Erratum to: Preclinical activity of gefitinib in non-keratinizing nasopharyngeal carcinoma cell lines and biomarkers of response

published_or_final_versionSpringer Open Choice, 01 Dec 201

Transcriptional repression of the RUNX3/AML2 gene by the t(8;21) and inv(16) fusion proteins in acute myeloid leukemia

RUNX3/AML2 is a Runt domain transcription factor like RUNX1/AML1 and RUNX2/AML3. Regulated by 2 promoters P1 and P2, RUNX3 is frequently inactivated by P2 methylation in solid tumors. Growing evidence has suggested a role of this transcription factor in hematopoiesis. However, genetic alterations have not been reported in blood cancers. In this study on 73 acute myeloid leukemia (AML) patients (44 children and 29 adults), we first showed that high RUNX3 expression among childhood AML was associated with a shortened event-free survival, and RUNX3 was significantly underexpressed in the prognostically favorable subgroup of AML with the t(8;21) and inv(16) translocations. We further demonstrated that this RUNX3 repression was mediated not by P2 methylation, but RUNX1-ETO and CBFbeta-MYH11, the fusion products of t(8;21) and inv(16), via a novel transcriptional mechanism that acts directly or indirectly in collaboration with RUNX1, on 2 conserved RUNX binding sites in the P1 promoter. In in vitro studies, ectopically expressed RUNX1-ETO and CBFbeta-MYH11 also inhibited endogenous RUNX3 expression. Taken together, RUNX3 was the first transcriptional target found to be commonly repressed by the t(8;21) and inv(16) fusion proteins and might have an important role in core-binding factor AML

The Familial Risk and HLA Susceptibility among Narcolepsy Patients in Hong Kong Chinese

Study Objectives: To explore the familial aggregation and HLA susceptibility of narcolepsy in Hong Kong Chinese by objective sleep measurements and HLA typing. Design: Case control design Participants: Twelve narcoleptic probands, 34 first-degree relatives, and 30 healthy controls. Interventions: N/A Measurements and Results: Each subject underwent a standardized nocturnal polysomnogram (PSG), followed by a daytime multiple sleep latency test (MSLT). HLA typing was performed for all subjects. One relative (2.9%) was diagnosed as suffering from narcolepsy with cataplexy. Nearly 30% of the relatives fulfilled the criteria of narcolepsy spectrum disorder (shortened mean sleep latency [MSL] and/or the presence of sleep onset REM periods [SOREMPs]). When using the population data for comparison, the relative risk of narcolepsy in first-degree relatives was 85.3. The odds ratio of narcolepsy spectrum disorder in first-degree relatives was 5.8 (95% CI: 1.2-29.3) when compared to healthy controls. There existed 6 multiplex families, in which all 10 relatives with narcolepsy spectrum disorders, including all 3 relatives with multiple SOREMPs, were positive for HLA DQB1*0602. Conclusions: Our study demonstrated a definitive familial aggregation of narcolepsy, narcolepsy spectrum disorders, and possibly cataplexy in Hong Kong Chinese. This familial aggregation supported an inherited basis for narcolepsy spectrum. The tight co-segregation of HLA DQB1*0602 and narcolepsy spectrum disorders might suggest that HLA typing, especially DQB1*0602, at least partly confer the familial risk of narcolepsy. In addition, our study suggested that the subjective questionnaire measurements including Ullanlinna Narcolepsy Scale and Epworth Sleepiness Scale were unable to detect the presence of narcolepsy spectrum disorders among the relatives. Astringent objective measurement-based design for family studies is suggested for future study. Further studies are indicated for the determination of the mode and molecular level of narcolepsy transmission.link_to_subscribed_fulltex

2009

ARTICLES 913 Acute Myeloid Leukemia Introduction The NPM1 gene is frequently altered in hematologic malignancies. 2 NPM1-mutated AML has distinctive clinicopathological and molecular features. Most notably, the mutation is closely associated with normal karyotype and relatively favorable prognosis in the absence of FLT3-internal tandem duplication (ITD). 3 While genotyping the NPM1 mutations, a polymorphic nucleotide T deletion (delT) at position 1,146 of the NPM1 3'-untranslated region (UTR) was reported in 60%-70% of AML patients. 6,7 Here, we revealed that the homozygous state of the NPM1 delT polymorphism had important clinical and biological implications in AML involving an illegitimate microRNA (miRNA) regulation. Design and Methods Patients We analyzed 149 adult and 70 childhood patients with de novo AML; therapy-related AML or AML arising from a prior myelodysplastic syndrome were excluded. Patients' characteristics are shown in Online Supplementary Table S1. All patients gave informed consent for the study, which was approved by the Joint CUHK-NTEC Clinical Research Ethics Committee and was conducted in accordance with the Declaration of Helsinki. Patients with acute promyelocytic leukemia (APL) were excluded for survival analysis. Overall, complete survival data were available from 93 adult and 61 childhood patients with non-APL who had received treatment. All the 93 adult patients were treated with the standard cytarabine plus daunorubicin '7+3' induction chemotherapy regimen. Normal bone marrow (BM) and peripheral blood samples were obtained from healthy donors who had no prior history of malignancy. Cell culture Cell lines were cultured in RPMI-1640 medium containing 10% fetal bovine serum. Nucleophosmin, encoded by NPM1, is a haploinsufficient suppressor in hematologic malignancies. NPM1 mutations are mostly found in acute myeloid leukemia patients with normal karyotype and associated with favorable prognosis. A polymorphic nucleotide T deletion with unknown significance is present in the NPM1 3'-untranslated region. Here, we showed that the homozygous nucleotide T deletion was associated with adverse outcomes and could independently predict shortened survival in patients with de novo acute myeloid leukemia. Mechanistically, we demonstrated that the nucleotide T deletion created an illegitimate binding NPM1 for miR-337-5p, which was widely expressed in different acute myeloid leukemia subtypes and inhibited NPM1 expression. Accordingly, NPM1 levels were found to be significantly reduced and correlated with miR-337-5p levels in patients carrying a homozygous nucleotide T-deletion genotype. Together, our findings uncover a microRNAmediated control of NPM1 expression that contributes to disease heterogeneity and suggest additional prognostic values of NPM1 in acute myeloid leukemia. A polymorphism in the 3'-untranslated region of the ABSTRACT Cytogenetic and mutational studies Cytogenetics were classified into favorable, intermediate, and adverse according to the UK MRC classification