<i>ERG</i> Is a Megakaryocytic Oncogene

Salek‐Ardakani, Samira; Smooha, Gil; Boer, Jasper de; Sebire, Neil J.; Morrow, Michelle; Rainis, Liat; Lee, Sandy; Williams, Owen; Izraeli, Shai; Brady, Hugh J.M.

doi:10.1158/0008-5472.can-09-0075

Cited by 113 publications

(128 citation statements)

References 37 publications

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“…Escalating healthcare expenditures triggers cost crisis in developing nations. This poses various challenges in resource allocation and budgeting (4,5). On the demand side, patient expectations, demographic characteristics, and disease models have changed.…”

Section: Introductionmentioning

confidence: 99%

Technical Efficiency of Teaching Hospitals in Iran: The Use of Stochastic Frontier Analysis, 1999–2011

Goudarzi

Pourreza

Shokoohi

et al. 2014

Int J Health Policy Manag

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Background: Hospitals are highly resource-dependent settings, which spend a large proportion of healthcare financial resources. The analysis of hospital efficiency can provide insight into how scarce resources are used to create health values. This study examines the Technical Efficiency (TE) of 12 teaching hospitals affiliated with Tehran University of Medical Sciences (TUMS) between 1999 and 2011. Methods: The Stochastic Frontier Analysis (SFA) method was applied to estimate the efficiency of TUMS hospitals. A best function, referred to as output and input parameters, was calculated for the hospitals. Number of medical doctors, nurses, and other personnel, active beds, and outpatient admissions were considered as the input variables and number of inpatient admissions as an output variable. Results: The mean level of TE was 59% (ranging from 22 to 81%). During the study period the efficiency increased from 61 to 71%. Outpatient admission, other personnel and medical doctors significantly and positively affected the production (P< 0.05). Concerning the Constant Return to Scale (CRS), an optimal production scale was found, implying that the productions of the hospitals were approximately constant. Conclusion: Findings of this study show a remarkable waste of resources in the TUMS hospital during the decade considered. This warrants policy-makers and top management in TUMS to consider steps to improve the financial management of the university hospitals.

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Section: Introductionmentioning

confidence: 99%

Technical Efficiency of Teaching Hospitals in Iran: The Use of Stochastic Frontier Analysis, 1999–2011

Goudarzi

Pourreza

Shokoohi

et al. 2014

Int J Health Policy Manag

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“…High ERG expressers were associated with an inferior clinical outcome (Marcucci et al, 2005;Baldus et al, 2006). The pathogenesis of ERG was also observed in sublethally irradiated mice transplanted with ERG transduced progenitor cells, whereby megakaryoblastic leukemia developed (Salek-Ardakani et al, 2009). Thus, several clinical and experimental studies indicate that ERG contributes to the pathogenesis in cancer and leukemia; however, the underlying biological mechanisms are not yet fully understood.…”

Section: Introductionmentioning

confidence: 99%

Genome-wide screen reveals WNT11, a non-canonical WNT gene, as a direct target of ETS transcription factor ERG

et al. 2011

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E26 transforming sequence-related gene (ERG) is a transcription factor involved in normal hematopoiesis and is dysregulated in leukemia. ERG mRNA overexpression was associated with poor prognosis in a subset of patients with T-cell acute lymphoblastic leukemia (T-ALL) and acute myeloid leukemia (AML). Herein, a genome-wide screen of ERG target genes was conducted by chromatin immunoprecipitation-on-chip (ChIP-chip) in Jurkat cells. In this screen, 342 significant annotated genes were derived from this global approach. Notably, ERG-enriched targets included WNT signaling genes: WNT11, WNT2, WNT9A, CCND1 and FZD7. Furthermore, chromatin immunoprecipitation (ChIP) of normal and primary leukemia bone marrow material also confirmed WNT11 as a target of ERG in six of seven patient samples. A larger sampling of patient diagnostic material revealed that ERG and WNT11 mRNA were coexpressed in 80% of AML (n ¼ 30) and 40% in T-ALL (n ¼ 30) bone marrow samples. Small interfering RNA (siRNA)-mediated knockdown of ERG confirmed downregulation of WNT11 transcripts. Conversely, in a tet-on ERG-inducible assay, WNT11 transcripts were costimulated. A WNT pathway agonist, 6-bromoindirubin-3-oxime (BIO), was used to determine the effect of cell growth on the ERG-inducible cells. The addition of BIO resulted in an ERG-dependent proliferative growth advantage over ERG-uninduced cells. Finally, ERG induction prompted morphological transformation whereby round unpolarized K562 cells developed elongated protrusions and became polarized. This morphological transformation could effectively be inhibited with BIO and with siRNA knockdown of WNT11. In conclusion, ERG transcriptional networks in leukemia converge on WNT signaling targets. Specifically, WNT11 emerged as a direct target of ERG. Potent ERG induction promoted morphological transformation through WNT11 signals. The findings in this study unravel new ERG-directed molecular signals that may contribute to the resistance of current therapies in acute leukemia patients with poor prognosis characterized by high ERG mRNA expression.

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“…GATA1 knockdown mice accumulate immature erythroid progenitors [45], and when transgenically 'rescued' with GATA1s these mice have an abnormal accumulation of CD41+ megakaryocytic progenitors [46]. Furthermore, forced expression of GATA1s in fetal hematopoietic progenitors from mice bearing wild-type GATA1 causes marked expansion of megakaryoblastic progenitors [25]. Toki et al [47] also revealed that GATA1s promotes megakaryocyte proliferation more profoundly than that induced by GATA1 deficiency, supporting a gain-offunction mechanism for GATA1s.…”

Section: Gata1 Mutation Induces Tam In Ds Neonatesmentioning

confidence: 99%

“…Ts65Dn mice, which are trisomic for 104 orthologs of Hsa21 genes, display persistent macrocytosis and develop a myeloproliferative disease characterized by megakaryocyte hyperplasia and dysplasia, and myelofibrosis [19]. Several genes on Hsa21, such as RUNX1, ETS2, ERG, GAPBA, BACH1, and DYRK1A, encode proteins relating to hematopoiesis and leukemogenesis [9,[21][22][23][24][25][26]. Further analysis of the models may reveal the effect of chromosome 21 gene dosage on human hematopoiesis and hematological malignancies.…”

Section: Abnormal Hematopoiesis In Dsmentioning

confidence: 99%

Evolution of myeloid leukemia in children with Down syndrome

Saida

2016

Int J Hematol

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the general population, the distribution of malignancies is different [3]. Patients with DS show a unique spectrum of malignancies, with a 10-to 20-fold higher risk of acute leukemia and a lower incidence of solid tumors [3,4]. Death from malignancies other than leukemia is strikingly less common in patients of all ages in DS, and death from leukemia is more likely in children younger than 10 years of age with DS than in those without [5]. The most frequent form of leukemia during childhood, both with and without DS, is acute lymphoblastic leukemia (ALL), and the incidence of ALL in children with DS is approximately 20-fold higher than in non-DS children [3]. However, the most marked increase in incidence in DS infants is with acute megakaryoblastic leukemia (AMKL), a myeloid malignancy of platelet precursors. The relative risk of developing AMKL is estimated to be 500 times higher in children with DS than in the general population [6]. Unlike AMKL in non-DS patients, most AMKL associated with DS (DS-AMKL) patients usually respond well to chemotherapy.In most cases, DS-AMKL is preceded by a temporary form of megakaryoblastic leukemia unique to newborns with DS and known as transient abnormal myelopoiesis (TAM) or transient leukemia. TAM, a clonal myeloproliferative syndrome, presents in the fetus or a few days after birth and in most cases resolves spontaneously within 3 months [7,8]. Typically, TAM is characterized by the presence of high numbers of circulating blast cells expressing CD33, CD38, CD117, CD34, CD7, CD56, CD36, CD71, and CD42b [9], which are indistinguishable from blasts observed in DS-AMKL. More often, the clinical presentation of TAM varies from asymptomatic alterations in the blood count to disseminated leukemic infiltration. Clinically severe TAM (liver failure, pleural/pericardial effusion, ascites, renal failure, and coagulopathy) affects 10-30 % of patients with clinically diagnosed TAM, and Abstract Children with Down syndrome (DS) have a markedly increased risk of leukemia. They are at particular risk of acute megakaryoblastic leukemia, known as myeloid leukemia associated with DS (ML-DS), the development of which is closely linked to a preceding temporary form of neonatal leukemia called transient abnormal myelopoiesis (TAM). Findings from recent clinical and laboratory studies suggest that constitutional trisomy 21 and GATA1 mutation(s) cause TAM, and that additional genetic alteration(s) including those in epigenetic regulators and signaling molecules are involved in the progression from TAM to ML-DS. Thus, this disease progression represents an important model of multi-step leukemogenesis. The present review focuses on the evolutionary process of TAM to ML-DS, and advances in the understanding of perturbed hematopoiesis in DS with respect to GATA1 mutation and recent findings, including cooperating genetic events, are discussed.

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ERG Is a Megakaryocytic Oncogene

Cited by 113 publications

References 37 publications

Technical Efficiency of Teaching Hospitals in Iran: The Use of Stochastic Frontier Analysis, 1999–2011

Technical Efficiency of Teaching Hospitals in Iran: The Use of Stochastic Frontier Analysis, 1999–2011

Genome-wide screen reveals WNT11, a non-canonical WNT gene, as a direct target of ETS transcription factor ERG

Evolution of myeloid leukemia in children with Down syndrome

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