MicroRNAs in Pediatric Acute Lymphoblastic Leukemia: Functions and Targets

__Abstract__ All different types of circulating blood cells originate from hematopoietic stem cells (HSCs). The pluripotential HSCs have the capacity of self-renewal, which provides the body with a secure backup of HSCs. HSCs can also differentiate into progenitor cells, which can further differentiate to different types of blood cells. This continuous process of blood cell production mainly happens in the bone marrow and is called “hematopoiesis”. At the first step of hematopoiesis two distinct populations of cells are generated: common lymphoid progenitors and common myeloid progenitors. As shown in Figure 1, these common progenitors give rise to a variety of mature blood cells via several processes: thrombopoiesis (to produce thrombocytes), erythropoiesis (to produce erythrocytes), granulopoiesis (to produce basophils, neutrophils and eosinophils), monopoiesis (to produce monocytes and then macrophages and myeloid dendritic cells) and lymphopoiesis (to produce B-cells, T-cells and natural killer cells). During hematopoiesis, the differentiated cells lose their proliferative potential but gain more functionality. This is a crucial process, which keeps the number of circulating blood cells under control. Division and differentiation of hematopoietic cells are controlled by several regulators such as epigenetic modifiers, transcription factors, posttranscriptional modulators, cytokines and growth factors. Disruption in hematopoiesis may lead to a differentiation arrest and excessive growth of immature blood cells, which are called "blasts". Acute leukemia (leukos and haima means white and blood in Greek, respectively) is a disease of uncontrolled high proliferation of the blasts and classified according to the lineage origin of the blasts (lymphoid or myeloid). In addition, leukemia with slow onset and slow progression is called "chronic leukemia"

Job burnout and some of its risk factors on the health workers (Behvarz) in Koohrang County, I.R.Iran, in 2010

زمینه و هدف : فرسودگی شغلی، شامل خستگی عاطفی ، مسخ شخصیت و کاهش موفقیت فردی است و زمانی که توانایی های فرد برای تقاضاهای محیط کار کافی نباشد علائم آن آشکار می شود. کارکنان نظام سلامت به دلیل مواجهه با استرس های فیزیکی و روانی در معرض فرسودگی می باشند. این مطالعه با هدف تعیین میزان فرسودگی شغلی بهورزان و بررسی ارتباط خصوصیات جمعیت شناختی با آن انجام گرفت . روش بررسی: این پژوهش توصیفی-تحلیلی، بر روی همه بهورزان شهرستان کوهرنگ ( 81 نفر) در آبانماه سال 1389 انجام شد . ابزار گردآوری داده ها پرسشنامه­ای شامل اطلاعات جمعیت شناختی و پرسشنامه فرسودگی شغلی مازلاک ( MBI ) بود. پرسشنامه توسط بهورزان تکمیل و داده­ها با استفاده از آزمون های آماری ANOVA ، ضریب همبستگی اسپیرمن و آزمون تی مستقل تحلیل گردید. یافته ها: از نظر فراوانی، کاهش موفقیت فردی زیاد ( 5/24 ) ، خستگی عاطفی زیاد ( 6/4 ) و مسخ شخصیت زیاد ( 7/2 ) ، به ترتیب از بیشترین فراوانی و از نظر شدت، خستگی عاطفی شدید ( 7/6 ) و مسخ شخصیت شدید ( 3/1 ) ، به ترتیب از بیشترین شدت برخوردار بودند. هیچ یک از بهورزان کاهش شدید موفقیت فردی را گزارش ننمود. میزان خستگی عاطفی با مسخ شخصیت و میزان کاهش موفقیت فردی با خستگی عاطفی رابطه معنی داری داشت (001/0 > P ) . بین جنس، سن، وضعیت تأهل، سابقه کار، نوع استخدام و میزان تحصیلات بهورزان و فرسودگی رابطه معنی داری دیده نشد. نتیجه گیری: این مطالعه نشان داد که فراوانی و شدت فرسودگی شغلی در بهورزان شهرستان کوهرنگ پایین است که از دلایل آن می توان به موقعیت اجتماعی مناسب، نزدیکی محل کار و زندگی، درآمد متناسب با حجم کار و تحصیلات، امنیت شغلی، سطح توقع پایین و شرایط آب و هوایی و فرهنگی منطقه اشاره کر

Genome-wide profiling of p53-regulated enhancer RNAs uncovers a subset of enhancers controlled by a lncRNA

p53 binds enhancers to regulate key target genes. Here, we globally mapped p53-regulated enhancers by looking at enhancer RNA (eRNA) production. Intriguingly, while many p53-induced enhancers contained p53-binding sites, most did not. As long non-coding RNAs(lncRNAs) are prominent regulators of chromatin dynamics, we hypothesized that p53-induced lncRNAs contribute to the activation of enhancers by p53. Among p53-induced lncRNAs, we identified LED and demonstrate that its suppression attenuates p53 function. Chromatin-binding and eRNA expression analyses show that LED associates with and activates strong enhancers. One prominent target of LED was located at an enhancer region within CDKN1A gene, a potent p53-responsive cell cycle inhibitor. LED knockdown reduces CDKN1A enhancer induction and activity, and cell cycle arrest following p53 activation. Finally, promoter-associated hypermethylation analysis shows silencing of LED in human tumours. Thus, our study identifies a new layer of complexity in the p53 pathway and suggests its dysregulation in cancer

MicroRNA characterize genetic diversity and drug resistance in pediatric acute lymphoblastic leukemia

textabstractBackground MicroRNA regulate the activity of protein-coding genes including those involved in hematopoietic cancers. The aim of the current study was to explore which microRNA are unique for seven different subtypes of pediatric acute lymphoblastic leukemia. Design and Methods Expression levels of 397 microRNA (including novel microRNA) were measured by quantitative real-time polymerase chain reaction in 81 cases of pediatric leukemia and 17 normal hematopoietic control cases. Results All major subtypes of acute lymphoblastic leukemia, i.e. T-cell, MLL-rearranged, TEL-AML1- positive, E2A-PBX1-positive and hyperdiploid acute lymphoblastic leukemia, with the exception of BCR-ABL-positive and 'B-other' acute lymphoblastic leukemias (defined as precursor Bcell acute lymphoblastic leukemia not carrying the foregoing cytogenetic aberrations), were found to have unique microRNA-signatures that differed from each other and from those of healthy hematopoietic cells. Strikingly, the microRNA signature of TEL-AML1-positive and hyperdiploid cases partly overlapped, which may suggest a common underlying biology. Moreover, aberrant down-regulation of let-7b (~70-fold) in MLL-rearranged acute lymphoblastic leukemia was linked to up-regulation of oncoprotein c-Myc (PFDR<0.0001). Resistance to vincristine and daunorubicin was characterized by an approximately 20-fold up-regulation of miR- 125b, miR-99a and miR-100 (PFDR≤0.002). No discriminative microRNA were found for prednisolone response and only one microRNA was linked to resistance to L-asparaginase. A combined expression profile based on 14 microRNA that were individually associated with prognosis, was highly predictive of clinical outcome in pediatric acute lymphoblastic leukemia (5- year disease-free survival of 89.4%±7% versus 60.8±12%, P=0.001). Conclusions Genetic subtypes and drug-resistant leukemic cells display characteristic microRNA signatures in pediatric acute lymphoblastic leukemia. Functional studies of discriminative and prognostically important microRNA may provide new insights into the biology of pediatric acute lymphoblastic leukemia