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Leukaemic stem cell

Karen A Boehme, Juliane Nitsch, Rosa Riester, Rupert Handgretinger, Sabine B Schleicher, Torsten Kluba, Frank Traub
Ewing sarcomas (ES) are rare mesenchymal tumours, most commonly diagnosed in children and adolescents. Arsenic trioxide (ATO) has been shown to efficiently and selectively target leukaemic blasts as well as solid tumour cells. Since multidrug resistance often occurs in recurrent and metastatic ES, we tested potential additive effects of ATO in combination with the cytostatic drugs etoposide and doxorubicin. The Ewing sarcoma cell lines A673, RD-ES and SK-N-MC as well as mesenchymal stem cells (MSC) for control were treated with ATO, etoposide and doxorubicin in single and combined application...
September 21, 2016: International Journal of Oncology
Marie Toft-Petersen, Line Nederby, Eigil Kjeldsen, Gitte B Kerndrup, Gordon D Brown, Peter Hokland, Anne Stidsholt Roug
Evidence of distinct disease propagating stem cells in myelodysplastic syndrome (MDS) has emerged in recent years. However, immunophenotypic characterization of these cancer stem cells remains sparse. In acute myeloid leukaemia (AML), we have previously described aberrant expression of the C-type lectin domain family 12, member A (CLEC12A) as a stable and reliable marker of leukaemia blasts and as a tool for assessing minimal residual disease. Furthermore, CLEC12A has been proposed as a promising marker of leukaemic stem cells in AML...
September 9, 2016: British Journal of Haematology
Ashwin Unnikrishnan, Yi F Guan, Yizhou Huang, Dominik Beck, Julie A I Thoms, Sofie Peirs, Kathy Knezevic, Shiyong Ma, Inge V de Walle, Ineke de Jong, Zara Ali, Ling Zhong, Mark J Raftery, Tom Taghon, Jonas Larsson, Karen L MacKenzie, Pieter V Vlierberghe, Jason W H Wong, John E Pimanda
Aberrant stem cell-like gene regulatory networks are a feature of leukaemogenesis. The ETS-related gene (ERG), an important regulator of normal haematopoiesis, is also highly expressed in T-ALL and acute myeloid leukaemia (AML). However, the transcriptional regulation of ERG in leukaemic cells remains poorly understood. In order to discover transcriptional regulators of ERG, we employed a quantitative mass spectrometry-based method to identify factors binding the 321 bp ERG +85 stem cell enhancer region in MOLT-4 T-ALL and KG-1 AML cells...
September 6, 2016: Nucleic Acids Research
Dorothea Fischbacher, Marion Merle, Anja Liepert, Christine Grabrucker, Tanja Kroell, Andreas Kremser, Julia Dreyßig, Markus Freudenreich, Friedhelm Schuster, Arndt Borkhardt, Doris Kraemer, Claus-Henning Koehne, Hans-Jochem Kolb, Christoph Schmid, Helga Maria Schmetzer
To enlighten interactions between autologous, allogeneic or T-cells from patients after stem cell transplantation with leukaemia-derived-dendritic-cells containing dendritic cells or blast containing mononuclear cells (n = 21, respectively), we determined cytokine-concentrations (interleukin 2, 4, 6, 10, tumor-necrosis-factor-α, interferon-γ) in supernatants of mixed-lymphocyte-culture and in serum (n = 16) of 20 patients with acute myeloid leukaemia and three patients with myelodysplastic syndromes by cytometric-bead-assay...
September 7, 2016: Cell Communication & Adhesion
Doreen Reichert, Julia Scheinpflug, Jana Karbanová, Daniel Freund, Martin Bornhäuser, Denis Corbeil
Deciphering all mechanisms of intercellular communication used by haematopoietic progenitors is important, not only for basic stem cell research, but also in view of their therapeutic relevance. Here, we investigated whether these cells can produce thin F-actin-based plasma membrane protrusions, referred to as tunnelling nanotubes (TNTs), which are known to bridge cells over long distances without contact with the substratum, and transfer cargo molecules along them in various biological processes. We found that human primary CD34(+) haematopoietic progenitors and leukaemic KG1a cells develop such structures upon culture on primary mesenchymal stromal cells or specific extracellular matrix-based substrata...
July 26, 2016: Experimental Hematology
Gillian Horne, Lorna Jackson, Vignir Helgason, Tessa L Holyoake
The introduction of tyrosine kinase inhibitors in chronic myeloid leukaemia (CML) has revolutionised disease outcome. However, despite this, progression to blast phase disease is high in those that do not achieve complete cytogenetic and major molecular response on standard therapy. As well as BCR-ABL-dependent mechanisms, disease persistence has been shown to play a key role. Disease persistence suggests that, despite a targeted therapeutic approach, BCR-ABL-independent mechanisms are being exploited to sustain the survival of a small population of cells termed leukaemic stem cells (LSCs)...
July 11, 2016: Current Drug Targets
Haniyeh Fooladinezhad, Hossein Khanahmad, Mazdak Ganjalikhani-Hakemi, Abbas Doosti
BACKGROUND: Uncontrolled proliferation and accumulation of leukaemic stem cells (LSCs) in bone marrow leads to acute myeloma leukaemia (AML). T cell immunoglobulin and mucine domain (TIM)-3 is a specific surface marker for LSCs and is highly expressed on LSCs compared with normal bone marrow cells, haematopoietic stem cells. Studies have indicated that microRNAs can affect AML progression through targeting different genes expressions like TIM-3. So, based on bioinformatics assessments, we predicted that miR-330-5p may highly inhibit TIM-3 expression...
June 24, 2016: British Journal of Biomedical Science
Sheela A Abraham, Lisa E M Hopcroft, Emma Carrick, Mark E Drotar, Karen Dunn, Andrew J K Williamson, Koorosh Korfi, Pablo Baquero, Laura E Park, Mary T Scott, Francesca Pellicano, Andrew Pierce, Mhairi Copland, Craig Nourse, Sean M Grimmond, David Vetrie, Anthony D Whetton, Tessa L Holyoake
Chronic myeloid leukaemia (CML) arises after transformation of a haemopoietic stem cell (HSC) by the protein-tyrosine kinase BCR-ABL. Direct inhibition of BCR-ABL kinase has revolutionized disease management, but fails to eradicate leukaemic stem cells (LSCs), which maintain CML. LSCs are independent of BCR-ABL for survival, providing a rationale for identifying and targeting kinase-independent pathways. Here we show--using proteomics, transcriptomics and network analyses--that in human LSCs, aberrantly expressed proteins, in both imatinib-responder and non-responder patients, are modulated in concert with p53 (also known as TP53) and c-MYC regulation...
June 16, 2016: Nature
Sukhraj Pal S Dhami, Shanthi S Kappala, Alexander Thompson, Eva Szegezdi
Acute myeloid leukaemia (AML) is a hierarchically structured malignancy in which aberrant leukemic stem cells drive the production of leukaemic blast cell clones. AML cells strictly depend on the bone marrow microenvironment (BMM) in which they reside. Classical AML cell cultures fail to mimic the BMM and, therefore, drug discovery studies are dominated by in vivo models. However, animal models are time consuming, labour intensive, provide limited mechanistic insight, and are unsuited for high-throughput studies, necessitating the development of novel AML models...
September 2016: Drug Discovery Today
Junji Koya, Keisuke Kataoka, Tomohiko Sato, Masashige Bando, Yuki Kato, Takako Tsuruta-Kishino, Hiroshi Kobayashi, Kensuke Narukawa, Hiroyuki Miyoshi, Katsuhiko Shirahige, Mineo Kurokawa
Despite the clinical impact of DNMT3A mutation on acute myeloid leukaemia, the molecular mechanisms regarding how this mutation causes leukaemogenesis in vivo are largely unknown. Here we show that, in murine transplantation experiments, recipients transplanted with DNMT3A mutant-transduced cells exhibit aberrant haematopoietic stem cell (HSC) accumulation. Differentiation-associated genes are downregulated without accompanying changes in methylation status of their promoter-associated CpG islands in DNMT3A mutant-transduced stem/progenitor cells, representing a DNA methylation-independent role of mutated DNMT3A...
2016: Nature Communications
J M Schuurhuis, L F R Span, M A Stokman, A J van Winkelhoff, A Vissink, F K L Spijkervet
BACKGROUND: Leukaemic patients receiving intensive chemotherapy and patients undergoing autologous stem-cell transplantation (ASCT) are routinely screened for oral foci of infection to reduce infectious complications that could occur during therapy. In this prospective study we assessed the effect of leaving chronic oral foci of infection untreated on the development of infectious complications in intensively treated haematological patients. METHODS: We included and prospectively evaluated all intensively treated leukaemic patients and patients undergoing ASCT who were referred to our medical centre between September 2012 and May 2014, and who matched the inclusion/exclusion criteria...
April 26, 2016: British Journal of Cancer
Bruno Di Stefano, Samuel Collombet, Janus Schou Jakobsen, Michael Wierer, Jose Luis Sardina, Andreas Lackner, Ralph Stadhouders, Carolina Segura-Morales, Mirko Francesconi, Francesco Limone, Matthias Mann, Bo Porse, Denis Thieffry, Thomas Graf
Reprogramming somatic cells into induced pluripotent stem cells (iPSCs) is typically inefficient and has been explained by elite-cell and stochastic models. We recently reported that B cells exposed to a pulse of C/EBPα (Bα' cells) behave as elite cells, in that they can be rapidly and efficiently reprogrammed into iPSCs by the Yamanaka factors OSKM. Here we show that C/EBPα post-transcriptionally increases the abundance of several hundred proteins, including Lsd1, Hdac1, Brd4, Med1 and Cdk9, components of chromatin-modifying complexes present at super-enhancers...
April 2016: Nature Cell Biology
Bas Kersten, Matthijs Valkering, Rolf Wouters, Rosa van Amerongen, Diana Hanekamp, Zinia Kwidama, Peter Valk, Gert Ossenkoppele, Wendelien Zeijlemaker, Gertjan Kaspers, Jacqueline Cloos, Gerrit J Schuurhuis
Chemotherapy resistant leukaemic stem cells (LSC) are thought to be responsible for relapses after therapy in acute myeloid leukaemia (AML). Flow cytometry can discriminate CD34(+) CD38(-) LSC and normal haematopoietic stem cells (HSC) by using aberrant expression of markers and scatter properties. However, not all LSC can be identified using currently available markers, so new markers are needed. CD45RA is expressed on leukaemic cells in the majority of AML patients. We investigated the potency of CD45RA to specifically identify LSC and HSC and improve LSC quantification...
April 2016: British Journal of Haematology
Sabrina Tosi, Yasser Mostafa Kamel, Temitayo Owoka, Concetta Federico, Tony H Truong, Salvatore Saccone
The presence of chromosomal abnormalities is one of the most important criteria for leukaemia diagnosis and management. Infant leukaemia is a rare disease that affects children in their first year of life. It has been estimated that approximately one third of infants with acute myeloid leukaemia harbour the t(7;12)(q36;p13) rearrangement in their leukaemic blasts. However, the WHO classification of acute myeloid leukaemia does not yet include the t(7;12) as a separate entity among the different genetic subtypes, although the presence of this chromosomal abnormality has been associated with an extremely poor clinical outcome...
2015: Biomarker Research
V Adam Cruickshank, Patrycja Sroczynska, Aditya Sankar, Satoru Miyagi, Carsten Friis Rundsten, Jens Vilstrup Johansen, Kristian Helin
Alterations in chromatin structure caused by deregulated epigenetic mechanisms collaborate with underlying genetic lesions to promote cancer. SMARCA4/BRG1, a core component of the SWI/SNF ATP-dependent chromatin-remodelling complex, has been implicated by its mutational spectrum as exerting a tumour-suppressor function in many solid tumours; recently however, it has been reported to sustain leukaemogenic transformation in MLL-rearranged leukaemia in mice. Here we further explore the role of SMARCA4 and the two SWI/SNF subunits SMARCD2/BAF60B and DPF2/BAF45D in leukaemia...
2015: PloS One
Dandan Li, Li Wang, Honghu Zhu, Liping Dou, Daihong Liu, Lin Fu, Cong Ma, Xuebin Ma, Yushi Yao, Lei Zhou, Qian Wang, Lijun Wang, Yu Zhao, Yu Jing, Lili Wang, Yonghui Li, Li Yu
Hematopoietic stem cell transplantation (HSCT) and consolidation chemotherapy have been used to treat intermediate-risk acute myeloid leukemia (AML) patients in first complete remission (CR1). However, it is still unclear which treatments are most effective for these patients. The aim of our study was to analyze the relapse-free survival (RFS) and overall survival (OS) benefit of allogeneic HSCT (alloHSCT) for intermediate-risk AML patients in CR1. A meta-analysis of prospective trials comparing alloHSCT to non-alloHSCT (autologous HSCT [autoHSCT] and/or chemotherapy) was undertaken...
2015: PloS One
Jae-Sook Ahn, Yeo-Kyeoung Kim, Yoo Hong Min, June-Won Cheong, Jun Ho Jang, Chul Won Jung, In Ho Kim, Hwi-Joong Yoon, Hong Ghi Lee, Sang Kyun Sohn, Joon Ho Moon, Hawk Kim, Yoo-Jin Kim, Jong-Ho Won, Joo-Seop Chung, Yeung Chul Mun, Je-Hwan Lee, Hyeoung-Joon Kim
Azacitidine (AZA) is commonly used in patients with myelodysplastic syndrome (MDS). To determine the role of AZA before allogeneic stem cell transplantation (allo-SCT), we conducted a prospective study of AZA pre-treatment followed by allo-SCT in patients with higher-risk MDS. Twenty-one patients who were scheduled for their third to sixth cycle of AZA pre-treatment followed by allo-SCT were enrolled. AZA pre-treatment was interrupted early in 3 patients (14.3%) because of leukaemic transformation or death...
2015: Acta Haematologica
Shahzya S Chaudhury, Jessica K Morison, Brenda E S Gibson, Karen Keeshan
Acute myeloid leukemia (AML) is a heterogenous disease of hematopoietic stem cells (HSCs) and progenitor cells (HSPCs). The pathogenesis of AML involves cytogenetic abnormalities, genetic mutations, and epigenetic anomalies. Although it is widely accepted that the cellular biology, gene expression, and epigenetic landscape of normal HSCs change with age, little is known about the interplay between the age at which the cell becomes leukemic and the resultant leukemia. Despite its rarity, childhood AML is a leading cause of childhood cancer mortality...
September 2015: Experimental Hematology
Sanjeev Kumar Gupta, Jagan Chandramohan, Lalit Kumar
A 59-year-old male patient was diagnosed as multiple myeloma in 2005 and received chemotherapy consisting of thalidomide, cyclophosphamide, and dexamethasone. The patient subsequently received high-dose melphalan followed by autologous stem cell transplantation and maintenance therapy with thalidomide. During the follow-up, the patient developed fever and cytopenias in 2012. The work up revealed 55% blasts in the marrow with myeloid phenotype leading to a diagnosis of acute myeloma leukaemia (AML). The karyotype was normal (46,XY) on conventional cytogenetics...
2015: BMJ Case Reports
Kakkad Regha, Salam A Assi, Olga Tsoulaki, Jane Gilmour, Georges Lacaud, Constanze Bonifer
Acute myeloid leukaemia (AML) is characterized by a block in myeloid differentiation the stage of which is dependent on the nature of the transforming oncogene and the developmental stage of the oncogenic hit. This is also true for the t(8;21) translocation that gives rise to the RUNX1-ETO fusion protein and initiates the most common form of human AML. Here we study the differentiation of mouse embryonic stem cells expressing an inducible RUNX1-ETO gene into blood cells as a model, combined with genome-wide analyses of transcription factor binding and gene expression...
2015: Nature Communications
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