Search bioRxiv⌕ Search
Home/Archive/bioRxiv

bioRxiv · 10.1101/2022.12.19.520971

Deletion of the transcriptional regulator TFAP4 accelerates c-MYC-driven lymphomagenesis

Herold, M.·Potts, M. A.·Mizutani, S.·Garnham, A.·Li-Wai-Suen, C. S. N.·Kueh, A. J.·Tai, L.·Pal, M.·Strasser, A.
View original source ↗Export metadata ↓

Abstract

Many lymphoid malignancies arise from deregulated c-MYC expression in cooperation with additional genetic lesions. While many of these cooperative genetic lesions have been discovered, DNA sequence data suggest that many more do exist. However, their contributions to c-MYC driven lymphomagenesis have not yet been investigated. We identified TFAP4 as a potent suppressor of c-MYC driven lymphoma development in a previous genome-wide CRISPR knockout screen in primary cells in vivo (Mizutani et al, 2022). CRISPR deletion of TFAP4 in E-MYC transgenic hematopoietic stem and progenitor cells (HSPCs) significantly accelerated c-MYC-driven lymphoma development in mice. TFAP4 deficient E-MYC lymphomas all arose at the pre-B cell stage. Characterization of the transcriptional profile of pre-leukemic pre-B cells in E-MYC/Cas9/sgTFAP4 transplanted mice, revealed that TFAP4 deletion reduced expression of several master regulators of B cell differentiation, such as Spi1, SpiB and Pax5, which all have been shown to be bound by TFAP4. We therefore conclude that loss of TFAP4 leads to a block in differentiation during early B cell development, causing accelerated c-MYC-driven lymphoma development.

Source connections

Explore related subjects

cancer biologyPreprint

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Herold, M., Potts, M. A., Mizutani, S., Garnham, A., Li-Wai-Suen, C. S. N., Kueh, A. J., Tai, L., Pal, M., Strasser, A.. 2022-12-20. Deletion of the transcriptional regulator TFAP4 accelerates c-MYC-driven lymphomagenesis. https://doi.org/10.1101/2022.12.19.520971

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

BAF complexes cooperate with lineage-restricted transcription factors to establish cell-state-specific regulatory programs

BRG1/BRM-associated factor (BAF) complexes are essential regulators of chromatin organization and cell identity. Genes encoding BAF subunits are among the most frequently mutated in human cancer. Yet, how disruption of a single subunit gives rise to distinct tumor states remains poorly understood. Atypical teratoid rhabdoid tumors (ATRTs) provide a compelling model, as they are uniformly driven by bi-allelic loss of the BAF subunit SMARCB1, yet segregate into distinct molecular subtypes. Using integrated multi-omics profiling of patient-derived ATRT organoids and primary tumor tissues, we show that transcriptional and chromatin accessibility changes upon SMARCB1 reconstitution are directed by subtype- and lineage-specific transcription factor (TF) repertoires. Genome-wide binding and transcriptomic analyses reveal that SMARCB1 reconstitution enables the lineage-specific TF RFX4 to engage regulatory elements and activate neuronal differentiation programs, partially reprogramming ATRT-MYC toward an ATRT-SHH-like identity. Together, these findings demonstrate that SMARCB1 loss disrupts TF-dependent chromatin priming, revealing that the lineage-specific regulatory output of BAF complexes is constrained by the underlying TF repertoire.

cancer biology↗
bioRxiv2026

Curvature-based schedule ordering is preserved in homogeneous and heterogeneous tumors

During treatment, dosing protocols with identical total dose may favor one schedule over another depending on how exposure is distributed over time. In homogeneous cell populations, Jensen's inequality has been shown to predict whether continuous or intermittent high-dose followed by low-dose is favored, based on the curvature of the concentration-effect function. Scheduling ordering can be performed based on curvature only: concave functions favor continuous dosing while convex functions favor intermittent dosing schedules with a high time-variance. However, tumors exhibit heterogeneous drug sensitivities, and treatment preferentially eliminates drug-sensitive cells, progressively shifting the surviving population toward greater drug resistance. Whether this treatment-induced selection can reverse curvature-based schedule ordering remains unclear. We develop a mathematical framework in which phenotypes share a common concentration-effect function but differ by fixed, nonnegative sensitivity scales. We prove that the ordering of equal-mean schedules is administrated solely by the scalar cumulative treatment effect, that is, by the curvature of the effect function alone. Consequently, baseline heterogeneity and treatment-induced selection can alter the magnitude of treatment response and the composition of surviving cells, but cannot reverse the ordering of equal-mean schedules predicted by the curvature of the single-cell concentration-effect function. This preservation holds across different temporal dosing profiles and repeated treatment cycles. Our work uncovers a general principle that curvature-based schedule ordering is preserved in heterogeneous tumors despite treatment-induced selection toward resistance.

cancer biology↗
bioRxiv2026

Enhanced antitumour activity of combined PD-1 blockade and HER2-targeted therapy is associated with reduced epithelial-mesenchymal transition and extracellular matrix-remodelling signatures in gastric cancer

Background The combination of PD-1 blockade, HER2-targeted therapy and chemotherapy improves outcomes in HER2-positive advanced gastric and gastro-oesophageal junction adenocarcinoma. However, chemotherapy can independently alter the tumour microenvironment, making the biological effects of PD-1 and HER2 targeting difficult to distinguish. We therefore investigated how PD-1 and HER2 blockade, alone and in combination, affect tumour growth and associated transcriptional programmes. Methods Immunodeficient NOG mice received human PBMCs by tail-vein injection. Three days later, NCI-N87 gastric cancer cells were implanted subcutaneously. Mice were randomised to vehicle, pembrolizumab, trastuzumab, or combination treatment. Tumour growth was assessed, and bulk RNA sequencing was used to identify treatment-associated changes in gene expression, pathway enrichment, and tumour, stromal, and immune cell-associated signatures. Results Combined treatment produced greater tumour growth control than either monotherapy. Trastuzumab-treated tumours showed enrichment of immune activation, epithelial-mesenchymal transition (EMT), and TGF{beta}-associated signatures, whereas pembrolizumab alone produced a limited transcriptional effect. Combination treatment was associated with reduced proliferation, EMT, and stromal-remodelling signatures, alongside increased cytotoxic immune-associated signatures. Expression of extracellular matrix-associated genes, including VCAN, SPARC, POSTN, collagen genes, and FAP, was lower in combination-treated tumours. Complement-related transcriptional pathways were also enriched. Conclusions In this chemotherapy-free model, combined PD-1 blockade and HER2-targeted therapy was associated with greater tumour growth control, enrichment of cytotoxic immune-associated transcriptional signatures, and reduced EMT and extracellular matrix remodelling signatures. These findings provide hypotheses for further mechanistic validation.

cancer biology↗