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leukemia MicroEnvironment

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https://www.readbyqxmd.com/read/29342200/inhibiting-tgf-beta-signaling-preserves-the-function-of-highly-activated-in-vitro-expanded-natural-killer-cells-in-aml-and-colon-cancer-models
#1
Folashade Otegbeye, Evelyn Ojo, Stephen Moreton, Nathan Mackowski, Dean A Lee, Marcos de Lima, David N Wald
Natural killer cells harnessed from healthy individuals can be expanded ex vivo using various platforms to produce large doses for adoptive transfer into cancer patients. During such expansion, NK cells are increasingly activated and more efficient at killing cancer cells. Adoptive transfer however introduces these activated cells into a highly immunosuppressive tumor microenvironment mediated in part by excessive transforming growth factor beta (TGF-beta) from both cancer cells and their surrounding stroma...
2018: PloS One
https://www.readbyqxmd.com/read/29326123/tnf-receptor-signaling-is-a-driver-of-chronic-lymphocytic-leukemia-that-can-be-therapeutically-targeted-by-the-flavonoid-wogonin
#2
Claudia Dürr, Bola S Hanna, Angela Schulz, Fabienne Lucas, Manuela Zucknick, Axel Benner, Andrew Clear, Sibylle Ohl, Selcen Öztürk, Thorsten Zenz, Stephan Stilgenbauer, Min Li-Weber, Peter H Krammer, John G Gribben, Peter Lichter, Martina Seiffert
Chronic lymphocytic leukemia is a malignancy of mature B cells that strongly depend on microenvironmental factors and their deprivation has been identified as promising treatment approach for this incurable disease. Cytokine array screening of 247 chronic lymphocytic leukemia serum samples revealed elevated levels of TNF receptor-1 which were associated with poor clinical outcome. We detected a microenvironment-induced expression of TNF receptor-1 in chronic lymphocytic leukemia cells in vitro and aberrantly high expression of this receptor in proliferation centers of patients' lymph nodes...
January 11, 2018: Haematologica
https://www.readbyqxmd.com/read/29317997/experience-with-ibrutinib-for-first-line-use-in-patients-with-chronic-lymphocytic-leukemia
#3
REVIEW
Gilad Itchaki, Jennifer R Brown
Ibrutinib is the first in-class, orally administered, Bruton's tyrosine kinase (BTK) inhibitor that abrogates the critical signaling downstream of the B-cell receptor (BCR). This signaling is required for B-cell survival, proliferation and interaction with the microenvironment. Ibrutinib proved active in preclinical models of lymphoproliferative diseases and achieved impressive response rates in heavily pretreated relapsed and refractory (R/R) patients with chronic lymphocytic leukemia (CLL). Ibrutinib prolonged survival compared to standard therapy and mitigated the effect of most poor prognostic factors in CLL, thus becoming the main therapeutic option in high-risk populations...
January 2018: Therapeutic Advances in Hematology
https://www.readbyqxmd.com/read/29306107/leukemia-cells-impair-normal-hematopoiesis-and-induce-functionally-loss-of-hematopoietic-stem-cells-through-immune-cells-and-inflammation
#4
Ping Cui, Yuhua Zhang, Maoxiang Cui, Zhihong Li, Guang Ma, Rufeng Wang, Ning Wang, Shujuan Huang, Jie Gao
Bone marrow (BM) failure is often seen in leukemia patients, indicating an abnormal hematopoietic process. However, hematopoiesis in leukemic milieus is largely unknown. In the present study, we utilized one of the most frequent leukemogenic translocations MLL-AF9 to induce leukemia and investigated the hematopoiesis and the activity of hematopoietic stem and progenitor cells (HSPCs) in a leukemic milieu. We found that the phenotypes of the non-leukemic population in leukemic BM were drastically different than normal BM, including blockage of differentiation and a drastically reduced Lin-/Sca+/c-kit+ (LSK) population that contains all HSPCs in leukemic BM...
January 2, 2018: Leukemia Research
https://www.readbyqxmd.com/read/29304342/chewing-through-roots-how-leukemia-invades-and-disrupts-the-bone-marrow-microenvironment
#5
Owen J Tamplin
The bone marrow (BM) niche is a complex microenvironment that supports healthy hematopoietic stem cells (HSCs) throughout life. In this issue of Cell Stem Cell, Duarte et al. (2018) reveal the spatio-temporal progress of leukemic cells as they invade and occupy the niche, ultimately outcompeting native HSCs.
January 4, 2018: Cell Stem Cell
https://www.readbyqxmd.com/read/29299123/inhibition-of-sdf-1-induced-migration-of-oncogene-driven-myeloid-leukemia-by-the-l-rna-aptamer-spiegelmer-nox-a12-and-potentiation-of-tyrosine-kinase-inhibition
#6
Ellen L Weisberg, Martin Sattler, Abdel Kareem Azab, Dirk Eulberg, Anna Kruschinski, Paul W Manley, Richard Stone, James D Griffin
Resistance to targeted tyrosine kinase inhibitors (TKI) remains a challenge for the treatment of myeloid leukemias. Following treatment with TKIs, the bone marrow microenvironment has been found to harbor a small pool of surviving leukemic CD34+ progenitor cells. The long-term survival of these leukemic cells has been attributed, at least in part, to the protective effects of bone marrow stroma. We found that the NOX-A12 'Spiegelmer', an L-enantiomeric RNA oligonucleotide that inhibits SDF-1α, showed in vitro and in vivo activity against BCR-ABL- and FLT3-ITD-dependent leukemia cells...
December 15, 2017: Oncotarget
https://www.readbyqxmd.com/read/29297942/expression-pattern-of-immunosurveillance-related-antigen-in-adult-t-cell-leukemia-lymphoma
#7
Naoko Asano, Hiroaki Miyoshi, Takeharu Kato, Joji Shimono, Noriaki Yoshida, Daisuke Kurita, Yuya Sasaki, Keisuke Kawamoto, Koichi Ohshima, Masao Seto
AIMS: Adult T-cell leukemia/lymphoma (ATLL) is an aggressive malignancy with a poor prognosis. Human leukocyte antigen (HLA) and β2M serve as key molecules in tumor immunity, and their expression is frequently reduced in tumor cells. Programmed cell death (PD)-1/PD-ligand1 (PD-L1) interactions play a role in escape of tumor cells from T-cell immunity. Therefore, this study aimed to determine the clinicopathological relevance of HLA and β2M expressions in ATLL cells and PD-L1 expression in lymphoma or stromal cells and predict the overall survival of patients with ATLL...
January 3, 2018: Histopathology
https://www.readbyqxmd.com/read/29296780/interleukin-6-levels-predict-event-free-survival-in-pediatric-aml-and-suggest-a-mechanism-of-chemotherapy-resistance
#8
Alexandra M Stevens, Jennifer M Miller, Jaime O Munoz, Amos S Gaikwad, Michele S Redell
The tumor microenvironment can protect cancer cells from conventional anticancer therapies. Thus, targeting these protective mechanisms could eradicate therapy-resistant cancer cells and improve outcomes. Interleukin-6 (IL-6) provides extrinsic protection for several solid tumors and multiple myeloma. In pediatric acute myeloid leukemia (AML), IL-6-induced STAT3 signaling frequently becomes stronger at relapse, and increases in IL-6-induced STAT3 activity are associated with inferior survival after relapse...
August 8, 2017: Blood Advances
https://www.readbyqxmd.com/read/29296749/high-cd123-levels-enhance-proliferation-in-response-to-il-3-but-reduce-chemotaxis-by-downregulating-cxcr4-expression
#9
Nicole L Wittwer, Gabriela Brumatti, Ceilidh Marchant, Jarrod J Sandow, Melanie K Pudney, Mara Dottore, Richard J D'Andrea, Angel F Lopez, Paul G Ekert, Hayley S Ramshaw
High expression of the α chain of the interleukin-3 receptor (IL-3Rα; CD123) is a hallmark of acute myeloid leukemia (AML) leukemic stem cells (LSCs). Elevated CD123 expression is part of the diagnostic immunophenotyping of myeloid leukemia, and higher expression is associated with poor prognosis. However, the biological basis of the poorer prognosis is unclear, and may include heightened IL-3 signaling and non-cell autonomous interactions with the bone marrow (BM) microenvironment. We used TF-1 cells expressing different levels of CD123 and found elevated CD123 levels amplified the proliferative response to exogenous IL-3 and maintained viability in reducing IL-3 concentrations...
June 27, 2017: Blood Advances
https://www.readbyqxmd.com/read/29290814/dual-targeting-of-acute-leukemia-and-supporting-niche-by-cxcr4-directed-theranostics
#10
Stefan Habringer, Constantin Lapa, Peter Herhaus, Margret Schottelius, Rouzanna Istvanffy, Katja Steiger, Julia Slotta-Huspenina, Andreas Schirbel, Heribert Hänscheid, Stefan Kircher, Andreas K Buck, Katharina Götze, Binje Vick, Irmela Jeremias, Markus Schwaiger, Christian Peschel, Robert Oostendorp, Hans-Jürgen Wester, Götz-Ulrich Grigoleit, Ulrich Keller
C-X-C chemokine receptor 4 (CXCR4) is a transmembrane receptor with pivotal roles in cell homing and hematopoiesis. CXCR4 is also involved in survival, proliferation and dissemination of cancer, including acute lymphoblastic and myeloid leukemia (ALL, AML). Relapsed/refractory ALL and AML are frequently resistant to conventional therapy and novel highly active strategies are urgently needed to overcome resistance. Methods: We used patient-derived (PDX) and cell line-based xenograft mouse models of ALL and AML to evaluate the efficacy and toxicity of a CXCR4-targeted endoradiotherapy (ERT) theranostic approach...
2018: Theranostics
https://www.readbyqxmd.com/read/29245929/harnessing-the-heart-s-resistance-to-malignant-tumors-cardiac-derived-extracellular-vesicles-decrease-fibrosarcoma-growth-and-leukemia-related-mortality-in-rodents
#11
Lilian Grigorian-Shamagian, Soraya Fereydooni, Weixin Liu, Antonio Echavez, Eduardo Marbán
The heart is known for its resistance to cancer. Although different conjectures have been proposed to explain this phenomenon, none has been tested. We propose that the heart microenvironment may exert anti-cancer properties. So, our objective was to test the anti-oncogenic potential of cardiac-derived extracellular vesicles (EVs). For that EVs secreted by cardiosphere-derived cells (CDCs, heart progenitor cells) were tested in vitro on fibrosarcoma HT1080. In vivo models comprised the xenograft HT1080 fibrosarcoma in athymic mice (n=35), and spontaneous acute lymphocyte leukemia in old rats (n=44)...
November 21, 2017: Oncotarget
https://www.readbyqxmd.com/read/29235199/adaptation-of-the-bone-marrow-stroma-in-hematopoietic-malignancies-current-concepts-and-models
#12
REVIEW
Ben Doron, Mithila Handu, Peter Kurre
The bone marrow stroma maintains hematopoiesis and coordinately regulates regenerative responses through dynamic interactions with hematopoietic stem and progenitor cells. Recent studies indicate that stromal components in the bone marrow of leukemia patients undergo a process of successive adaptation that in turn exerts dramatic effects on the hematopoietic stem cell compartment and promotes leukemic drug resistance. Functional changes in discrete marrow stromal populations can therefore be considered an aspect of leukemia biogenesis in that they create an aberrant, self-reinforcing microenvironment...
December 13, 2017: Stem Cells
https://www.readbyqxmd.com/read/29235095/immune-cells-regulate-vegf-signaling-via-release-of-vegf-and-antagonistic-soluble-vegf-receptor-1
#13
Timm Hoeres, Martin Wilhelm, Manfred Smetak, Elisabeth Holzmann, Gundula Schulze-Tanzil, Josef Birkmann
Vascular endothelial growth factor (VEGF) is an important regulator of physiological and pathological angiogenesis. Beside malignant and stromal cells, local immune cells shape VEGF signaling in the tumor microenvironment. Aminobisphosphonates like zoledronic acid (Zol) are drugs known to inhibit osteoclast activity and bone resorption, but also have immunomodulatory and anti-tumor effects. These properties have previously been linked to the downregulation of VEGF and interference with tumor neo-angiogenesis...
December 13, 2017: Clinical and Experimental Immunology
https://www.readbyqxmd.com/read/29227304/cell-based-immunotherapy-in-gynecologic-malignancies
#14
Bruce Schaar, Venkatesh Krishnan, Supreeti Tallapragada, Oliver Dorigo
PURPOSE OF REVIEW: To provide an overview of the principles, safety and efficacy of adoptive cell therapy (ACT) in solid tumors particularly in gynecological cancers. RECENT FINDINGS: Efforts to target solid tumors using tumor-infiltrating lymphocytes and genetically modified T cells have shown promising efficacy in some patients. Two food and drug administration approvals for the treatment of leukemia are the first gene therapies available for cancer treatment in the United States...
December 7, 2017: Current Opinion in Obstetrics & Gynecology
https://www.readbyqxmd.com/read/29227282/hypoxia-induced-upregulation-of-bmx-kinase-mediates-therapeutic-resistance-in-acute-myeloid-leukemia
#15
Jolieke G van Oosterwijk, Daelynn R Buelow, Christina D Drenberg, Aksana Vasilyeva, Lie Li, Lei Shi, Yong-Dong Wang, David Finkelstein, Sheila A Shurtleff, Laura J Janke, Stanley Pounds, Jeffrey E Rubnitz, Hiroto Inaba, Navjotsingh Pabla, Sharyn D Baker
Oncogenic addiction to the Fms-like tyrosine kinase 3 (FLT3) is a hallmark of acute myeloid leukemia (AML) that harbors the FLT3-internal tandem duplication (FLT3-ITD) mutation. While FLT3 inhibitors like sorafenib show initial therapeutic efficacy, resistance rapidly develops through mechanisms that are incompletely understood. Here, we used RNA-Seq-based analysis of patient leukemic cells and found that upregulation of the Tec family kinase BMX occurs during sorafenib resistance. This upregulation was recapitulated in an in vivo murine FLT3-ITD-positive (FLT3-ITD+) model of sorafenib resistance...
December 11, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/29212250/histone-deacetylase-inhibitors-reduce-differentiating-osteoblast-mediated-protection-of-acute-myeloid-leukemia-cells-from-cytarabine
#16
Rosalie M Sterner, Kimberly N Kremer, Aref Al-Kali, Mrinal M Patnaik, Naseema Gangat, Mark R Litzow, Scott H Kaufmann, Jennifer J Westendorf, Andre J van Wijnen, Karen E Hedin
The bone marrow microenvironment protects acute myeloid leukemia (AML) cells during chemotherapy and is a major factor in relapse. Here, we examined which type(s) of bone marrow cells are responsible for the relapse of AML following treatment with cytarabine (Ara-C), and we identified a means to inhibit this protection. To determine the protective cell type(s), AML cells were treated with Ara-C, and AML cell survival in the presence or absence of osteoblast lineage cells was assessed. Cultured AML cells and patient bone marrow isolates were each significantly protected from Ara-C-induced apoptosis by co-culture with differentiating osteoblasts...
November 7, 2017: Oncotarget
https://www.readbyqxmd.com/read/29211600/understanding-the-bone-marrow-microenvironment-in-hematologic-malignancies-a-focus-on-chemokine-integrin-and-extracellular-vesicle-signaling
#17
Edward Allan Racela Sison, Peter Kurre, Yong-Mi Kim
Signaling between leukemia cells and nonhematopoietic cells in the bone marrow microenvironment contributes to leukemia cell growth and survival. This complicated extrinsic mechanism of chemotherapy resistance relies on a number of pathways and factors, some of which have yet to be determined. Research on cell-cell crosstalk the bone marrow microenvironment in acute leukemia was presented at the 2016 annual Therapeutic Advances in Childhood Leukemia (TACL) investigator meeting. This review summarizes the mini-symposium proceedings and focuses on chemokine signaling via the cell surface receptor CXCR4, adhesion molecule signaling via integrin α4, and crosstalk between leukemia cells and the bone marrow microenvironment that is mediated through extracellular vesicles...
December 6, 2017: Pediatric Hematology and Oncology
https://www.readbyqxmd.com/read/29209651/pml-degradation-fosters-an-immunosuppressive-and-pro-metastatic-tumor-microenvironment
#18
Ya-Ting Wang, Ruey-Hwa Chen
The tumor suppressive functions of promyelocytic leukemia (PML) have been attributed mainly to its inhibition of various malignant properties of tumor cells. Our recent work identifies a PML ubiquitination and degradation pathway, which regulates both cell and non-cell components of the tumor microenvironment, thereby potentiating immune evasion and metastasis.
2017: Molecular & Cellular Oncology
https://www.readbyqxmd.com/read/29204827/leukemia-stem-cells-microenvironment
#19
Yoko Tabe, Marina Konopleva
The dynamic interactions between leukemic cells and bone marrow (BM) cells in the leukemia BM microenvironment regulate leukemia stem cell (LSC) properties including localization, self-renewal, differentiation, and proliferation. Recent research of normal and leukemia BM microenvironments has revealed several key components of specific niches that provide a sanctuary where subpopulations of leukemia cells evade chemotherapy-induced death and acquire a drug-resistant phenotype, as well as the molecular pathways critical for microenvironment/leukemia interactions...
2017: Advances in Experimental Medicine and Biology
https://www.readbyqxmd.com/read/29198439/mitochondrial-transfer-in-the-leukemia-microenvironment
#20
REVIEW
Emmanuel Griessinger, Ruxanda Moschoi, Giulia Biondani, Jean-François Peyron
The bone marrow microenvironment (BMME) is a complex ecosystem that instructs and protects hematopoietic stem cells (HSCs) and their malignant counterparts, the leukemia-initiating cells (LICs). Within the physical and functional crosstalk that takes place between HSCs, LICs, and the BMME, the transfer of organelles and of mitochondria in particular is an important new intercellular communication mode in addition to adhesion molecules, tunneling nanotubes (TNTs), and the paracrine secretion of cytokines, (onco)metabolites, and extracellular vesicles (EVs)...
December 2017: Trends in Cancer
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