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leukemia MicroEnvironment

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https://www.readbyqxmd.com/read/29773599/tgf%C3%AE-1-mediated-functional-inhibition-of-mesenchymal-stromal-cells-in-myelodysplastic-syndromes-and-acute-myeloid-leukemia
#1
Stefanie Geyh, Manuel Rodríguez-Paredes, Paul Jäger, Annemarie Koch, Felix Bormann, Julian Gutekunst, Christoph Zilkens, Ulrich Germing, Guido Kobbe, Frank Lyko, Rainer Haas, Thomas Schroeder
Mesenchymal stromal cells are involved in the pathogenesis of myelodysplastic syndromes and acute myeloid leukemia, but the underlying mechanisms are incompletely understood. To further characterize the pathological phenotype we performed RNA sequencing of mesenchymal stromal cells from patients with myelodysplastic syndromes and acute myeloid leukemia revealing a specific molecular signature of genes commonly deregulated in myelodysplastic syndromes and acute myeloid leukemia. Pathway analysis showed a strong enrichment of genes related to osteogenesis, senescence, inflammation and inhibitory cytokines thereby reflecting the structural and functional deficits of mesenchymal stromal cells in myelodysplastic syndromes and acute myeloid leukemia on a molecular level...
May 17, 2018: Haematologica
https://www.readbyqxmd.com/read/29768210/engineered-tumor-targeted-t-cells-mediate-enhanced-anti-tumor-efficacy-both-directly-and-through-activation-of-the-endogenous-immune-system
#2
Mauro P Avanzi, Oladapo Yeku, Xinghuo Li, Dinali P Wijewarnasuriya, Dayenne G van Leeuwen, Kenneth Cheung, Hyebin Park, Terence J Purdon, Anthony F Daniyan, Matthew H Spitzer, Renier J Brentjens
Chimeric antigen receptor (CAR) T cell therapy has proven clinically beneficial against B cell acute lymphoblastic leukemia and non-Hodgkin's lymphoma. However, suboptimal clinical outcomes have been associated with decreased expansion and persistence of adoptively transferred CAR T cells, antigen-negative relapses, and impairment by an immunosuppressive tumor microenvironment. Improvements in CAR T cell design are required to enhance clinical efficacy, as well as broaden the applicability of this technology...
May 15, 2018: Cell Reports
https://www.readbyqxmd.com/read/29764250/immunological-changes-with-kinase-inhibitor-therapy-for-chronic-lymphocytic-leukemia
#3
Christopher Pleyer, Adrian Wiestner, Clare Sun
Ibrutinib and idelalisib are kinase inhibitors that have revolutionized the treatment of chronic lymphocytic leukemia (CLL). Capable of inducing durable remissions, these agents also modulate the immune system. Both ibrutinib and idelalisib abrogate the tumor-supporting microenvironment by disrupting cell-cell interactions, modulating the T-cell compartment, and altering the cytokine milieu. Ibrutinib also partially restores T-cell and myeloid defects associated with CLL. In contrast, immune-related adverse effects, including pneumonitis, colitis, hepatotoxicity, and infections are of particular concern with idelalisib...
May 15, 2018: Leukemia & Lymphoma
https://www.readbyqxmd.com/read/29759563/targeting-the-tumor-promoting-effects-of-adenosine-in-chronic-lymphocytic-leukemia
#4
REVIEW
Yiqing Cai, Lili Feng, Xin Wang
Chronic lymphocytic leukemia (CLL) is a hematological malignancy which is characterized by progressive accumulation of functionally deficient B cells in blood, bone marrow, and lymphatic tissue. The tumor microenvironment (TME) appears to play a critical role in genesis and progression of CLL. High levels of extracellular adenosine (ADO) are detected in CLL as a consequence of expression of ecto-enzymes, such as CD39 and CD73. Extracellular ADO exhibits a broad range of effects on cell cycle control, immunoregulation, angiogenesis and cytokine regulation through both direct and indirect mechanisms...
June 2018: Critical Reviews in Oncology/hematology
https://www.readbyqxmd.com/read/29749707/automated-expansion-of-primary-human-t-cells-in-scalable-and-cell-friendly-hydrogel-microtubes-for-adoptive-immunotherapy
#5
Haishuang Lin, Qiang Li, Ou Wang, Jack Rauch, Braden Harm, Hendrik J Viljoen, Chi Zhang, Erika Van Wyk, Chi Zhang, Yuguo Lei
Adoptive immunotherapy is a highly effective strategy for treating many human cancers, such as melanoma, cervical cancer, lymphoma, and leukemia. Here, a novel cell culture technology is reported for expanding primary human T cells for adoptive immunotherapy. T cells are suspended and cultured in microscale alginate hydrogel tubes (AlgTubes) that are suspended in the cell culture medium in a culture vessel. The hydrogel tubes protect cells from hydrodynamic stresses and confine the cell mass less than 400 µm (in radial diameter) to ensure efficient mass transport, creating a cell-friendly microenvironment for growing T cells...
May 11, 2018: Advanced Healthcare Materials
https://www.readbyqxmd.com/read/29749536/biib021-an-hsp90-inhibitor-a-promising-therapeutic-strategy-for-blood-malignancies-review
#6
Wei He, Huixian Hu
Heat shock proteins (HSPs) are molecular chaperones that are consistently increased to help cells survive under conditions of stress. As a member of the Hsps, Hsp90 is involved in protein post‑translational maturation and disposition. This protein is ubiquitously expressed in normal cells. However, in cancer cells and particularly in hematological malignancies, Hsp90 is unexpectedly abundant to maintain levels of proteins vital for cancer pathology. Hsp90 inhibitors can target the ATP domain of Hsp90 and prohibit its exchange of ADP for ATP, leading to the degradation of client proteins and disruption of signaling cascades...
May 8, 2018: Oncology Reports
https://www.readbyqxmd.com/read/29742289/the-genetic-and-molecular-pathogenesis-of-myelodysplastic-syndromes
#7
REVIEW
Rory M Shallis, Rami Ahmad, Amer M Zeidan
Myelodysplastic syndromes (MDS) comprise a diverse group of clonal and malignant myeloid disorders characterized by ineffective hematopoiesis, resultant peripheral cytopenias, and a meaningful increased risk of progression to acute myeloid leukemia. A wide array of recurring genetic mutations involved in RNA splicing, histone manipulation, DNA methylation, transcription factors, kinase signaling, DNA repair, cohesin proteins, and other signal transduction elements have been identified as important substrates for the development of MDS...
May 9, 2018: European Journal of Haematology
https://www.readbyqxmd.com/read/29740536/regulation-of-malignant-hematopoiesis-by-bone-marrow-microenvironment
#8
REVIEW
Noboru Asada
Hematopoietic stem cells (HSCs) that give rise to all kinds of hematopoietic lineage cells on various demands throughout life are maintained in a specialized microenvironment called "niche" in the bone marrow (BM). Defining niche cells and unveiling its function have been the subject of intense study, and it is becoming increasingly clear how niche cells regulate HSCs in normal hematopoiesis. Leukemia stem cells (LSCs), which are able to produce leukemic cells and maintain leukemic clones, are assumed to share common features with healthy HSCs...
2018: Frontiers in Oncology
https://www.readbyqxmd.com/read/29740160/new-therapeutic-opportunities-from-dissecting-the-pre-b-leukemia-bone-marrow-microenvironment
#9
Laurence C Cheung, Jennifer Tickner, Anastasia M Hughes, Patrycja Skut, Meegan Howlett, Bree Foley, Joyce Oommen, Julia E Wells, Bo He, Sajla Singh, Grace-Alyssa Chua, Jette Ford, Charles G Mullighan, Rishi S Kotecha, Ursula R Kees
The microenvironments of leukemia and cancer are critical for multiple stages of malignancies, and they are an attractive therapeutic target. While skeletal abnormalities are commonly seen in children with acute lymphoblastic leukemia (ALL) prior to initiating osteotoxic therapy, little is known about the alterations to the bone marrow microenvironment during leukemogenesis. Therefore, in this study, we focused on the development of precursor-B cell ALL (pre-B ALL) in an immunocompetent BCR-ABL1+ model. Here we show that hematopoiesis was perturbed, B lymphopoiesis was impaired, collagen production was reduced, and the number of osteoblastic cells was decreased in the bone marrow microenvironment...
May 8, 2018: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/29725010/a-retinoic-acid-dependent-stroma-leukemia-crosstalk-promotes-chronic-lymphocytic-leukemia-progression
#10
Diego Farinello, Monika Wozińska, Elisa Lenti, Luca Genovese, Silvia Bianchessi, Edoardo Migliori, Nicolò Sacchetti, Alessia di Lillo, Maria Teresa Sabrina Bertilaccio, Claudia de Lalla, Roberta Valsecchi, Sabrina Bascones Gleave, David Lligé, Cristina Scielzo, Laura Mauri, Maria Grazia Ciampa, Lydia Scarfò, Rosa Bernardi, Dejan Lazarevic, Blanca Gonzalez-Farre, Lucia Bongiovanni, Elias Campo, Andrea Cerutti, Maurilio Ponzoni, Linda Pattini, Federico Caligaris-Cappio, Paolo Ghia, Andrea Brendolan
In chronic lymphocytic leukemia (CLL), the non-hematopoietic stromal microenvironment plays a critical role in promoting tumor cell recruitment, activation, survival, and expansion. However, the nature of the stromal cells and molecular pathways involved remain largely unknown. Here, we demonstrate that leukemic B lymphocytes induce the activation of retinoid acid synthesis and signaling in the microenvironment. Inhibition of RA-signaling in stromal cells causes deregulation of genes associated with adhesion, tissue organization and chemokine secretion including the B-cell chemokine CXCL13...
May 3, 2018: Nature Communications
https://www.readbyqxmd.com/read/29705535/associations-of-myeloid-hematological-diseases-of-the-elderly-with-osteoporosis-a-longitudinal-analysis-of-routine-health-care-data
#11
Thomas Datzmann, Freya Trautmann, Falko Tesch, Anna Mies, Lorenz C Hofbauer, Uwe Platzbecker, Jochen Schmitt
BACKGROUND: Myelodysplastic Syndromes (MDS) and Acute Myeloid Leukemia (AML) are hematological stem cell diseases mainly of the elderly. Studies indicate a close relationship between bone metabolism and hematopoietic stem cells within the osteo-hematopoietic niche. However, it remains unclear how the disturbed interaction within the osteo-hematopoietic niche affects bone homeostasis in MDS and AML patients. METHODS: We utilized data of a large German statutory health insurance of approximately 2 million persons living in the German federal state of Saxony...
April 21, 2018: Leukemia Research
https://www.readbyqxmd.com/read/29698131/exposure-of-the-bone-marrow-microenvironment-to-simulated-solar-and-galactic-cosmic-radiation-induces-biological-bystander-effects-on-human-hematopoiesis
#12
Graça Almeida-Porada, Christopher Rodman, Bradford Kuhlman, Egil Brudvik, John Moon, Sunil George, Peter Guida, Satria P Sajuthi, Carl D Langefeld, Stephen J Walker, Paul F Wilson, Christopher D Porada
The stem cell compartment of the hematopoietic system constitutes one of the most radiosensitive tissues of the body and leukemias represent one of the most frequent radiogenic cancers with short latency periods. As such, leukemias may pose a particular threat to astronauts during prolonged space missions. Control of hematopoiesis is tightly governed by a specialized bone marrow (BM) microenvironment/niche. As such, any environmental insult that damages cells of this niche would be expected to produce pronounced effects on the types and functionality of hematopoietic/immune cells generated...
April 26, 2018: Stem Cells and Development
https://www.readbyqxmd.com/read/29682980/aging-and-senescence-associated-changes-of-mesenchymal-stromal-cells-in-myelodysplastic-syndromes
#13
Domenico Mattiucci, Giulia Maurizi, Pietro Leoni, Antonella Poloni
Hematopoietic stem and progenitor cells reside within the bone marrow (BM) microenvironment. By a well-balanced interplay between self-renewal and differentiation, they ensure a lifelong supply of mature blood cells. Physiologically, multiple different cell types contribute to the regulation of stem and progenitor cells in the BM microenvironment by cell-extrinsic and cell-intrinsic mechanisms. During the last decades, mesenchymal stromal cells (MSCs) have been identified as one of the main cellular components of the BM microenvironment holding an indispensable role for normal hematopoiesis...
January 1, 2018: Cell Transplantation
https://www.readbyqxmd.com/read/29666114/chronic-lymphocytic-leukemia-and-mantle-cell-lymphoma-crossroads-of-genetic-and-microenvironment-interactions
#14
Xose S Puente, Pedro Jares, Elias Campo
Chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL) are two well defined entities that diverge in their basic pathogenic mechanisms and clinical evolution but they share epidemiological characteristics, cells of origin, molecular alterations, and clinical features that differ from other lymphoid neoplasms. CLL and MCL are classically considered indolent and aggressive neoplasms, respectively. However, the clinical evolution of both tumors is very heterogeneous, with subsets of patients having a stable disease for long time whereas others require immediate intervention...
April 17, 2018: Blood
https://www.readbyqxmd.com/read/29655803/role-of-msc-derived-galectin-3-in-the-aml-microenvironment
#15
Peter P Ruvolo, Vivian R Ruvolo, Jared K Burks, YiHua Qiu, Rui-Yu Wang, Elizabeth J Shpall, Leonardo Mirandola, Numsen Hail, Zhihong Zeng, Teresa McQueen, Naval Daver, Sean M Post, Maurizio Chiriva-Internati, Steven M Kornblau, Michael Andreeff
In acute myeloid leukemia (AML), high Galectin 3 (LGALS3) expression is associated with poor prognosis. The role of LGALS3 derived from mesenchymal stromal cells (MSC) in the AML microenvironment is unclear; however, we have recently found high LGALS3 expression in MSC derived from AML patients is associated with relapse. In this study, we used reverse phase protein analysis (RPPA) to correlate LGALS3 expression in AML MSC with 119 other proteins including variants of these proteins such as phosphorylated forms or cleaved forms to identify biologically relevant pathways...
April 12, 2018: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/29617289/a-developed-nk-92mi-cell-line-with-siglec-7-neg-phenotype-exhibits-high-and-sustainable-cytotoxicity-against-leukemia-cells
#16
Chin-Han Huang, Yi-Jen Liao, Ting-Hsi Fan, Tzeon-Jye Chiou, Yen-Hsi Lin, Yuh-Ching Twu
Altered sialic acid processing that leads to upregulation of cell surface sialylation is recognized as a key change in malignant tissue glycosylation. This cancer-associated hypersialylation directly impacts the signaling interactions between tumor cells and their surrounding microenvironment, especially the interactions mediated by immune cell surface sialic acid-binding immunoglobulin-like lectins (Siglecs) to relay inhibitory signals for cytotoxicity. First, we obtained a Siglec-7neg NK-92MI cell line, NK-92MI-S7N, by separating a group of Siglec-7neg cell population from an eight-month-long-term NK-92MI in vitro culture by fluorescence-activated cell sorting (FACS)...
April 4, 2018: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29605874/the-hematopoietic-stem-cell-diet
#17
REVIEW
Adam C Wilkinson, Satoshi Yamazaki
Hematopoietic stem cells (HSCs) are responsible for sustaining life-long blood formation or hematopoiesis and are also used clinically in a form of bone marrow transplantation, a curative cellular therapy for a range of hematological diseases. HSCs are maintained throughout adult life by a complex biological niche or microenvironment, which is thought to be composed of a range of cellular, molecular, and metabolic components. The metabolic components of the HSC niche have become of increasing interest over the past few years...
June 2018: International Journal of Hematology
https://www.readbyqxmd.com/read/29587428/nf-%C3%AE%C2%BAb-activation-in-lymphoid-malignancies-genetics-signaling-and-targeted-therapy
#18
REVIEW
Paula Grondona, Philip Bucher, Klaus Schulze-Osthoff, Stephan Hailfinger, Anja Schmitt
The NF-κB transcription factor family plays a crucial role in lymphocyte proliferation and survival. Consequently, aberrant NF-κB activation has been described in a variety of lymphoid malignancies, including diffuse large B-cell lymphoma, Hodgkin lymphoma, and adult T-cell leukemia. Several factors, such as persistent infections (e.g., with Helicobacter pylori ), the pro-inflammatory microenvironment of the cancer, self-reactive immune receptors as well as genetic lesions altering the function of key signaling effectors, contribute to constitutive NF-κB activity in these malignancies...
March 26, 2018: Biomedicines
https://www.readbyqxmd.com/read/29580262/treatment-of-b-cell-precursor-acute-lymphoblastic-leukemia-with-the-galectin-1-inhibitor-ptx008
#19
Helicia Paz, Eun Ji Joo, Chih-Hsing Chou, Fei Fei, Kevin H Mayo, Hisham Abdel-Azim, Haike Ghazarian, John Groffen, Nora Heisterkamp
BACKGROUND: Drug resistance of B-cell precursor acute lymphoblastic leukemia (BP-ALL) cells is conferred by both intrinsic and extrinsic factors, which could be targeted to promote chemo-sensitization. Our previous studies showed that Galectin-3, a lectin that clusters galactose-modified glycoproteins and that has both an intracellular and extracellular location, protects different subtypes of BP-ALL cells against chemotherapy. Galectin-1 is related to Galectin-3 and its expression was previously reported to be restricted to the MLL subtype of BP-ALL...
March 27, 2018: Journal of Experimental & Clinical Cancer Research: CR
https://www.readbyqxmd.com/read/29559471/co-targeting-bcl-2-and-pi3k-induces-bax-dependent-mitochondrial-apoptosis-in-aml-cells
#20
Mohamed Rahmani, Jewel Nkwocha, Elisa Hawkins, Xinyan Pei, Rebecca E Parker, Maciej Kmieciak, Joel D Leverson, Deepak Sampath, Andrea Ferreira-Gonzalez, Steven Grant
Inhibitors targeting BCL-2 apoptotic proteins have significant potential for the treatment of acute myeloid leukemia (AML); however, complete responses are observed in only 20% of patients suggesting targeting BCL-2 alone is insufficient to yield durable responses. Here we assessed the efficacy of co-administration of the PI3K/mTOR inhibitor GDC-0980 or the p110β-sparing PI3K inhibitor taselisib with the selective BCL-2 antagonist venetoclax in AML cells. Tetracycline-inducible downregulation of BCL-2 significantly sensitized MV4-11 and MOLM-13 AML cells to PI3K inhibition...
March 20, 2018: Cancer Research
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