NAP1L1

During base excision repair (BER), the apurinic or apyrimidinic (AP) site serves as an intermediate product following base excision. In plants, APE-redox protein (ARP) represents the major AP site of cleavage activity. Despite the well-established understanding that the nucleosomal structure acts as a barrier to various DNA-templated processes, the regulatory mechanisms underlying BER at the chromatin level remain elusive, especially in plants. In this study, we identified plant chromatin remodeler Excision Repair Cross-Complementing protein group 6 (ERCC6) and histone chaperone Nucleosome Assembly Protein 1 (NAP1) as interacting proteins with ARP. The catalytic ATPase domain of ERCC6 facilitates its interaction with both ARP and NAP1. Additionally, ERCC6 and NAP1 synergistically contribute to nucleosome sliding and exposure of hindered endonuclease cleavage sites. Loss-of-function mutations in Arabidopsis (Arabidopsis thaliana) ERCC6 or NAP1 resulted in arp-dependent plant hypersensitivity to 5-fluorouracil (5-FU), a toxic agent inducing BER, and the accumulation of AP sites. Furthermore, similar protein interactions are also found in yeast cells, suggesting a conserved recruitment mechanism employed by the AP endonuclease to overcome chromatin barriers during BER progression.

MLLT10 gene rearrangements with KMT2A occur in pediatric acute myeloid leukemia (AML) and confer poor prognosis, but the prognostic impact of MLLT10 in partnership with other genes is unknown. We conducted a retrospective study from 2,080 children and young adults with AML registered on Children's Oncology Group (COG)-AAML0531 and AAML1031 trials. Transcriptome profiling and/or karyotyping were performed to identify leukemia-associated fusions associated with prognosis. Collectively, 127 patients (6.1%) were identified with MLLT10 fusions:104 (81.9%) with KMT2A::MLLT10, 13 (10.2%) with PICALM::MLLT10, and 10 (7.9%) X::MLLT10: two each of DDX3X and TEC, with six partners (DDX3Y, CEP164, SCN2B, TREH, NAP1L1 and XPO1) observed in single patients. Patients with MLLT10 (n=127) demonstrated adverse outcomes, with 5-year event-free survival (EFS) of 18.6% vs. 49% in non-MLLT10 patients (N=1953, P <0.001), inferior 5 year overall-survival (OS) of 38.2% vs. 65.7% (P ≤ 0.001) and a higher relapse risk of 76% vs 38.6% (P <0.001). Patients with KMT2A::MLLT10 had an EFS from study entry of 19.5% vs 12.7% (P=0.628), and an OS from study entry of 40.4% vs 27.6% (P=0.361) in those with other MLLT10 fusion partners. Patients with PICALM::MLLT10 had an EFS of 9.2% vs 20% in other MLLT10- without PICALM ( X::MLLT10) (P=0.788). Patients with PICALM::MLLT10 and X::MLLT10 fusions exhibit a DNA hypermethylation signature resembling NUP98::NSD1 fusions, while KMT2A::MLLT10 patients bear aberrations primarily affecting distal regulatory elements. Regardless of the fusion partner, patients with AML harboring MLLT10 fusions exhibit very high-risk features and should be prioritized for alternative therapeutic interventions. Clinical trials #NCT00372593 NCT01371981.

The nucleosome assembly protein 1-like 1 (NAP1L1) is suggested to have an oncogenic role in several tumors based on its overexpression. However, its diagnostic and prognostic role in gastric cancer remains unclarified. This study aimed to evaluate the diagnostic and prognostic utility of NAP1L1 in gastric cancer patients.

A total of 85 patients (mean(SD) age: 60.9(1.6) years, 49.4% were males) with newly-diagnosed gastric cancer and 40 healthy individuals (mean(SD) age: 60.7(1.7) years, 52.5% were males) were included. Data on patient demographics (age, gender), TNM stages and tumor size, and the serum NAP1L1 levels were recorded.

Serum NAP1L1 levels were significantly higher in gastric cancer patients than in control subjects (12(9.5-13.8) vs. 1.8(1.5-2.4) ng/mL, p < 0.001). Also, certain tumor characteristics such as tumor size of >4 cm vs. <4 cm (p < 0.001), M1 vs. M0 stage (p < 0.001), N2 vs. N0 and N1 stage (p < 0.001) and T4 vs. lower T stage (p < 0.001) were associated with significantly higher serum NAP1L1 levels in gastric cancer patients.

Our findings revealed for the first time that serum levels for NAP1L1 was overexpressed in the gastric cancer, as also correlated with the disease progression. NAP1L1 seems to be a potential biomarker for gastric cancer, providing clinically important information on early diagnosis and risk stratification.