SAMHD1 (SAM And HD Domain Containing Deoxynucleoside Triphosphate Triphosphohydrolase 1)

We show that approved drugs inhibiting IMPDH-mycophenolic acid and ribavirin-imbalance deoxyribonucleoside triphosphate pools and increase ara-C efficacy in SAMHD1-proficient, but not deficient, leukaemic cells. Altogether, we provide insight into SAMHD1 regulation in leukaemic cells and show how this process can be exploited by approved drugs to improve ara-C therapy.

This research identifies a key mechanism of SAMHD1-driven immunosuppression and highlights its important role in oncolytic adenovirus therapy. This study provides a theoretical basis for targeting SAMHD1 as a drug therapy strategy in patients with NSCLC.

Moreover, selective depletion of tumor-associated SAMHD1 activated innate immune responses, leading to enhanced tumor cell killing by immune cells. Collectively, these findings suggest that targeting tumor-specific SAMHD1 represents a novel and promising therapeutic strategy for cancers characterized by elevated SAMHD1 expression, offering potential for improved treatment outcomes in cancer patients with high SAMHD1 expression.

These findings indicated that SAMHD1 and p-ATM may serve as valuable prognostic biomarkers in STS. Their involvement in DDR mechanisms also highlights their potential as novel therapeutic targets, especially for patients with aggressive or high-risk disease profiles.

Furthermore, leukaemic SAMHD1 protein expression negatively correlated with overall survival in a cohort of FLA-treated refractory AML patients. Our findings suggest that the addition of HU improves the efficacy of FLA-based regimens and warrant clinical trials to test the safety and efficacy of this combination in patients with relapsed/refractory AML.

DYRK1A is involved in Ara-C resistance in AML cells, and its mechanism may be related to increased expression of SAMHD1 by interacting with Cyclin L2.

CR, DFS, and OS were not significantly associated to SAMHD1 rs28372906 and NME2 rs3744660 polymorphisms.

Clinically, SAMHD1 dysfunction negatively impacts clinical outcome of CLL cases: SAMHD1 mutations reduce failure-free survival (median 46 vs 57 months, p = 0.033), while low SAMHD1 expression associates with shorter time to first treatment (median 47 vs 77 months; p = 0.00073). Overall, this study elucidates that SAMHD1 dysfunction compromises DNA damage response mechanisms, potentially contributing to unfavorable clinical outcomes in CLL, and proposes PARP-inhibitors as a potential therapeutic approach for SAMHD1-mutated CLL cells.

In metastatic BC, SAMHD1 mRNA levels were higher in responders receiving capecitabine. In conclusion SAMHD1 gene and protein expression represent promising prognostic biomarkers in BL early BC.

Mechanistically, SAMHD1 interacts with the cohesin complex in nucleus, enhancing sister chromatid cohesion during cell division, which delays metaphase progression. Our findings suggest that nuclear SAMHD1 plays a critical role in slowing HCC progression by regulating mitosis, highlighting its potential as a therapeutic target by manipulating cohesin dynamics.

Finally, we demonstrate that the phosphatase inhibitor endothall promotes hyper-recruitment of endogenous SAMHD1 to HPV16 replicating DNA and can attenuate the growth of both HPV16-immortalized human foreskin keratinocytes (HFKs) and HPV16-positive head and neck cancer cell lines. We propose that phosphatase inhibitors represent a novel tool for combating HPV infections and disease.

Affected members of each pedigree shared multiple deleterious variants (median, n = 18), but the overlap between the families was modest. In summary, P/LP variants in highly penetrant genes constitute a modest proportion of the deleterious variants; each pedigree is largely unique in its genetic architecture, and multiple genes are likely involved in the etiology of WM.