LncRNA KCNQ1OT1 activated by c-Myc promotes cell proliferation via interacting with FUS to stabilize MAP3K1 in acute promyelocytic leukemia.

Uncontrolled proliferation is the hallmark of cancer cells. Previous studies mainly focused on the role of protein-coding genes in cancer cell proliferation. Emerging evidence showed that long non-coding RNAs (lncRNAs) also play critical roles in cancer cell proliferation and growth. LncRNA KCNQ1OT1 is found to contribute to carcinogenesis, but its role in acute promyelocytic leukemia (APL) is unclear. In this study, by analyzing data from Gene Expression Omnibus, The Cancer Genome Atlas database and our clinical samples, we found that KCNQ1OT1 was selectively highly expressed in APL. Functional assays demonstrated that knockdown of KCNQ1OT1 reduced APL cell proliferation and increased apoptosis. Further evidence showed that KCNQ1OT1 was mainly located in the cytoplasm of APL patient-derived NB4 cells and APL patient bone marrow samples. Mechanistically, KCNQ1OT1 bound to RNA binding protein FUS, and silencing either KCNQ1OT1 or FUS reduced the expression level and stability of MAP3K1 mRNA. Whereas KCNQ1OT1 and FUS did not affect each other. Importantly, knockdown of MAP3K1 impaired APL cell proliferation. Finally, c-Myc transactivated KCNQ1OT1 in APL cells through binding to its promoter while knockdown of c-Myc decreased KCNQ1OT1 expression. Our results not only revealed that c-Myc transactivated KCNQ1OT1 and upregulated KCNQ1OT1 promoted APL cell proliferation, but also demonstrated that KCNQ1OT1 bound to FUS to synergistically stabilize MAP3K1 mRNA, thus facilitating APL cell proliferation. This study established a previously unidentified role of KCNQ1OT1 in the development of APL, and KCNQ1OT1 may serve as a potential therapeutic target for APL.

Acute leukemia in pregnancy: a single institutional experience with 21 cases at 10 years and a review of the literature.

INTRODUCTION: Acute leukemia (AL) occurring in pregnancy is extremely rare, and its treatment is a clinical dilemma. METHODS: We retrospectively reviewed the medical records of our hospital from 2010 to 2019. RESULTS: Twenty-one patients were diagnosed with AL during pregnancy. Of whom, eighteen had acute myeloid leukemia, and 3 had acute lymphoblastic leukemia. Six, eight and seven patients were diagnosed during the first, second, and third trimester, respectively. Six of the 21 patients experienced therapeutic abortion and 1 had spontaneous abortion, whereas 9 gave birth to healthy babies (4 through vaginal deliveries and 5 with Caesarean sections). Four babies had been exposed to chemotherapeutic agents, but no congenital malformations were observed. Sixteen patients received chemotherapy, while 4 patients died before chemotherapy and one was discharged after refusing chemotherapy. The complete remission rate of the 10 patients who began chemotherapy immediately after diagnosis was 80%, compared with 66.7% in the 6 patients who started chemotherapy after abortion or delivery. Three remain alive. CONCLUSIONS: In general, initiation of chemotherapy as early as possible may increase the CR rate. Combined with literature data, we proposed that, for patients diagnosed in early and late stages of pregnancy (>30 weeks), elective termination or induced delivery before chemotherapy may be a good choice for better maternal (and fetal) outcome.KEY MESSAGESAcute leukaemia diagnosed in pregnancy is extremely rare, and its treatment is a clinical dilemma.In general, initiation of chemotherapy as early as possible may increase the CR rate.For patients who are diagnosed in the first trimester or late stage of pregnancy (>30 weeks), elective termination or induced delivery before starting chemotherapy may be a good choice for better maternal (and fetal) outcome.

C/EBPα is indispensable for PML/RARα-mediated suppression of long non-coding RNA NEAT1 in acute promyelocytic leukemia cells.

Better understanding of the transcriptional regulatory network in acute promyelocytic leukemia (APL) cells is critical to illustrate the pathogenesis of other types of acute myeloid leukemia. Previous studies have primarily focused on the retinoic acid signaling pathway and how it is interfered with by promyelocytic leukemia/retinoic acid receptor-α (PML/RARα) fusion protein. However, this hardly explains how APL cells are blocked at the promyelocytic stage. Here, we demonstrated that C/EBPα bound and transactivated the promoter of long non-coding RNA NEAT1, an essential element for terminal differentiation of APL cells, through C/EBP binding sites. More importantly, PML/RARα repressed C/EBPα-mediated transactivation of NEAT1 through binding to NEAT1 promoter. Consistently, mutation of the C/EBP sites or deletion of retinoic acid responsive elements (RAREs) and RARE half motifs abrogated the PML/RARα-mediated repression. Moreover, silencing of C/EBPα attenuated ATRA-induced NEAT1 upregulation and APL cell differentiation. Finally, simultaneous knockdown of C/EBPα and C/EBPß reduces ATRA-induced upregulation of C/EBPε and dramatically impaired NEAT1 activation and APL cell differentiation. In sum, C/EBPα binds and transactivates NEAT1 whereas PML/RARα represses this process. This study describes an essential role for C/EBPα in PML/RARα-mediated repression of NEAT1 and suggests that PML/RARα could contribute to the pathogenesis of APL through suppressing C/EBPα targets.

Recent progress in study of circRNAs and its role in leukemia.

Circular RNAs (circRNAs) are a class of newly identified noncoding RNA and are considered as a new feature of eukaryotic gene expression. Hundreds of thousands of endogenous circRNAs have been found in mammalian cells, which we knew little before. CircRNAs are covalently closed, circular RNA molecules that typically comprise exonic sequences and are spliced at canonical splice sites. Researchers with RNA-Seq technology have identified that the expression of circRNAs is developmentally regulated, tissue- and cell-type specific. Like long noncoding RNAs (lncRNAs), circRNAs are becoming a new research hotspot in the RNA field, and aberrant expression of circRNAs could contribute to carcinogenesis. Recent studies have demonstrated that circRNAs play important roles in the development, maintenance, and progression of leukemia. Herein, we describe the biologic characteristics and functions of circRNAs, with a focus on circRNAs that play essential roles in leukemia.

Effects of soil amendments on cadmium transfer along the lettuce-snail food chain: Influence of chemical speciation.

Cadmium (Cd) trophic transfer along the soil-lettuce-snail food chain was investigated using the root bags-based pot experiments. Two amendments (corn straw biochar and micro-hydroxyapatite (µHAP)) were investigated on Cd (0, 2.5, and 5 mg/kg soil) availability in soils, chemical distribution in plant cells and accumulation in snails. After 60 days, both the CaCl2 extractable Cd in rhizosphere soil (CdCaCl2,rhizo) and Cd accumulation in lettuce decreased with amendments addition. Biochar had a great capacity to reduce both Cd contents and toxicity-sensitive associated Cd (CdFi+Fii) percentages in lettuce roots at 2.5 mg/kg Cd contaminated soil; while µHAP generates a higher reduction in both Cd contents and chain transfer associated Cd (CdFi+Fii+Fiii) percentages in lettuce shoots at 5 mg/kg Cd contaminated soil. Linear regression showed that both contents of root CdFi+Fii and shoot CdFi+Fii+Fiii are better correlated with the CdCaCl2,rhizo (R2 > 0.70, p < 0.01). After 15 days feeding, almost 90% content of Cd accumulated in snail viscera. µHAP had a higher reduction in snail soft tissues Cd accumulation than biochar. Distributions of Cd in snail tissues are significantly correlated with CdFi+Fii+Fiii in shoots (viscera R2 = 0.835; soft tissue R2 = 0.771). Established quantitative relationships could be used to predict the bioavailability and transfer of Cd in terrestrial food chain in the presence of amendments.

C/EBPß contributes to transcriptional activation of long non-coding RNA NEAT1 during APL cell differentiation.

Emerging evidences have shown that long non-coding RNAs (lncRNAs) play critical roles in cancer development and cancer therapy. LncRNA Nuclear Enriched Abundant Transcript 1 (NEAT1) is indispensable during acute promyelocytic leukemia (APL) cell differentiation induced by all-trans retinoic acid (ATRA). However, the precise mechanism of NEAT1 upregulation has not been fully understood. In this study, we performed chromatin immunoprecipitation and luciferase reporter assays to demonstrate that C/EBP family transcription factor C/EBPß bind to and transactivate the promoter of lncRNA NEAT1 through the C/EBPß binding sites both around -54 bp and -1453 bp upstream of the transcription start site. Moreover, the expression of C/EBPß was increased after ATRA treatment, and the binding of C/EBPß in the NEAT1 promoter was also dramatically increased. Finally, knockdown of C/EBPß significantly reduced the ATRA-induced upregulation of NEAT1. In conclusion, C/EBPß directly activates the expression of NEAT1 through binding to the promoter of NEAT1. Knockdown of C/EBPß impairs ATRA-induced transcriptional activation of NEAT1. Our data indicate that C/EBPß contributes to ATRA-induced activation of NEAT1 during APL cell differentiation. Our results enrich our knowledge on the regulation of lncRNAs and the regulatory role of C/EBPß in APL cell differentiation.