Biology subjects

Tuval, A.

Publications and source records attributed to Tuval, A..

4 recordsLinked to original sources

bioRxiv2026

APR-246 and DNA polymerase theta inhibitor Novobiocinsynergize to eliminate TP53 mutant AML cells

Patients with TP53-mutant myelodysplasic syndromes (MDS) and acute myeloid leukemia (AML) are usually elderly and frail with highly resistant malignant clones and a median survival of less than one year. The molecule APR-246 targets mutant p53 but also perturbs redox homeostasis. APR-246 showed favorable safety in a phase 3 trial in TP53 mutant MDS/AML but did not meet efficacy endpoints in combination with azacitidine (AZA), highlighting the need for more effective combination strategies. Conversion of APR-246 to the active compound MQ releases formaldehyde which generates DNA-protein crosslinks. AML cells depend on DNA polymerase theta (Pol[O]) to repair such lesions and Pol[O] protects cells from ferroptosis. Using a panel of isogenic MOLM13 AML cell lines each carrying a common TP53 variant, we show that the Pol[O] inhibitor Novobiocin (NVB) synergizes with APR-246 to induce AML cell death. We demonstrate strong synergy with this combination in all TP53 mutant cell lines and to a lesser extent in the TP53 wildtype and null cells, indicating both p53-dependent and p53-independent mechanisms behind the synergy. APR-246 provides selectivity for TP53-mutated cells while NVB enhances p53-independent apoptosis and p53-dependent ferroptosis. Levels of ferroptosis induction correlate with the observed synergy in TP53-mutant and WT cells. Combination of APR-246 and NVB induces potent in vitro growth inhibition of primary TP53-mutated AML/CMML patient samples, with significant activity achieved at low micromolar or nanomolar concentrations of APR-246. Our findings hold promise for combination of APR-246 and NVB as a new therapeutic strategy tailored for TP53-mutated AML patients with high efficacy and low toxicity.

cancer biology↗

bioRxiv2025

DNMT3A-R882 mutations intrinsically drive dysfunctional neutropoiesis from human haematopoietic stem cells

Clonal haematopoiesis (CH) arises from the expansion of hematopoietic stem cells (HSCs) carrying leukaemia-associated somatic mutations. CH is linked to pathological immune dysregulation and a greater risk of age-related inflammatory diseases. Yet, how CH mutations impact HSC differentiation into immune effector cells remains understudied. Here, we report a single-cell resolution functional and multi-omic investigation of HSC clonal and differentiation dynamics in individuals with DNMT3A-R882 CH. DNMT3A-R882 reshapes the clonal architecture of haematopoiesis towards an aged phylogenetic structure. Functionally, DNMT3A-R882 HSCs produce decreased monocytic output but more abundant and mature neutrophil progeny compared to WT HSCs in the same individual. Whereas DNMT3A-R882 myeloid progenitors display attenuated inflammatory transcriptional programmes, DNMT3A- R882 mature neutrophils acquire proinflammatory and immunomodulatory features typical of maladaptive immunity and CH co-morbidities. Our findings, validated in humanised mice, identify aberrant DNMT3A-R882 HSC-driven neutropoiesis as a key link between CH, immune dysregulation and risk of inflammatory disease.

cell biology↗

bioRxiv2024

Automated, Stress-Free, and Precise Measurement of Songbird Weight in Neuroscience Experiments

Monitoring the health and well-being of research animals is essential for both ethical and scientific purposes. In songbirds, body weight is one of the main indicators for their overall condition, yet traditional weighing methods can be intrusive and stress-inducing, which could decrease their song rate. We developed a novel, automated system designed to continuously monitor the weight of untethered and tethered birds without disrupting their natural behavior in neuroscience experiments. We used the system to track weight fluctuations in six canaries over several weeks, revealing physiological patterns such as overnight weight loss, with one bird losing approximately 5.17% of its body weight during a 9.5-hour period of inactivity. Our systems high sensitivity detected weight changes below 1% of body mass, validating its reliability for long-term studies. Control experiments confirmed that weight fluctuations observed were physiological rather than due to equipment deviations. By eliminating the need for manual handling, this system offers a non-invasive, hands-free approach that reduces stress and improves the accuracy of health assessments. This study demonstrates the systems potential for expanding research on how environmental factors, diet, and other variables influence bird physiology and behavior. Future applications could integrate additional health metrics, providing a more comprehensive understanding of animal welfare in neuroscience and behavioral studies.

neuroscience↗

bioRxiv2021

Pseudo-mutant p53 as a targetable phenotype of DNMT3A-mutated pre-leukemia

Pre-leukemic clones carrying DNMT3A mutations have a selective advantage and an inherent chemo-resistance, however the basis for this phenotype has not been fully elucidated. Mutations affecting the gene TP53 occur in pre-leukemic hematopoietic stem/progenitor cells (preL-HSPCs) and lead to chemo-resistance. Many of these mutations cause a conformational change and some of them were shown to enhance self-renewal capacity of preL-HSPCs. Intriguingly, a misfolded p53 was described in AML blasts that do not harbor mutations in TP53, emphasizing the dynamic equilibrium between a wild-type (WT) and a "pseudomutant" conformations of p53. By combining single cell analyses and p53 conformation-specific monoclonal antibodies we studied preL-HSPCs from primary human DNMT3A AML samples. We found that while leukemic blasts express mainly the WT conformation, in preL-HSPCs the pseudomutant conformation is the dominant. HSPCs from non-leukemic samples expressed both conformations to a similar extent. Treatment with a short peptide that can shift the dynamic equilibrium favoring the WT conformation of p53, specifically eliminated preL-HSPCs that had dysfunctional canonical p53 pathway activity as reflected by single cell RNA sequencing. Our observations shed light upon a possible targetable p53 dysfunction in human preL-HSPCs carrying DNMT3A mutations. This opens new avenues for leukemia prevention.

cancer biology↗