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https://www.readbyqxmd.com/read/29031704/evaluation-of-cooperative-anti-leukemic-effects-of-nilotinib-and-vildagliptin-in-ph-chronic-myeloid-leukemia
#1
Michael Willmann, Irina Sadovnik, Gregor Eisenwort, Martin Entner, Tina Bernthaler, Gabriele Stefanzl, Emir Hadzijusufovic, Daniela Berger, Harald Herrmann, Gregor Hoermann, Peter Valent, Thomas Rülicke
Chronic myeloid leukemia (CML) is a stem cell neoplasm characterized by the BCR/ABL1 oncogene. Although the disease can be kept under control using BCR/ABL1 tyrosine kinase inhibitors (TKI) in most cases, some patients relapse or have resistant disease which points to the need to identify new therapeutic targets in this malignancy. Recent data suggest that leukemic stem cell (LSC) in CML display the SC-mobilizing cell surface enzyme dipeptidyl-peptidase IV (DPPIV=CD26) in an aberrant manner. In the present study, we analyzed the effects of the DPPIV blocker vildagliptin as single agent or in combination with the BCR/ABL1 TKI imatinib or nilotinib on growth and survival of CML LSC in vitro and on LSC engraftment in an in vivo xenotransplantation NSG mouse model...
October 12, 2017: Experimental Hematology
https://www.readbyqxmd.com/read/29019081/modification-of-nk-cell-subset-repartition-and-functions-in-granulocyte-colony-stimulating-factor-mobilized-leukapheresis-after-expansion-with-il-15
#2
Yu Xiong, Manon Mouginot, Loic Reppel, Chongsheng Qian, Jean-Francois Stoltz, Danièle Bensoussan, Véronique Decot
The ability of natural killer (NK) cells to kill tumor cells without antigen recognition makes them appealing as an adoptive immunotherapy. However, NK cells are not routinely used in the context of leukemic relapse after hematopoietic stem cell transplantation. Patients who experience relapse can be treated with donor lymphocyte infusions (DLI) based on small-cell fractions frozen at the time of transplantation. Since peripheral blood stem cells (PBSCs) are increasingly used as a stem cell source and as a source of cells for DLI, we aimed to evaluate the impact of G-SCF mobilization on NK cell phenotype, subset repartition, and functionality...
October 10, 2017: Immunologic Research
https://www.readbyqxmd.com/read/29018080/chd7-deficiency-delays-leukemogenesis-in-mice-induced-by-cbfb-myh11
#3
Tao Zhen, Erika Kwon, Ling Zhao, Jingmei Hsu, R Katherine Hyde, Ying Lu, Lemlem Alemu, Nancy A Speck, P Paul Liu
Inversion of chromosome 16 is a consistent finding in patients with acute myeloid leukemia subtype M4 with eosinophilia (AML M4Eo), which generates a CBFB-MYH11 fusion gene. Previous studies showed that the interaction between CBFβ-SMMHC (encoded by CBFB-MYH11) and RUNX1 plays a critical role in the pathogenesis of this leukemia. Recently, it was shown that chromodomain-helicase-DNA binding protein 7 (CHD7) interacts with RUNX1 and suppresses RUNX1-induced expansion of hematopoietic stem and progenitor cells...
October 10, 2017: Blood
https://www.readbyqxmd.com/read/28989582/patterns-of-dnmt1-promoter-methylation-in-patients-with-acute-lymphoblastic-leukemia
#4
Tirdad Rahmani, Mehdi Azad, Bahram Chahardouli, Hajar Nasiri, Mousa Vatanmakanian, Saeid Kaviani
Background: Acute lymphoblastic leukemia (ALL) is a clonal malignant disorder characterized by an uncontrolled proliferation of immature T or B lymphocytes. Extensive studies have shown that the epigenetic changes, especially modified DNA methylation patterns in the regulatory regions through the DNA methyltransferase (DNMTs), play an important role in the development of genetic disorders and abnormal growth and maturation capacity of leukemic stem cells (LSCs).The aim of this study was to evaluate the changes in DNMT1 promoter methylation and its expression pattern in patients with ALL...
July 1, 2017: International Journal of Hematology-oncology and Stem Cell Research
https://www.readbyqxmd.com/read/28985760/an-improved-pre-clinical-patient-derived-liquid-xenograft-mouse-model-for-acute-myeloid-leukemia
#5
Zhisheng Her, Kylie Su Mei Yong, Kathirvel Paramasivam, Wilson Wei Sheng Tan, Xue Ying Chan, Sue Yee Tan, Min Liu, Yong Fan, Yeh Ching Linn, Kam Man Hui, Uttam Surana, Qingfeng Chen
BACKGROUND: Xenotransplantation of patient-derived AML (acute myeloid leukemia) cells in NOD-scid Il2rγ (null) (NSG) mice is the method of choice for evaluating this human hematologic malignancy. However, existing models constructed using intravenous injection in adult or newborn NSG mice have inferior engraftment efficiency, poor peripheral blood engraftment, or are difficult to construct. METHODS: Here, we describe an improved AML xenograft model where primary human AML cells were injected into NSG newborn pups intrahepatically...
October 6, 2017: Journal of Hematology & Oncology
https://www.readbyqxmd.com/read/28984203/system-modeling-reveals-the-molecular-mechanisms-of-hsc-cell-cycle-alteration-mediated-by-maff-and-egr3-under-leukemia
#6
Rudong Li, Yin Wang, Hui Cheng, Gang Liu, Tao Cheng, Yunlong Liu, Lei Liu
BACKGROUND: Molecular mechanisms of the functional alteration of hematopoietic stem cells (HSCs) in leukemic environment attract intensive research interests. As known in previous researches, Maff and Egr3 are two important genes having opposite functions on cell cycle; however, they are both highly expressed in HSCs under leukemia. Hence, exploring the molecular mechanisms of how the genes act on cell cycle will help revealing the functional alteration of HSCs. RESULTS: We herein utilize the bioinformatic resources to computationally model the acting mechanisms of Maff and Egr3 on cell cycle...
October 3, 2017: BMC Systems Biology
https://www.readbyqxmd.com/read/28980766/cancer-related-mrna-expression-analysis-using-a-novel-flow-cytometry-based-assay
#7
REVIEW
Barbara Depreter, Jan Philippé, Magali Meul, Barbara Denys, Karl Vandepoele, Barbara De Moerloose, Tim Lammens
BACKGROUND: Cancer-related gene expression data mostly originate from unfractionated bulk samples, leading to 'expression averaging' of heterogeneous populations. Multicolor flow cytometry (FCM) may distinguish heterogeneous populations based on the phenotypic characterization of single-cells, but is not applicable for RNA targets. Here, we evaluated the PrimeFlow™ RNA assay, a novel FCM-based assay designed to measure gene expressions, in two cancer entities with high and low RNA target levels...
October 5, 2017: Cytometry. Part B, Clinical Cytometry
https://www.readbyqxmd.com/read/28978837/treatment-for-myelodysplastic-syndrome-with-a-focus-on-the-low-risk-group
#8
Akihiko Gotoh
Myelodysplastic syndrome (MDS) is a group of clonal disorders affecting hematopoietic stem cells. Thus, the only potential curative therapy is hematopoietic stem cell transplantation (HSCT). Indeed, for high-risk patients with MDS, who have a higher anticipated risk of leukemic transformation and shorter survival, HSCT is the first choice for eligible patients. DNA hypomethylating agents, the only agents proved to prolong survival, are used in non-HSCT-eligible high-risk patients with MDS. In contrast, due to high transplant-related mortality rate, treatment strategies other than HSCT are mainly applied for the low-risk group with expected long-term survival...
2017: [Rinshō Ketsueki] the Japanese Journal of Clinical Hematology
https://www.readbyqxmd.com/read/28978822/progress-in-the-leukemic-stem-cell-study-and-a-novel-therapeutic-approach-targeting-leukemic-stem-cells
#9
Yoshikane Kikushige, Toshihiro Miyamoto, Koichi Akashi
Hematopoietic stem cells (HSCs) have the potential to self-renew and differentiate into multi-lineage mature hematopoietic cells; thus, these cells can maintain hematopoiesis. Human HSCs reside within the CD34(+)CD38(-) cell fractions. Similarly, in acute myelogenous leukemia (AML), a small number of leukemic cells, called leukemic stem cells (LSCs), can be enriched within the identical CD34(+)CD38(-) cell fractions. LSCs can self-renew and produce clonogenic leukemic cells, whereas non-LSCs lack the potential to self-renew or maintain leukemia; thus, AML is organized as a hierarchy that originated from LSCs...
2017: [Rinshō Ketsueki] the Japanese Journal of Clinical Hematology
https://www.readbyqxmd.com/read/28978671/transcriptional-memory-of-cells-of-origin-overrides-%C3%AE-catenin-requirement-of-mll-cancer-stem-cells
#10
Teerapong Siriboonpiputtana, Bernd B Zeisig, Magdalena Zarowiecki, Tsz Kan Fung, Maria Mallardo, Chiou-Tsun Tsai, Priscilla Nga Ieng Lau, Quoc Chinh Hoang, Pedro Veiga, Jo Barnes, Claire Lynn, Amanda Wilson, Boris Lenhard, Chi Wai Eric So
While β-catenin has been demonstrated as an essential molecule and therapeutic target for various cancer stem cells (CSCs) including those driven by MLL fusions, here we show that transcriptional memory from cells of origin predicts AML patient survival and allows β-catenin-independent transformation in MLL-CSCs derived from hematopoietic stem cell (HSC)-enriched LSK population but not myeloid-granulocyte progenitors. Mechanistically, β-catenin regulates expression of downstream targets of a key transcriptional memory gene, Hoxa9 that is highly enriched in LSK-derived MLL-CSCs and helps sustain leukemic self-renewal...
October 4, 2017: EMBO Journal
https://www.readbyqxmd.com/read/28978065/the-pan-bcl-2-blocker-obatoclax-gx15-070-and-the-pi3-kinase-mtor-inhibitor-bez235-produce-cooperative-growth-inhibitory-effects-in-all-cells
#11
Gabriele Stefanzl, Daniela Berger, Sabine Cerny-Reiterer, Katharina Blatt, Gregor Eisenwort, Wolfgang R Sperr, Gregor Hoermann, Karin Lind, Alexander W Hauswirth, Peter Bettelheim, Heinz Sill, Junia V Melo, Ulrich Jäger, Peter Valent
Acute lymphoblastic leukemia (ALL) is characterized by leukemic expansion of lymphoid blasts in hematopoietic tissues. Despite improved therapy only a subset of patients can be cured. Therefore, current research is focusing on new drug-targets. Members of the BCL-2 family and components of the PI3-kinase/mTOR pathway are critically involved in the regulation of growth and survival of ALL cells. We examined the effects of the pan-BCL-2 blocker obatoclax and the PI3-kinase/mTOR-inhibitor BEZ235 on growth and survival of ALL cells...
September 15, 2017: Oncotarget
https://www.readbyqxmd.com/read/28974232/the-stem-cell-factor-sall4-is-an-essential-transcriptional-regulator-in-mixed-lineage-leukemia-rearranged-leukemogenesis
#12
Lina Yang, Li Liu, Hong Gao, Jaya Pratap Pinnamaneni, Deepthi Sanagasetti, Vivek P Singh, Kai Wang, Megumi Mathison, Qianzi Zhang, Fengju Chen, Qianxing Mo, Todd Rosengart, Jianchang Yang
BACKGROUND: The stem cell factor spalt-like transcription factor 4 (SALL4) plays important roles in normal hematopoiesis and also in leukemogenesis. We previously reported that SALL4 exerts its effect by recruiting important epigenetic factors such as DNA methyltransferases DNMT1 and lysine-specific demethylase 1 (LSD1/KDM1A). Both of these proteins are critically involved in mixed lineage leukemia (MLL)-rearranged (MLL-r) leukemia, which has a very poor clinical prognosis. Recently, SALL4 has been further linked to the functions of MLL and its target gene homeobox A9 (HOXA9)...
October 3, 2017: Journal of Hematology & Oncology
https://www.readbyqxmd.com/read/28972073/jam-c-identifies-src-family-kinase-activated-leukemia-initiating-cells-and-predicts-poor-prognosis-in-acute-myeloid-leukemia
#13
Maria De Grandis, Florence Bardin, Cyril Fauriat, Christophe Zemmour, Abdessamad El Kaoutari, Arnauld Sergé, Samuel Granjeaud, Laurent Pouyet, Camille Montersino, Anne-Sophie Chrétien, Marie-Joelle Mozziconacci, Remy Castellano, Ghislain Bidaut, Jean-Marie Boher, Yves Collette, Stéphane Jc Mancini, Norbert Vey, Michel Aurrand-Lions
Acute Myeloid Leukemia (AML) originates from hematopoietic stem and progenitor cells that acquire somatic mutations, leading to disease and clonogenic evolution. AML is characterized by accumulation of immature myeloid cells in the bone marrow and phenotypic cellular heterogeneity reflective of normal hematopoietic differentiation. Here we show that JAM-C expression defines a subset of leukemic cells endowed with leukemia-initiating cell activity (LIC). Stratification of de novo AML patients at diagnosis based on JAM-C-expressing cells frequencies in the blood served as an independent prognostic marker for disease outcome...
September 28, 2017: Cancer Research
https://www.readbyqxmd.com/read/28963654/k562-chronic-myeloid-leukemia-cells-modify-osteogenic-differentiation-and-gene-expression-of-bone-marrow-stromal-cells
#14
Atul Kumar, Trishna Anand, Jina Bhattacharyya, Amit Sharma, Bithiah Grace Jaganathan
Bone marrow (BM) microenvironment plays an important role in normal and malignant hematopoiesis. As a consequence of interaction with the leukemic cells, the stromal cells of the bone marrow become deregulated in their normal function and gene expression. In our study, we found that mesenchymal stem cells (MSC) from BM of chronic myeloid leukemia (CML) patients have defective osteogenic differentiation and on interaction with K562 CML cells, the normal MSC showed reduced osteogenic differentiation. On interaction with K562 cells or its secreted factors, MSC acquired phenotypic abnormalities and secreted high levels of IL6 through NFκB activation...
September 30, 2017: Journal of Cell Communication and Signaling
https://www.readbyqxmd.com/read/28963358/tigecycline-may-selectively-target-leukemic-stem-cells-in-cml
#15
(no author information available yet)
Tigecycline inhibits mitochondrial oxidative phosphorylation to target leukemic stem cells (LSC).
September 29, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28960191/meis2-as-a-critical-player-in-mn1-induced-leukemia
#16
C K Lai, G L Norddahl, T Maetzig, P Rosten, T Lohr, L Sanchez Milde, N von Krosigk, T R Docking, M Heuser, A Karsan, R K Humphries
Meningioma 1 (MN1) is an independent prognostic marker for normal karyotype acute myeloid leukemia (AML), with high expression linked to all-trans retinoic acid resistance and poor survival. MN1 is also a potent and sufficient oncogene in murine leukemia models, strongly dependent on the MEIS1/AbdB-like HOX protein complex to transform common myeloid progenitors, block myeloid differentiation, and promote leukemic stem cell self-renewal. To identify key genes and pathways underlying leukemic activity, we functionally assessed MN1 cell phenotypic heterogeneity, revealing leukemic and non-leukemic subsets...
September 29, 2017: Blood Cancer Journal
https://www.readbyqxmd.com/read/28952709/opn-b-and-c-isoforms-doubtless-veto-anti-angiogenesis-effects-of-curcumin-in-combination-with-conventional-aml-regiment
#17
Akram Mirzaei, Seyed H Ghaffari, Mohsen Nikbakht, Hosein Kamranzadeh Foumani, Mohammad Vaezi, Saeed Mohammadi, Kamran Alimoghaddam, Ardeshir Ghavamzadeh
Osteopontin (OPN) is an extracellular structural protein that is secreted by osteoblasts and hematopoietic cells. It suppresses the proliferation of hematopoietic stem and also plays an important role in promoting survival and drug resistance in leukemic stem cells (LSCs). Since the role of OPN isoforms in AML angiogenesis are remaining controversial, in the present study, we aimed to evaluate whether curcumin (CUR), as a known natural component with anti-angiogenesis effects, in a combination of AML conventional regiment has the potency to preclude induced anti-angiogenesis effects of OPN isoforms or not? Leukemia cells were treated with different concentration of CUR and AML conventional drugs alone and/or in combination with together to find effective doses and IC50 values...
September 27, 2017: Asian Pacific Journal of Cancer Prevention: APJCP
https://www.readbyqxmd.com/read/28947904/mesenchymal-stem-cells-in-myeloid-malignancies-a-focus-on-immune-escaping-and-therapeutic-implications
#18
REVIEW
Nicola Stefano Fracchiolla, Bruno Fattizzo, Agostino Cortelezzi
The importance of the bone marrow microenvironment forming the so-called niche in physiologic hemopoiesis is largely known, and recent evidences support the presence of stromal alterations from the molecular to the cytoarchitectural level in hematologic malignancies. Various alterations in cell adhesion, metabolism, cytokine signaling, autophagy, and methylation patterns of tumor-derived mesenchymal stem cells have been demonstrated, contributing to the genesis of a leukemic permissive niche. This niche allows both the ineffective haematopoiesis typical of myelodysplastic syndromes and the differentiation arrest, proliferation advantage, and clone selection which is the hallmark of acute myeloid leukemia...
2017: Stem Cells International
https://www.readbyqxmd.com/read/28945115/advances-in-immunotherapy-for-pediatric-acute-myeloid-leukemia
#19
Challice L Bonifant, Mireya Paulina Velasquez, Stephen Gottschalk
Achieving better disease control in patients diagnosed with acute myeloid leukemia (AML) has proven challenging. Overall survival has been impacted by addressing treatment related mortality with focused supportive care measures. Despite this improvement, it remains difficult to induce durable leukemia remissions despite aggressive chemotherapeutic regimens. The addition of hematopoietic stem cell transplants (HSCT) has allowed further treatment intensification and provided the benefit of graft-versus-leukemia (GVL) effect...
October 11, 2017: Expert Opinion on Biological Therapy
https://www.readbyqxmd.com/read/28933312/characterization-of-imatinib-resistant-cml-leukemic-stem-initiating-cells-and-their-sensitivity-to-cbp-catenin-antagonists
#20
Yi Zhao, Kaijin Wu, Yongfeng Wu, Elizabeth Melendez, Goar Smbatyan, David Massiello, Michael Kahn
The development of the tyrosine kinase inhibitor Imatinib (IM) represents a milestone breakthrough in CML (Chronic Myeloid Leukemia) treatment. However, it is not curative and patients develop IM resistance. IM resistance has been previously correlated with the emergence of drug-resistant LIC/LSC (Leukemia Initiating Cell/Leukemia Stem Cell) and increased nuclear catenin levels and enhanced Wnt signaling. It has been demonstrated previously that drug resistant CML LIC/LSC can be safely eliminated both in vitro and in vivo via disruption of the CBP/catenin interaction, utilizing the highly biochemically selective small molecule CBP/catenin antagonist ICG-001...
September 19, 2017: Current Molecular Pharmacology
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