Biology subjects

Dace, P.

Publications and source records attributed to Dace, P..

3 recordsLinked to original sources

bioRxiv2026

PTPRJ Drives Clonal Selection in CEBPA mutated AML

Transcription factor CEBPA is mutated in 10-15% of acute myeloid leukaemia (AML), a haematopoietic malignancy with high mortality. CEBPA mutations show a distinct pattern, and most patients are biallelic, carrying both an in-frame C-terminal mutation and a frameshift N-terminal mutation on opposing alleles. Rare N-terminal germline cases have 100% penetrance to AML, all with an acquired a C-terminal mutation. This suggests a selective pressure from one CEBPA mutation to develop another. Our zebrafish models faithfully recapitulate the human disease. All biallelic mutant combinations die by 4-6 weeks of age, with pre-leukaemic haematopoietic stem cell (HSC) expansion. C-terminal and N-terminal mutants show phenotypic differences in myeloid-primed HSC and differences in the myeloid differentiation block. RNA-Seq identified differentially expressed genes in opposing vectors. We identified phosphatase receptor PTPRJ as a candidate driver of clonal selection, with knock-out of ptprja in our fish accelerating pre-leukaemic expansion of HSC in C-terminal mutants, decelerating it in N-terminal mutants. Cebpa-mutant murine cells exhibit changes in differentiation and a clonal advantage with loss of Ptprj, which perturbs key signalling pathways. Our data suggest that PTPRJ contributes to the mechanism of leukaemogenesis in CEBPA mutant AML by driving the selective pressure from each mutation to develop the other.

cancer biology↗

bioRxiv2023

Saturation Genome Editing Resolves the Functional Spectrum of Pathogenic VHL Alleles

To maximize the impact of precision medicine approaches, it is critical to accurately identify genetic variants in cancer-associated genes with functional consequences. Yet, our knowledge of rare variants conferring clinically relevant phenotypes and the mechanisms through which they act remains highly limited. A tumor suppressor gene exemplifying the challenge of variant interpretation is VHL. VHL encodes an E3 ubiquitin ligase that regulates the cellular response to hypoxia. Germline pathogenic variants in VHL predispose patients to tumors including clear cell renal cell carcinoma (ccRCC) and pheochromocytoma, and somatic VHL mutations are frequently observed in sporadic renal cancer. Here, we optimize and apply Saturation Genome Editing (SGE) to assay nearly all possible single nucleotide variants (SNVs) across VHLs coding sequence. To delineate mechanisms, we quantify mRNA dosage effects over time and compare effects in isogenic cell lines. Function scores for 2,268 VHL SNVs identify a core set of pathogenic alleles driving ccRCC with perfect accuracy, inform differential risk across tumor types, and reveal novel mechanisms by which variants impact function. These results have immediate utility for classifying VHL variants encountered in both germline testing and tumor profiling and illustrate how precise functional measurements can resolve pleiotropic and dosage-dependent genotype-phenotype relationships across complete genes.

genomics↗

bioRxiv2020

TLR7 ligation augments haematopoiesis in Rps14 (uS11) deficiency via paradoxical suppression of inflammatory signalling and enhanced differentiation

Myelodysplastic syndrome (MDS) is a haematological malignancy characterised by blood cytopenias and predisposition to acute myeloid leukaemia (AML). Therapies for MDS are lacking, particularly those that impact the early stages of disease. We developed a model of MDS using zebrafish using knockout of Rps14, the primary mediator of the anaemia associated with del (5q) MDS. These mutant animals display dose- and age-dependent abnormalities in haematopoiesis, culminating in bone marrow failure with dysplastic features. We utilized rps14 knockdown to undertake an in vivo small molecule screen to identify compounds that ameliorate the MDS phenotype, identifying imiquimod, an agonist of TLR7 and TLR8. Imiquimod alleviates anaemia by promoting haematopoietic stem and progenitor cell expansion and erythroid differentiation, the mechanism of which is dependent on TLR7 ligation. TLR7 activation in this setting paradoxically promoted an anti-inflammatory gene signature suggesting crosstalk between pro-inflammatory pathways endogenous to Rps14 loss and TLR7 pathway activation. Finally, we show that in highly purified human bone marrow samples from anaemic patients, imiquimod leads to an increase in erythroid output from myelo-erythroid progenitors and common myeloid progenitors. Our findings have both specific implications for the development of targeted therapeutics for del (5q) MDS and wider significance identifying a potential role for TLR7 ligation in modifying anaemia.Competing Interest StatementThe authors have declared no competing interest.View Full Text

cancer biology↗