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Leukemic stem cell

Bethany L Mundy-Bosse, Steven D Scoville, Li Chen, Kathleen McConnell, Hsiaoyin C Mao, Elshafa H Ahmed, Nicholas Zorko, Sophia Harvey, Jordan Cole, Xiaoli Zhang, Stefan Costinean, Carlo M Croce, Karilyn Larkin, John C Byrd, Sumithira Vasu, William Blum, Jianhua Yu, Aharon G Freud, Michael A Caligiuri
Natural killer (NK) cells can have potent antileukemic activity following haplo-mismatched, T cell-depleted stem cell transplantations for the treatment of acute myeloid leukemia (AML), but they are not successful in eradicating de novo AML. Here, we have used a mouse model of de novo AML to elucidate the mechanisms by which AML evades NK cell surveillance. NK cells in leukemic mice displayed a marked reduction in the cytolytic granules perforin and granzyme B. Further, as AML progressed, we noted the selective loss of an immature subset of NK cells in leukemic mice and in AML patients...
October 24, 2016: Journal of Clinical Investigation
Wenwen Wang, Elena Foerner, Eike Buss, Anna Jauch, Volker Eckstein, Patrick Wuchter, Anthony D Ho, Christoph Lutz
In B-cell acute lymphoblastic leukemia (B-ALL) separation of normal hematopoietic stem cells (HSC) has so far been limited to a subgroup of patients. As aldehyde dehydrogenase (ALDH)-activity is enriched in various stem cells we investigated its value for HSC isolation in adult B-ALL. Based on ALDH-activity patients could be stratified in ALDH-numerous (≥1.9% ALDH(+ )cells) and ALDH-rare (<1.9% ALDH(+ )cells) cases. In ALDH-rare B-ALL clonal-marker negative HSC could be separated by the CD34(+)CD38(-)ALDH(+ ) phenotype, whereas this separation was not possible in ALDH-numerous B-ALL...
October 13, 2016: Leukemia & Lymphoma
Deena Samir Eissa, Eman Zaghloul Kandeel, Mohamed Ghareeb
The prognosis of acute myeloid leukemia (AML) is poor because of relapses occurring on conventional chemotherapy. The distinction between leukemic and normal stem cells relies on the expression of antigen combinations defining leukemia-associated immunophenotypes (LAIPs), which are absent or extremely infrequent in normal bone marrow. However, LAIPs are very different from patient to patient and are not necessarily stable over the course of the disease. Accordingly, we addressed the applicability of human myeloid inhibitory C-lectin (hMICL) by flow cytometry as a specific leukemic myeloid stem cell marker for the diagnosis of AML in CD34(+) and CD34(-) cases and evaluated the stability of hMICL during the course of the disease...
October 13, 2016: Hematological Oncology
Laura G Rico, Jordi Juncà, Mike D Ward, Jolene Bradford, Jordi Petriz
With the aim to detect candidate malignant primitive progenitor populations, we modified an original alkaline phosphatase (ALP) stem cell detection method based on the identification of alkaline phosphatase fluorescent cells in combination with flow cytometry immunophenotyping. Over a period of one year, we have been using this technique to study its activity in patients with leukemia and lymphoma, showing that changes in the alkaline phosphatase levels can be used to detect rare populations of highly refractory malignant cells...
October 6, 2016: Oncotarget
Shohei Murakami, Hozumi Motohashi
The KEAP1-NRF2 system is an inducible molecular mechanism enhancing transcriptions of several cytoprotective genes in response to xenobiotics and oxidative stress. Recently, the KEAP1-NRF2 system has been suggested to directly regulate a portion of the genes related to cell proliferation and differentiation. In hematopoietic cells, NRF2 activation plays a role in maintenance and cell fate determination of hematopoietic stem cells, as well as in maturation processes and homeostasis of megakaryocytes and erythrocytes...
2016: [Rinshō Ketsueki] the Japanese Journal of Clinical Hematology
Suelen Martins Perobelli, Ana Carolina Terra Mercadante, Rômulo Gonçalves Galvani, Triciana Gonçalves-Silva, Ana Paula Gregório Alves, Antonio Pereira-Neves, Marlene Benchimol, Alberto Nóbrega, Adriana Bonomo
Acute graft-versus-host disease (aGVHD) is the main complication of allogeneic hematopoietic stem cell transplantation, and many efforts have been made to overcome this important limitation. We showed previously that G-CSF treatment generates low-density splenic granulocytes that inhibit experimental aGVHD. In this article, we show that aGVHD protection relies on incoming IL-10(+) neutrophils from G-CSF-treated donor spleen (G-Neutrophils). These G-Neutrophils have high phagocytic capacity, high peroxide production, low myeloperoxidase activity, and low cytoplasmic granule content, which accounts for their low density...
October 5, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
Dilini C Gunasekara, Mary M Zheng, Tara Mojtahed, James R Woods, Tamer E Fandy, Mark V Riofski, Carlotta A Glackin, Hazem E Hassan, Julia Kirshner, David A Colby
Recent studies suggest that leukemia stem cells (LSCs) play a critical role in the initiation, propagation, and relapse of leukemia. Herein we show that (-)-15-methylene-eburnamonine, a derivative of the alkaloid (-)-eburnamonine, is cytotoxic against acute and chronic lymphocytic leukemias (ALL and CLL) and acute myelogenous leukemia (AML). The agent also decreases primary LSC frequency in vitro. The cytotoxic effects appear to be mediated via the oxidative stress pathways. Furthermore, we show that the compound kills AML, ALL, and CLL stem cells...
September 28, 2016: ChemMedChem
Francisco Bautista, Jasper Van der Lugt, Pamela R Kearns, Francis J Mussai, C Michel Zwaan, Lucas Moreno
Survival rates in pediatric leukemia have greatly improved in the last decades but still a substantial number of patients will relapse and die. New agents are necessary to overcome the limitations of conventional chemotherapy and hematopoietic stem cell transplantation and to reduce their undesirable long-term toxicities. The identification of driving molecular alterations of leukemogenesis in subsets of patients will allow the incorporation of new-targeted therapies. Areas covered: In this article the authors present a detailed review of the most recent advances in targeted therapies for pediatric leukemias...
November 2016: Expert Opinion on Drug Discovery
Naeem Khan, Robert K Hills, Steve Knapper, Lora Steadman, Ushna Qureshi, Jerrald L Rector, Charlotte Bradbury, Nigel H Russell, Paresh Vyas, Alan K Burnett, David Grimwade, Paul S Hole, Sylvie D Freeman
In acute myeloid leukemia (AML) quiescence and low oxidative state, linked to BCL2 mitochondrial regulation, endow leukemic stem cells (LSC) with treatment-resistance. LSC in CD34+ and more mature CD34- AML have heterogeneous immunophenotypes overlapping with normal stem/progenitor cells (SPC) but may be differentiated by functional markers. We therefore investigated the oxidative/reactive oxygen species (ROS) profile, its relationship with cell-cycle/BCL2 for normal SPC, and whether altered in AML and myelodysplasia (MDS)...
2016: PloS One
Shinsuke Takagi, Kazuhiro Masuoka, Naoyuki Uchida, Mineo Kurokawa, Hirohisa Nakamae, Kazunori Imada, Koji Iwato, Tatsuo Ichinohe, Yoshiko Atsuta, Akiyoshi Takami, Shingo Yano
To clarify the outcome of allogeneic hematopoietic cell transplantation (HCT) for leukemic transformation (LT) preceded by Philadelphia chromosome-negative (Ph-neg) myeloproliferative neoplasms (MPNs), we conducted a retrospective study using the national registry database of the Japan Society for Hematopoietic Cell Transplantation. From 2000 to 2013, 39 patients underwent their first allogeneic HCT with related bone marrow or peripheral blood stem cells (n = 8), unrelated bone marrow (n = 15), and unrelated umbilical cord blood (n = 16)...
September 22, 2016: Biology of Blood and Marrow Transplantation
Alvaro Muñoz-López, Damià Romero-Moya, Cristina Prieto, Verónica Ramos-Mejía, Antonio Agraz-Doblas, Ignacio Varela, Marcus Buschbeck, Anna Palau, Xonia Carvajal-Vergara, Alessandra Giorgetti, Anthony Ford, Majlinda Lako, Isabel Granada, Neus Ruiz-Xivillé, Sandra Rodríguez-Perales, Raul Torres-Ruíz, Ronald W Stam, Jose Luis Fuster, Mario F Fraga, Mahito Nakanishi, Gianni Cazzaniga, Michela Bardini, Isabel Cobo, Gustavo F Bayon, Agustin F Fernandez, Clara Bueno, Pablo Menendez
Induced pluripotent stem cells (iPSCs) are a powerful tool for disease modeling. They are routinely generated from healthy donors and patients from multiple cell types at different developmental stages. However, reprogramming leukemias is an extremely inefficient process. Few studies generated iPSCs from primary chronic myeloid leukemias, but iPSC generation from acute myeloid or lymphoid leukemias (ALL) has not been achieved. We attempted to generate iPSCs from different subtypes of B-ALL to address the developmental impact of leukemic fusion genes...
October 11, 2016: Stem Cell Reports
Noemi A Zambetti, Zhen Ping, Si Chen, Keane J G Kenswil, Maria A Mylona, Mathijs A Sanders, Remco M Hoogenboezem, Eric M J Bindels, Maria N Adisty, Paulina M H Van Strien, Cindy S van der Leije, Theresia M Westers, Eline M P Cremers, Chiara Milanese, Pier G Mastroberardino, Johannes P T M van Leeuwen, Bram C J van der Eerden, Ivo P Touw, Taco W Kuijpers, Roland Kanaar, Arjan A van de Loosdrecht, Thomas Vogl, Marc H G P Raaijmakers
Mesenchymal niche cells may drive tissue failure and malignant transformation in the hematopoietic system, but the underlying molecular mechanisms and relevance to human disease remain poorly defined. Here, we show that perturbation of mesenchymal cells in a mouse model of the pre-leukemic disorder Shwachman-Diamond syndrome (SDS) induces mitochondrial dysfunction, oxidative stress, and activation of DNA damage responses in hematopoietic stem and progenitor cells. Massive parallel RNA sequencing of highly purified mesenchymal cells in the SDS mouse model and a range of human pre-leukemic syndromes identified p53-S100A8/9-TLR inflammatory signaling as a common driving mechanism of genotoxic stress...
September 10, 2016: Cell Stem Cell
Robin R Weidemann, Rayk Behrendt, Kristina B Schoedel, Werner Müller, Axel Roers, Alexander Gerbaulet
Acute lymphoblastic leukemia (ALL) is the most common childhood malignancy and, in most cases, is of pro- or pre-B cell origin (B-ALL). The receptor tyrosine kinase KIT is expressed by hematopoietic stem and precursor cells. Gain-of-function mutations of KIT cause systemic mastocytosis, which is characterized by abnormal accumulations of mast cells. We previously reported a mouse model of mastocytosis based on conditional expression of a constitutively active Kit protein. Half of these animals developed leukemic disease of B-lineage origin...
September 21, 2016: Experimental Hematology
Sanga Mitra, Arpa Samadder, Pijush Das, Smarajit Das, Medhanjali Dasgupta, Jayprokas Chakrabarti
Screening large-scale ENCODE data of 625 cytoplasmic transfer RNA (tRNAs) and 37 aminoacyl tRNA synthetase (AARSs) human genes, we deconstruct the array of relations between 10 histone marks affecting 15 chromatin states; their tissue specificity and variations and interchange amongst normal, cancerous and stem cells. The histone marks of RNA Pol II transcribed AARS genes share, but also contrast with that on RNA Pol III transcribed tRNA genes. tRNAs with identical/similar sequences may be in significantly varying states even within the same cell line; the chromatin scaffold, where the tRNA gene resides, is the key determinant...
October 6, 2016: Journal of Biomolecular Structure & Dynamics
I Morath, T N Hartmann, V Orian-Rousseau
CD44 is a cell adhesion molecule that plays an important role in tumor progression and metastasis. The role of CD44 in tumorigenesis is due to its binding to extracellular matrix components, including hyaluronan (HA) and osteopontin (OPN), and to messenger molecules, such as growth factors present in the tumor microenvironment. HA and OPN are highly abundant in the leukemic stem cell niche and in solid tumors of various cancer types, where they contribute to the maintenance of the stemness of malignant cells...
September 15, 2016: International Journal of Biochemistry & Cell Biology
Shinsuke Hirabayashi, Kentaro Ohki, Kazuhiko Nakabayashi, Hitoshi Ichikawa, Yukihide Momozawa, Kohji Okamura, Akinori Yaguchi, Kazuki Terada, Yuya Saito, Ai Yoshimi, Hiroko Ogata-Kawata, Hiromi Sakamoto, Motohiro Kato, Junya Fujimura, Moeko Hino, Akitoshi Kinoshita, Hiromi Kakuda, Hidemitsu Kurosawa, Keisuke Kato, Ryosuke Kajiwara, Koichi Moriwaki, Tsuyoshi Morimoto, Kozue Nakamura, Yasushi Noguchi, Tomoo Osumi, Kazuo Sakashita, Junko Takita, Yuki Yuza, Koich Matsuda, Teruhiko Yoshida, Kenji Matsumoto, Kenichiro Hata, Michiaki Kubo, Yoichi Matsubara, Takashi Fukushima, Katsuyoshi Koh, Atsushi Manabe, Akira Ohara, Nobutaka Kiyokawa
Fusion genes involving ZNF384 have recently been identified in B-cell precursor acute lymphoblastic leukemia, and 6 fusion partners have reported. We further characterized this type of fusion gene by whole transcriptome sequencing and/or PCR. In addition to previously reported genes, we identified BMP2K as a novel fusion partner for ZNF384. Including EP300-ZNF384 that we reported recently, the total frequency of ZNF384-related fusion genes was 4.1% in 291 B-cell precursor acute lymphoblastic leukemia patients enrolled in a single clinical trial, and TCF3-ZNF384 was the most recurrent, with a frequency of 2...
September 15, 2016: Haematologica
Mary T Scott, Koorosh Korfi, Peter Saffrey, Lisa E M Hopcroft, Ross Kinstrie, Francesca Pellicano, Carla Guenther, Paolo Gallipoli, Michelle Cruz, Karen Dunn, Heather G Jorgensen, Jennifer E Cassels, Ashley Hamilton, Andrew Crossan, Amy Sinclair, Tessa L Holyoake, David Vetrie
: A major obstacle to curing chronic myeloid leukemia (CML) is residual disease maintained by tyrosine kinase inhibitor (TKI)-persistent leukemic stem cells (LSC). These are BCR-ABL1 kinase independent, refractory to apoptosis, and serve as a reservoir to drive relapse or TKI resistance. We demonstrate that Polycomb Repressive Complex 2 is misregulated in chronic phase CML LSCs. This is associated with extensive reprogramming of H3K27me3 targets in LSCs, thus sensitizing them to apoptosis upon treatment with an EZH2-specific inhibitor (EZH2i)...
September 14, 2016: Cancer Discovery
A Queisser, S Hagedorn, H Wang, T Schaefer, M Konantz, S Alavi, M Deng, W Vogel, A von Mässenhausen, G Kristiansen, S Duensing, J Kirfel, C Lengerke, S Perner
Prostate cancer (PCa) is the most commonly diagnosed non-cutaneous cancer in men in the western world. Mutations in tumor suppressor genes and in oncogenes are important for PCa progression, whereas the role of stem cell proteins in prostate carcinogenesis is insufficiently examined. This study investigates the role of the transcriptional regulator Ecotropic Viral Integration site 1 (EVI1), known as an essential modulator of hematopoietic and leukemic stem cell biology, in prostate carcinogenesis. We show that in healthy prostatic tissue, EVI1 expression is confined to the prostate stem cell compartment located at the basal layer, as identified by the stem cell marker CD44...
September 12, 2016: Oncogene
G Venton, M Pérez-Alea, C Baier, G Fournet, G Quash, Y Labiad, G Martin, F Sanderson, P Poullin, P Suchon, L Farnault, C Nguyen, C Brunet, I Ceylan, R T Costello
The vast majority of patients with acute myeloid leukemia (AML) achieve complete remission (CR) after standard induction chemotherapy. However, the majority subsequently relapse and die of the disease. A leukemia stem cell (LSC) paradigm has been invoked to explain this failure of CR to reliably translate into cure. Indeed, LSCs are highly enriched in CD34+CD38- leukemic cells that exhibit positive aldehyde dehydrogenase activity (ALDH+) on flow cytometry, these LSCs are resistant to currently existing treatments in AML such as cytarabine and anthracycline that, at the cost of great toxicity on normal cells, are highly active against the leukemic bulk, but spare the LSCs responsible for relapse...
2016: Blood Cancer Journal
Qiang Liu, Longgui Chen, Jennifer M Atkinson, David F Claxton, Hong-Gang Wang
Acute myeloid leukemia (AML) is a hierarchical hematopoietic malignancy originating from leukemic stem cells (LSCs). Autophagy is a lysosomal degradation pathway that is hypothesized to be important for the maintenance of AML as well as contribute to chemotherapy response. Here we employ a mouse model of AML expressing the fusion oncogene MLL-AF9 and explore the effects of Atg5 deletion, a key autophagy protein, on the malignant transformation and progression of AML. Consistent with a transient decrease in colony-forming potential in vitro, the in vivo deletion of Atg5 in MLL-AF9-transduced bone marrow cells during primary transplantation prolonged the survival of recipient mice, suggesting that autophagy has a role in MLL-AF9-driven leukemia initiation...
2016: Cell Death & Disease
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