Correction: Pakula et al. Deciphering the Molecular Mechanism of Spontaneous Senescence in Primary Epithelial Ovarian Cancer Cells. Cancers 2020, 12, 296.

In the original publication [...].

Deciphering the Molecular Mechanism of Spontaneous Senescence in Primary Epithelial Ovarian Cancer Cells.

Spontaneous senescence of cancer cells remains a puzzling and poorly understood phenomenon. Here we comprehensively characterize this process in primary epithelial ovarian cancer cells (pEOCs). Analysis of tumors from ovarian cancer patients showed an abundance of senescent cells in vivo. Further, serially passaged pEOCs become senescent after a few divisions. These senescent cultures display trace proliferation, high expression of senescence biomarkers (SA--Gal, -H2A.X), growth-arrest in the G1 phase, increased level of cyclins D1, D2, decreased cyclin B1, up-regulated p16, p21, and p53 proteins, eroded telomeres, reduced activity of telomerase, predominantly non-telomeric DNA damage, activated AKT, AP-1, and ERK1/2 signaling, diminished JNK, NF-B, and STAT3 pathways, increased formation of reactive oxygen species, unchanged activity of antioxidants, increased oxidative damage to DNA and proteins, and dysfunctional mitochondria. Moreover, pEOC senescence is inducible by normal peritoneal mesothelium, fibroblasts, and malignant ascites via the paracrine activity of GRO-1, HGF, and TGF-1. Collectively, pEOCs undergo spontaneous senescence in a mosaic, telomere-dependent and telomere-independent manner, plausibly in an oxidative stress-dependent mechanism. The process may also be activated by extracellular stimuli. The biological and clinical significance of pEOC senescence remains to be explored.

Polymorphisms in microRNA target sites modulate risk of lymphoblastic and myeloid leukemias and affect microRNA binding.

BACKGROUND: MicroRNA dysregulation is a common event in leukemia. Polymorphisms in microRNA-binding sites (miRSNPs) in target genes may alter the strength of microRNA interaction with target transcripts thereby affecting protein levels. In this study we aimed at identifying miRSNPs associated with leukemia risk and assessing impact of these miRSNPs on miRNA binding to target transcripts. METHODS: We analyzed with specialized algorithms the 3' untranslated regions of 137 leukemia-associated genes and identified 111 putative miRSNPs, of which 10 were chosen for further investigation. We genotyped patients with acute myeloid leukemia (AML, n = 87), chronic myeloid leukemia (CML, n = 140), childhood acute lymphoblastic leukemia (ALL, n = 101) and healthy controls (n = 471). Association between SNPs and leukemia risk was calculated by estimating odds ratios in the multivariate logistic regression analysis. For miRSNPs that were associated with leukemia risk we performed luciferase reporter assays to examine whether they influence miRNA binding. RESULTS: Here we show that variant alleles of TLX1_rs2742038 and ETV6_rs1573613 were associated with increased risk of childhood ALL (OR (95% CI) = 3.97 (1.43-11.02) and 1.9 (1.16-3.11), respectively), while PML_rs9479 was associated with decreased ALL risk (OR = 0.55 (0.36-0.86). In adult myeloid leukemias we found significant associations between the variant allele of PML_rs9479 and decreased AML risk (OR = 0.61 (0.38-0.97), and between variant alleles of IRF8_ rs10514611 and ARHGAP26_rs187729 and increased CML risk (OR = 2.4 (1.12-5.15) and 1.63 (1.07-2.47), respectively). Moreover, we observed a significant trend for an increasing ALL and CML risk with the growing number of risk genotypes with OR = 13.91 (4.38-44.11) for carriers of ≥3 risk genotypes in ALL and OR = 4.9 (1.27-18.85) for carriers of 2 risk genotypes in CML. Luciferase reporter assays revealed that the C allele of ARHGAP26_rs187729 creates an illegitimate binding site for miR-18a-3p, while the A allele of PML_rs9479 enhances binding of miR-510-5p and the C allele of ETV6_rs1573613 weakens binding of miR-34c-5p and miR-449b-5p. CONCLUSIONS: Our study implicates that microRNA-binding site polymorphisms modulate leukemia risk by interfering with the miRNA-mediated regulation. Our findings underscore the significance of variability in 3' untranslated regions in leukemia.

[Cytogenetic analysis of secondary myelodysplastic syndrome after rhabdomysarcoma treatment--case report]. / Zmiany cytogenetyczne we wtórnym zespole mielodysplastycznym wyindukowanym leczeniem miesaka prazkowanokomórkowego--opis przypadku.

Rhabdomyosarcoma (RMS) is the most common pediatric soft tissue sarcoma. Alveolar subtype of RMS is characterized by very poor prognosis and intensive chemotherapy, radiotherapy and surgery often failed. Frequently a secondary malignant neoplasms has been found in patients treated for primary cancer. Ten-years-old boy with RMS in the right thigh after 3 years of treatment revealed therapy related myelodysplastic syndrome and was lost to follow-up 4 months later.

Juvenile xanthogranuloma with clonal proliferation in the bone marrow.

The triple association between juvenile xanthogranuloma (JXG), juvenile myelomonocytic leukemia and neurofibromatosis was described in literature in about 20 cases. In this paper, the case of an 11-month-old infant boy with a disseminated JXG with unusual cytogenetic representation in the bone marrow was reported. Neurofibromatosis and juvenile myelomonocytic leukemia were excluded, just the same as other leukemias. Bone marrow and peripheral blood cytogenetic analysis revealed a karyotype with many rearrangements 46,XY,-6,der(12)t(6;12)(p21;p13),del(7)(p13p22),+9 once described in the literature as a B-acute lymphoblastic leukemia case. On the contrary, in our patient immunologic testing demonstrated a high activity of T lymphocytes, however, inflammation was excluded. To the best of our knowledge this is the first described case of systemic JXG with determined karyotype representing unusual chromosomal aberrations.

FLT3 internal tandem duplication and FLT3-D835 mutation in 80 AML patients categorized into cytogenetic risk groups.

BACKGROUND: Acute myeloid leukemia (AML) is a clonal disorder characterized by various genetic abnormalities and variable response to treatment. About 50% of patients with AML have no cytogenetic aberrations, presenting normal karyotype, and are categorized in the intermediate risk group. In this group detection of FLT3 mutations move a patient from the intermediate to the adverse risk group. MATERIAL/METHODS: Bone marrow from 80 AML patients was cultured to obtain chromosome slides and then karyotype. Simultaneously DNA was isolated from bone marrow and PCR reaction was conducted to test the FLT3 mutation status (ITD and D835). For statistical analysis Chi squared test was used. RESULTS: From the group of 80 AML patients seven were classified as a favorable risk group and FLT3/ITD was found only in one of these patients (14.28%), and FLT3/D835 in another one (14.28%). Fifteen patients showed a complex karyotype with more than three aberrations or with any aberration known as a poor prognosis. Among the adverse group FLT3/ITD was detected in three patients (20%) and D835 mutation in two other patients (13.33%). Among 58 patients with normal karyotype in GTG banding FLT3/ITD occurred in six cases (10.34%) and D835 mutation in two cases (3.45%). No significant difference was found among these three risk groups regarding presence or absence of FLT3/ITD and FLT/D835. DISCUSSION: Molecular characterization of mutations in several genes, such as FLT3, NPM1, MLL, CEBPA, in acute myeloid leukemia, especially in normal karyotype cases, could be another factor after cytogenetic analysis to stratify AML patients into different prognostic categories.