors that can target multiple disease-driving factors are thus an attractive approach to combat both drug resistance and combination therapy-related toxicities. Using SRX3305, a novel small-molecule BTK/PI3K/BRD4 inhibitor that targets three distinctive facets of CLL biology, we demonstrate that SRX3305 attenuates CLL cell proliferation and promotes apoptosis in a dose-dependent fashion. SRX3305 also inhibits activation-induced proliferation of primary CLL cells in vitro, and effectively blocks microenvironment-mediated survival signals including stromal cell contact. Furthermore, SRX3305 blocks CLL cell migration toward CXCL-12 and CXCL-13, major chemokines involved in CLL cell homing and retention in microenvironment niches. Importantly, SRX3305 maintains its anti-tumor effects in ibrutinib-resistant CLL cells. Collectively, this study establishes the preclinical efficacy of SRX3305 in CLL providing significant rationale for its development as a therapeutic agent for CLL and related disorders.

cancer biology↗