DAXX (Death-domain associated protein)

We further demonstrate that heterochromatin-driven PML-telomere colocalization is inhibited by α-thalassemia/mental retardation, X-linked and death domain-associated protein (ATRX/DAXX), factors frequently mutated in ALT+ tumors. Together, these findings establish telomeric heterochromatin as a driver of telomere clustering and PML nuclear body assembly, shaping ALT-associated subnuclear compartmentalization.

We also demonstrated that DAXX loss increased decitabine sensitivity in the myeloid leukemia (AML) cell line THP-1. Together, these findings show that DAXX promotes SUMOylation of DNMT1 trapped on DNA under both covalent and non-covalent trapping conditions.

Moreover, H3.3-specific post translational modifications, particularly K36 tri-methylation, play a key role in these processes. Altogether, these findings indicate that DAXX and H3.3 mutations may contribute to tumorigenesis-enhancing genome instability.

The genomic landscape of OCA is marked by frequent TERT promoter mutations and distinct mutational patterns associated with patient gender and tumor metastatic status. These findings highlight potential molecular subtypes, reveal pathways potentially driving metastasis (eg, involving MEN1/TSC2), and identify novel sex-specific alterations (MST1R, PRKDC), offering avenues for improved development of targeted therapeutic strategies for OCA.

P=N/A, N=100, Active, not recruiting, Azienda Ospedaliera Universitaria Integrata Verona | Recruiting --> Active, not recruiting

Approximately 5-10% of NETs are associated with hereditary syndromes, though recent findings suggest germline pathogenic variants, which were present in additional 5% of apparently sporadic NETs and NECs, requiring further study. An integrated histological, molecular, and clinical approach is essential to improve the classification, prognostication, and management of NENs, while recognizing the distinct biology of individual subtypes.

In contrast, in the bladder, expression of DAXX and ATRX declined with increasing tumour grade (p < 0.05). Our findings provide new insights into the potential of DAXX and ATRX as biomarkers, offering new insights into their clinical relevance in dogs.

TERT-negative osteosarcoma U2-OS (ALT) cells, that normally lack SLFN11 expression, show SLFN11 localization to telomeres upon doxycycline-induced SLFN11 expression...Furthermore, SLFN11 suppresses ALT induction in ATRX-depleted prostate carcinoma DU145 cells. Collectively, our findings identify SLFN11 as a negative telomeric regulator of the ALT pathway, indicating that its loss, together with ATRX/DAXX inactivation, contributes to ALT activation.

Unexpectedly, we find that mutations in the DAXX histone binding domain lead to failure of ATRX localization. We conclude that a key function of DAXX in ALT suppression is the localization of ATRX to nuclear foci.

While these findings validate the sensitivity of an IHC-based diagnostic panel in confirming the vast majority of LMS diagnoses, a subset, which more likely shows ambiguous diagnostic features, probably requires genomic testing. The previously proposed morphologic criteria seem to provide a robust prognostic stratification.

A key finding from drug sensitivity analysis was that the high-risk group exhibited significantly increased sensitivity to several drugs, including CCT018159, rapamycin, vinblastine, metformin, and roscovitine. Moreover, the expression levels of SESN3, CRIP1, DPP4 and PIK3CA were significantly upregulated in breast cancer samples compared to control samples. This study constructed a risk model based on seven prognostic genes, offering new potential strategies for breast cancer therapy.

Biallelic loss of DNA damage repair genes, ATRX and/or DAXX, was associated with a high fraction of the genome altered in PanNETs, with pathogenic alterations affecting those genes also being associated with a homologous recombination deficiency signature. These findings highlight molecular mechanisms driving PanNET progression and underscore the need for further molecular characterization and tumor evolution studies to evaluate targeted therapies for such a challenging disease.