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Meng-Meng Dou, Zhi-Hao Zhang, Zhu-Bo Li, Jie Zhang, Xiao-Yan Zhao
Dendrobium officinale Kimura et Migo has been used for thousands of years to promote body fluid production; however, little is currently known regarding its effects on the heart. The present study aimed to explore the cardioprotective potential of the water extract of Dendrobium officinale Kimura et Migo (DOE) on myocardial ischemia in mice. A mouse model of myocardial ischemia was induced following ligation of the left anterior descending coronary artery. Prior to the operation, mice were administered a vehicle or DOE for 2 weeks...
September 26, 2016: Molecular Medicine Reports
Edith Schneider, Anna Staffas, Linda Röhner, Kathrin Krowiorz, Michael Heuser, Konstanze Döhner, Lars Bullinger, Hartmut Döhner, Linda Fogelstrand, Arefeh Rouhi, Florian Kuchenbauer, Lars Palmqvist
MicroRNA-155 (miR-155) is an oncogenic miRNA upregulated in various tumor types and leukemias and has been suggested as a potential drug target. Based on our previous work detecting high miR-155 levels in response to Meis1 overexpression in a murine Hox leukemia model, we show here the relationship among HOXA9, MEIS1, and miR-155 levels in MLL-translocated acute myeloid leukemia (AML) patients. Using mouse bone marrow cells transformed by MLL-fusion genes expressing graduated levels of Meis1, we show a positive correlation between miR-155 and Meis1...
September 13, 2016: Experimental Hematology
A Staffas, L S Arabanian, S Y Wei, A Jansson, S Ståhlman, P Johansson, L Fogelstrand, J Cammenga, F Kuchenbauer, L Palmqvist
HOXA9, MEIS1 and FLT3 are genes frequently upregulated in human acute myeloid leukemia. Hoxa9 and Meis1 also cooperate to induce aggressive AML with high Flt3 expression in mice, suggesting an important role for Flt3 in Hoxa9/Meis1-induced leukemogenesis. To define the role of Flt3 in AML with high Hoxa9/Meis1, we treated mice with Hoxa9/Meis1-induced AML with the Flt3 inhibitor AC220, used an Flt3-ligand (FL-/-) knockout model, and investigated whether overexpression of Flt3 could induce leukemia together with overexpression of Hoxa9...
September 12, 2016: Oncogene
Junfang Zhang, Bingshe Han, Xiaoxia Li, Juraj Bies, Penglei Jiang, Richard P Koller, Linda Wolff
The c-Myb transcription factor is a major regulator that controls differentiation and proliferation of hematopoietic progenitor cells, which is frequently deregulated in hematological diseases, such as lymphoma and leukemia. Understanding of the mechanisms regulating the transcription of c-myb gene is challenging as it lacks a typical promoter and multiple factors are involved. Our previous studies identified some distal regulatory elements in the upstream regions of c-myb gene in murine myeloid progenitor M1 cells, but the detailed mechanisms still remain unclear...
2016: Cell Death & Disease
Johannes von Burstin, Friedrich Bachhuber, Mariel Paul, Roland M Schmid, Anil K Rustgi
Pancreatic ductal adenocarcinoma (PDAC) remains one of the most deadly types of cancer, and the majority of pancreatic cancer deaths is caused by metastasis. Therapeutic options for systemic disease are limited, in particular due to the heterogeneous events leading to tumor dissemination. Previous studies highlighted an association of the homeodomain transcription factor MEIS1 with a ductal phenotype in pancreatic tissue architecture. Using immunohistochemistry, we demonstrate that MEIS1 is expressed in aberrant duct structures of Ela-TGFα transgenic mice as well as in pancreatic intraepithelial neoplasia (PanINs), primary PDAC, and metastatic disease in Ptf1a(Cre/+) ;LSL-Kras(G12D/+) mice...
September 1, 2016: Molecular Carcinogenesis
Shima Rastegar-Pouyani, Niusha Khazaei, Ping Wee, Moein Yaqubi, Abdulshakour Mohammadnia
Ectopic expression of a defined set of transcription factors (TFs) can directly convert fibroblasts into a cardiac myocyte cell fate. Beside inefficiency in generating induced cardiomyocytes (iCMs), the molecular mechanisms that regulate this process remained to be well defined. The main purpose of this study was to provide better insight on the transcriptome regulation and to introduce a new strategy for candidating TFs for the transdifferentiation process. Eight mouse and three human high quality microarray data sets were analyzed to find differentially expressed genes (DEGs), which we integrated with TF-binding sites and protein-protein interactions to construct gene regulatory and protein-protein interaction networks...
August 31, 2016: Journal of Cellular Physiology
Abolfazl Rad, Saeed Esmaeili Dizghandi, Mohammad Reza Abbaszadegan, Negin Taghechian, Maryam Najafi, Mohammad Mahdi Forghanifard
SOX1, as a tumor suppressor, play anti-tumorigenecity role in different cells and its expression is inhibited in a variety of cancers. The aim of this study was to evaluate SOX1 expression and its correlation with cancer stem cell (CSC) markers in ESCC. Using real time PCR, the relative comparative expression of SOX1 in 40 ESCC samples was assessed compared to related margin normal tissues, and its correlation with CSC markers including SALL4, SOX2, and MEIS1 was analyzed statistically. The results revealed significant under-expression of SOX1 in ESCC in significant correlation with different indices of poor prognosis including depth of tumor invasion (P=0...
December 15, 2016: Gene
Brian B Koo, Kanika Bagai, Arthur S Walters
BACKGROUND: In the past few decades, much has been learned about the pathophysiology of restless legs syndrome (RLS). Investigators have studied neuropathology, imaging, electrophysiology, and genetics of RLS, identifying brain regions and biological systems affected in RLS. This manuscript will review RLS pathophysiology literature, examining the RLS state through consideration of the neuroanatomy, then the biological, organ, and genetic systems. METHODS: Pubmed (1966 to April 2016) was searched for the term "restless legs syndrome" cross-referenced with "pathophysiology," "pathogenesis," "pathology," or "imaging...
2016: Tremor and Other Hyperkinetic Movements
Michael W M Kühn, Evelyn Song, Zhaohui Feng, Amit Sinha, Chun-Wei Chen, Aniruddha J Deshpande, Monica Cusan, Noushin Farnoud, Annalisa Mupo, Carolyn Grove, Richard Koche, James E Bradner, Elisa de Stanchina, George S Vassiliou, Takayuki Hoshii, Scott A Armstrong
: Homeobox (HOX) proteins and the receptor tyrosine kinase FLT3 are frequently highly expressed and mutated in acute myeloid leukemia (AML). Aberrant HOX expression is found in nearly all AMLs that harbor a mutation in the Nucleophosmin (NPM1) gene, and FLT3 is concomitantly mutated in approximately 60% of these cases. Little is known about how mutant NPM1 (NPM1(mut)) cells maintain aberrant gene expression. Here, we demonstrate that the histone modifiers MLL1 and DOT1L control HOX and FLT3 expression and differentiation in NPM1(mut) AML...
October 2016: Cancer Discovery
Isabelle Chang, Marta Parrilla
Homeodomain proteins are encoded by homeobox genes and regulate development and differentiation in many neuronal systems. The mouse vomeronasal organ (VNO) generates in situ mature chemosensory neurons from stem cells. The roles of homeodomain proteins in neuronal differentiation in the VNO are poorly understood. Here we have characterized the expression patterns of 28 homeobox genes in the VNO of C57BL/6 mice at postnatal stages using multicolor fluorescent in situ hybridization. We identified 11 homeobox genes (Dlx3, Dlx4, Emx2, Lhx2, Meis1, Pbx3, Pknox2, Pou6f1, Tshz2, Zhx1, Zhx3) that were expressed exclusively in neurons; 4 homeobox genes (Pax6, Six1, Tgif1, Zfhx3) that were expressed in all non-neuronal cell populations, with Pax6, Six1 and Tgif1 also expressed in some neuronal progenitors and precursors; 12 homeobox genes (Adnp, Cux1, Dlx5, Dlx6, Meis2, Pbx2, Pknox1, Pou2f1, Satb1, Tshz1, Tshz3, Zhx2) with expression in both neuronal and non-neuronal cell populations; and one homeobox gene (Hopx) that was exclusively expressed in the non-sensory epithelium...
July 2016: Gene Expression Patterns: GEP
Naidu M Vegi, Josef Klappacher, Franz Oswald, Medhanie A Mulaw, Amit Mandoli, Verena N Thiel, Shiva Bamezai, Kristin Feder, Joost H A Martens, Vijay P S Rawat, Tamoghna Mandal, Leticia Quintanilla-Martinez, Karsten Spiekermann, Wolfgang Hiddemann, Konstanze Döhner, Hartmut Döhner, Hendrik G Stunnenberg, Michaela Feuring-Buske, Christian Buske
Homeobox genes are known to be key factors in leukemogenesis. Although the TALE family homeodomain factor Meis1 has been linked to malignancy, a role for MEIS2 is less clear. Here, we demonstrate that MEIS2 is expressed at high levels in patients with AML1-ETO-positive acute myeloid leukemia and that growth of AML1-ETO-positive leukemia depends on MEIS2 expression. In mice, MEIS2 collaborates with AML1-ETO to induce acute myeloid leukemia. MEIS2 binds strongly to the Runt domain of AML1-ETO, indicating a direct interaction between these transcription factors...
July 12, 2016: Cell Reports
Rui Lu, Ping Wang, Trevor Parton, Yang Zhou, Kaliopi Chrysovergis, Shira Rockowitz, Wei-Yi Chen, Omar Abdel-Wahab, Paul A Wade, Deyou Zheng, Gang Greg Wang
DNA methyltransferase 3A (DNMT3A) is frequently mutated in hematological cancers; however, the underlying oncogenic mechanism remains elusive. Here, we report that the DNMT3A mutational hotspot at Arg882 (DNMT3A(R882H)) cooperates with NRAS mutation to transform hematopoietic stem/progenitor cells and induce acute leukemia development. Mechanistically, DNMT3A(R882H) directly binds to and potentiates transactivation of stemness genes critical for leukemogenicity including Meis1, Mn1, and Hoxa gene cluster. DNMT3A(R882H) induces focal epigenetic alterations, including CpG hypomethylation and concurrent gain of active histone modifications, at cis-regulatory elements such as enhancers to facilitate gene transcription...
July 11, 2016: Cancer Cell
Ami V Patel, Katherine E Chaney, Kwangmin Choi, David A Largaespada, Ashish R Kumar, Nancy Ratner
Malignant peripheral nerve sheath tumors (MPNST) are rare soft tissue sarcomas that are a major source of mortality in neurofibromatosis type 1 (NF1) patients. To identify MPNST driver genes, we performed a lentiviral short hairpin (sh) RNA screen, targeting all 130 genes up-regulated in neurofibroma and MPNSTs versus normal human nerve Schwann cells. NF1 mutant cells show activation of RAS/MAPK signaling, so a counter-screen in RAS mutant carcinoma cells was performed to exclude common RAS-pathway driven genes...
July 2016: EBioMedicine
Klaartje Somers, Daria A Chudakova, Shiloh M C Middlemiss, Victoria W Wen, Molly Clifton, Alan Kwek, Bing Liu, Chelsea Mayoh, Angelika Bongers, Mawar Karsa, Sukey Pan, Sarah Cruikshank, Marissa Scandlyn, Wendi Hoang, Toshihiko Imamura, Ursula R Kees, Andrei V Gudkov, Olga B Chernova, Michelle Haber, Murray D Norris, Michelle J Henderson
There is an urgent need for the development of less toxic, more selective and targeted therapies for infants with leukemia characterized by translocation of the mixed lineage leukemia (MLL) gene. In this study, we performed a cell-based small molecule library screen on an infant MLL-rearranged (MLL-r) cell line, PER-485, in order to identify selective inhibitors for MLL-r leukemia. After screening initial hits for a cytotoxic effect against a panel of 30 cell lines including MLL-r and MLL wild-type (MLL-wt) leukemia, solid tumours and control cells, small molecule CCI-007 was identified as a compound that selectively and significantly decreased the viability of a subset of MLL-r and related leukemia cell lines with CALM-AF10 and SET-NUP214 translocation...
June 14, 2016: Oncotarget
Cailin T Collins, Jay L Hess
PURPOSE OF REVIEW: HOXA9 is a homeodomain transcription factor that plays an essential role in normal hematopoiesis and acute leukemia, in which its overexpression is strongly correlated with poor prognosis. The present review highlights recent advances in the understanding of genetic alterations leading to deregulation of HOXA9 and the downstream mechanisms of HOXA9-mediated transformation. RECENT FINDINGS: A variety of genetic alterations including MLL translocations, NUP98-fusions, NPM1 mutations, CDX deregulation, and MOZ-fusions lead to high-level HOXA9 expression in acute leukemias...
July 2016: Current Opinion in Hematology
Marta Parrilla, Isabelle Chang, Andrea Degl'Innocenti, Masayo Omura
Homeobox genes constitute a large family of genes widely studied because of their role in the establishment of the body pattern. However, they are also involved in many other events during development and adulthood. The main olfactory epithelium (MOE) is an excellent model to study neurogenesis in the adult nervous system. Analyses of homeobox genes during development show that some of these genes are involved in the formation and establishment of cell diversity in the MOE. Moreover, the mechanisms of expression of odorant receptors (ORs) constitute one of the biggest enigmas in the field...
October 1, 2016: Journal of Comparative Neurology
Artur Brandt, Katharina Löhers, Manfred Beier, Barbara Leube, Carmen de Torres, Jaume Mora, Parineeta Arora, Parmjit S Jat, Brigitte Royer-Pokora
We describe a stromal predominant Wilms tumor with focal anaplasia and a complex, tumor specific chromosome 11 aberration: a homozygous deletion of the entire WT1 gene within a heterozygous 11p13 deletion and an additional region of uniparental disomy (UPD) limited to 11p15.5-p15.2 including the IGF2 gene. The tumor carried a heterozygous p.T41A mutation in CTNNB1. Cells established from the tumor carried the same chromosome 11 aberration, but a different, homozygous p.S45Δ CTNNB1 mutation. Uniparental disomy (UPD) 3p21...
2016: PloS One
Meysam Moghbeli, Abolfazl Rad, Moein Farshchian, Negin Taghehchian, Mehran Gholamin, Mohammad Reza Abbaszadegan
PURPOSE: Homeobox (HOX) transcription factors are critical regulators of cell fate, stem cell functions, and gastrointestinal development. They require three-amino acid loop extension (TALE) homeodomain proteins such as Meis1 to enhance their transcriptional efficiencies. There are complicated associations between different signaling pathways such as the Wnt and NOTCH and tumor progression. It has been investigated that GSK-3 as an important component of the Wnt pathway facilitates the expression of HOX target genes...
September 2016: Journal of Gastrointestinal Cancer
Yousaf A Mian, Nancy J Zeleznik-Le
Mixed lineage leukemias have a relatively poor prognosis and arise as a result of translocations between the MLL(KMT2A) gene and one of multiple partner genes. Downstream targets of MLL are aberrantly upregulated and include the developmentally important HOX genes and MEIS1, as well as multiple microRNAs (miRNAs), including the miR-17∼92 cluster. Here we examined the contribution of specific miRNAs to MLL leukemias through knockdown studies utilizing custom anti-microRNA oligonucleotides. Combinatorial treatment against miR-17-5p and miR-19a-3p of the miR-17∼92 cluster dramatically reduces colony forming ability of MLL-fusion containing cell lines relative to non-MLL acute myeloid leukemia (AML) controls...
July 2016: Leukemia Research
D Daria, N Kirsten, A Muranyi, M Mulaw, S Ihme, A Kechter, M Hollnagel, L Bullinger, K Döhner, H Döhner, M Feuring-Buske, C Buske
The G protein-coupled receptor 56 (GPR56) was identified as part of the molecular signature of functionally validated leukemic stem cells isolated from patients with acute myeloid leukemia (AML). This report now demonstrates particularly high expression of GPR56 in patients with mutant NPM1 and FLT3-length mutation and association of high GPR56 expression with inferior prognosis in a large patient cohort treated in two independent multicenter phase III trials. Functional relevance of GPR56 expression was validated in mice, in which co-expression of Gpr56 significantly accelerated HOXA9-induced leukemogenesis and vice versa knockdown of Gpr56 delayed onset of HOXA9/MEIS1-induced AML...
August 2016: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
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