Biology subjects

Heiser, D.

Publications and source records attributed to Heiser, D..

4 recordsLinked to original sources

bioRxiv2026

CDK9 pharmacological inhibition with PRT2527 has antitumor activity in marginal zone lymphoma models and can improve the effects of BTK, PI3K, and BCL2 inhibitors

Cyclin-dependent kinase 9 (CDK9) drives transcriptional elongation and supports the expression of short-lived oncogenic and anti-apoptotic proteins such as MYC and MCL1. PRT2527 is a potent, selective CDK9 inhibitor currently in early clinical development. We evaluated its preclinical activity in marginal zone lymphoma (MZL) models, including cell lines with acquired resistance to BTK, PI3K, and BCL2 inhibitors. Short exposure (4 hours) to PRT2527 produced nanomolar cytotoxicity across all tested MZL cell lines, with efficacy maintained in resistant derivatives. Transcriptomic profiling of VL51 cells showed broad gene repression, including MYC, IRF4, NF-{kappa}B-related genes, and MCL1, alongside increased expression of HLA class II genes. Moreover, comparison with additional CDK inhibitors revealed a similar transcriptional repression signature, underscoring a conserved CDK-dependent regulatory network. Protein analyses confirmed rapid depletion of MCL1, MYC, RNA polymerase II, and IRF4. Flow cytometry validated increased HLA class II and decreased HLA class I surface expression. Combination studies demonstrated additive to synergistic effects with BTK inhibition (ibrutinib) or dual PI3K/BCL2 inhibition (copanlisib plus venetoclax), independent of baseline drug sensitivity. Mechanistically, these combinations may enhance apoptosis by concurrently suppressing survival signaling and transcriptional addiction. Analysis of patient samples revealed high CDK9 expression, further supporting the biological relevance and therapeutic rationale for targeting CDK9 in this disease. Our findings support the development of CDK9-based combination strategies for relapsed/refractory MZL and other B-cell malignancies, with an additional potential for integration with immunotherapies. Key PointsO_LICDK9 inhibitor PRT2527 kills marginal zone lymphoma cells, regardless of whether they are resistant to other targeted drugs. C_LIO_LIPRT2527 boosts the effects of BTK, PI3K, and BCL2 inhibitors and alters immune-related gene expression. C_LI Draft of graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=141 SRC="FIGDIR/small/705084v1_ufig1.gif" ALT="Figure 1"> View larger version (33K): org.highwire.dtl.DTLVardef@37b9e6org.highwire.dtl.DTLVardef@8de6a5org.highwire.dtl.DTLVardef@219771org.highwire.dtl.DTLVardef@15dabfe_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2024

Broad de-regulated U2AF1 splicing is prognostic and augments leukemic transformation via protein arginine methyltransferase activation

The role of splicing dysregulation in cancer is underscored by splicing factor mutations; however, its impact in the absence of such rare mutations is poorly understood. To reveal complex patient subtypes and putative regulators of pathogenic splicing in Acute Myeloid Leukemia (AML), we developed a new approach called OncoSplice. Among diverse new subtypes, OncoSplice identified a biphasic poor prognosis signature that partially phenocopies U2AF1-mutant splicing, impacting thousands of genes in over 40% of adult and pediatric AML cases. U2AF1-like splicing co-opted a healthy circadian splicing program, was stable over time and induced a leukemia stem cell (LSC) program. Pharmacological inhibition of the implicated U2AF1-like splicing regulator, PRMT5, rescued leukemia mis-splicing and inhibited leukemic cell growth. Genetic deletion of IRAK4, a common target of U2AF1-like and PRMT5 treated cells, blocked leukemia development in xenograft models and induced differentiation. These analyses reveal a new prognostic alternative-splicing mechanism in malignancy, independent of splicing-factor mutations. Statement of significanceUsing a new in silico strategy we reveal counteracting determinants of patient survival in Acute Myeloid Leukemia that co-opt well-defined mutation-dependent splicing programs. Broad poor-prognosis splicing and leukemia stem cell survival could be rescued through pharmacological inhibition (PRMT5) or target deletion (IRAK4), opening the door for new precision therapies. Competing InterestsConflict-of-interest disclosure: DTS. serves on the scientific advisory board at Kurome Therapeutics; is a consultant for and/or received funding from Kurome Therapeutics, Captor Therapeutics, Treeline Biosciences, and Tolero Therapeutics; and has equity in Kurome Therapeutics. AV has received research funding from GlaxoSmithKline, BMS, Jannsen, Incyte, MedPacto, Celgene, Novartis, Curis, Prelude and Eli Lilly and Company, has received compensation as a scientific advisor to Novartis, Stelexis Therapeutics, Acceleron Pharma, and Celgene, and has equity ownership in Throws Exception and Stelexis Therapeutics.

cancer biology↗

bioRxiv2021

Evaluation of protein kinase D auto-phosphorylation as biomarker for NLRP3 inflammasome activation

BackgroundThe NLRP3 inflammasome is a critical component of sterile inflammation, which is involved in many diseases. However, there is currently no known proximal biomarker for measuring NLRP3 activation in pathological conditions. Protein kinase D (PKD) has emerged as an important NLRP3 kinase that catalyzes the release of a phosphorylated NLRP3 species that is competent for inflammasome complex assembly. MethodsTo explore the potential for PKD activation to serve as a selective biomarker of the NLRP3 pathway, we tested various stimulatory conditions in THP-1 and U937 cell lines, probing the inflammasome space beyond NLRP3. We analyzed the correlation between PKD activation (monitored by its auto-phosphorylation) and functional inflammasome readouts. ResultsPKD activation/auto-phosphorylation always preceded cleavage of caspase-1 and gasdermin D, and treatment with the PKD inhibitor CRT0066101 could block NLRP3 inflammasome assembly and interleukin-1{beta} production. Conversely, blocking NLRP3 either genetically or using the MCC950 inhibitor prevented PKD auto-phosphorylation, indicating a bidirectional functional crosstalk between NLRP3 and PKD. Further assessments of the pyrin and NLRC4 pathways, however, revealed that PKD auto-phosphorylation can be triggered by a broad range of stimuli unrelated to NLRP3 inflammasome assembly. ConclusionAlthough PKD and NLRP3 become functionally interconnected during NLRP3 activation, the promiscuous reactivity of PKD challenges its potential use for tracing the NLRP3 inflammasome pathway.

cell biology↗

bioRxiv2020

A Multi-Phenotype System to Discover Therapies for Age-Related Dysregulation of the Immune Response to Viral Infections

Age-related immune dysregulation contributes to increased susceptibility to infection and disease in older adults. We combined high-throughput laboratory automation with machine learning to build a multi-phenotype aging profile that models the dysfunctional immune response to viral infection in older adults. From a single well, our multi-phenotype aging profile can capture changes in cell composition, physical cell-to-cell interaction, organelle structure, cytokines, and other hidden complexities contributing to age-related dysfunction. This system allows for rapid identification of new potential compounds to rejuvenate older adults immune response. We used our technology to screen thousands of compounds for their ability to make old immune cells respond to viral infection like young immune cells. We observed beneficial effects of multiple compounds, of which two of the most promising were disulfiram and triptonide. Our findings indicate that disulfiram could be considered as a treatment for severe coronavirus disease 2019 and other inflammatory infections.

immunology↗