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Stroma leukemia

Ping Chen, Weiwu Zhan, Bin Wang, Peidong You, Qing Jin, Diyu Hou, Xiaoting Wang, Ruolan You, Hong Zou, Yuanzhong Chen, Huifang Huang
Relapse of minimal residual disease (MRD) is a major problem after conventional chemotherapy in patients with acute myeloid leukemia (AML). The bone marrow stroma can protect AML cells from insults of chemotherapy, partly contributing to AML relapse. Arsenic trioxide (ATO) is the main component of arsenical traditional Chinese medicines and has been widely used for the treatment of hematologic malignancies particularly acute promyelocytic leukemia over the past three decades. ATO acts through a direct arsenic binding to cysteine residues in zinc fingers located in promyelocytic leukemia protein (PML), thus killing the leukemia stem cells (LSCs)...
February 11, 2019: Experimental Cell Research
Nathalie Javidi-Sharifi, Jacqueline Martinez, Isabel English, Sunil K Joshi, Renata Scopim-Ribiero, David K Edwards, Anupriya Agarwal, Claudia Lopez, Danielle Jorgens, Jeffrey W Tyner, Brian J Druker, Elie Traer
Protective signaling from the leukemia microenvironment leads to leukemia cell persistence, development of resistance, and disease relapse. Here, we demonstrate that fibroblast growth factor 2 (FGF2) from bone marrow stromal cells is secreted in exosomes, which are subsequently endocytosed by leukemia cells, and protect leukemia cells from tyrosine kinase inhibitors (TKIs). Expression of FGF2 and its receptor, FGFR1, are both increased in a subset of stromal cell lines and primary AML stroma; and increased FGF2/FGFR1 signaling is associated with increased exosome secretion...
February 5, 2019: ELife
Ga-Young Lee, Seon-Yeong Jeong, Hae-Ri Lee, Il-Hoan Oh
The bone marrow (BM) microenvironment serves as a stem cell niche regulating the in vivo cell fate of normal hematopoietic stem cells (HSC) as well as leukemia stem cells (LSCs). Accumulating studies have indicated that the regeneration of normal HSCs and the process of leukemogenesis change with advancing age. However, the role of microenvironmental factors in these age-related effects are unclear. Here, we compared the stem cell niche in neonatal and adult BM to investigate potential differences in their microenvironmental regulation of both normal and leukemic stem cells...
January 30, 2019: Scientific Reports
Vanessa Edna Sanchez, Cydney Nichols, Hye Na Kim, Eun Ji Gang, Yong-Mi Kim
Adhesion of acute lymphoblastic leukemia (ALL) cells to bone marrow stroma cells triggers intracellular signals regulating cell-adhesion-mediated drug resistance (CAM-DR). Stromal cell protection of ALL cells has been shown to require active AKT. In chronic lymphocytic leukemia (CLL), adhesion-mediated activation of the PI3K/AKT pathway is reported. A novel FDA-approved PI3Kδ inhibitor, CAL-101/idelalisib, leads to downregulation of p-AKT and increased apoptosis of CLL cells. Recently, two additional PI3K inhibitors have received FDA approval...
January 18, 2019: International Journal of Molecular Sciences
Belen Lopez-Millan, Diego Sanchéz-Martínez, Heleia Roca-Ho, Francisco Gutiérrez-Agüera, Oscar Molina, Rafael Diaz de la Guardia, Raúl Torres-Ruiz, Jose Luís Fuster, Paola Ballerini, Ute Suessbier, Cesar Nombela-Arrieta, Clara Bueno, Pablo Menéndez
B cell acute lymphoblastic leukemia (B-ALL) is the most common childhood cancer, with cure rates of ∼80%. MLL-rearranged (MLLr) B-ALL (MLLr-B-ALL) has, however, an unfavorable prognosis with common therapy refractoriness and early relapse, and therefore new therapeutic targets are needed for relapsed/refractory MLLr-B-ALL. MLLr leukemias are characterized by the specific expression of chondroitin sulfate proteoglycan-4, also known as neuron-glial antigen-2 (NG2). NG2 was recently shown involved in leukemia invasiveness and central nervous system infiltration in MLLr-B-ALL, and correlated with lower event-free survival (EFS)...
January 11, 2019: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Antonella Sola, Jessika Bertacchini, Daniele D'Avella, Laura Anselmi, Tullia Maraldi, Sandra Marmiroli, Massimo Messori
The need for new approaches to investigate ex vivo the causes and effects of tumor and to achieve improved cancer treatments and medical therapies is particularly urgent for malignant pathologies such as lymphomas and leukemias, whose tissue initiator cells interact with the stroma creating a three-dimensional (3D) protective environment that conventional mono- and bi-dimensional (2D) models are not able to simulate realistically. The solvent-casting particulate leaching (SCPL) technique, that is already a standard method to produce polymer-based scaffolds for bone tissue repair, is proposed here to fabricate innovative 3D porous structures to mimic the bone marrow niche in vitro...
March 2019: Materials Science & Engineering. C, Materials for Biological Applications
Shlomit Yehudai-Resheff, Shira Attias-Turgeman, Rawan Sabbah, Tal Gabay, Raneem Musallam, Anna Friedman-Dror, Tsila Zuckerman
Hematopoietic progenitors, residing in the bone marrow (BM) niche, are supported by mesenchymal stromal cells (MSCs). Cytogenetic and molecular aberrations in these progenitors lead to acute myeloid leukemia (AML). The BM-MSC role in leukemogenesis is not fully elucidated. In the current study, an ex-vivo system of patient's own stroma (POS), best mimicking the in-vivo BM niche, has been developed aiming to unravel interactions and crosstalk between MSCs and AML cells. POS derived from AML patients at diagnosis (Dx), relapse (Rx) and remission (Rm) was compared with healthy donor MSCs in terms of their morphology, growth pattern, support of leukemia cell viability and cytokine profile...
December 13, 2018: International Journal of Cancer. Journal International du Cancer
Marta Cuenca, Jordi Sintes, Árpád Lányi, Pablo Engel
CD84 (SLAMF5) is a member of the SLAM family of cell-surface immunoreceptors. Broadly expressed on most immune cell subsets, CD84 functions as a homophilic adhesion molecule, whose signaling can activate or inhibit leukocyte function depending on the cell type and its stage of activation or differentiation. CD84-mediated signaling regulates diverse immunological processes, including T cell cytokine secretion, natural killer cell cytotoxicity, monocyte activation, autophagy, cognate T:B interactions, and B cell tolerance at the germinal center checkpoint...
October 26, 2018: Clinical Immunology: the Official Journal of the Clinical Immunology Society
Genna M Luciani, Lihua Xie, David Dilworth, Anne Tierens, Yoni Moskovitz, Alex Murison, Magdalena M Szewczyk, Amanda Mitchell, Mathieu Lupien, Liran Shlush, John E Dick, Cheryl H Arrowsmith, Dalia Barsyte-Lovejoy, Mark D Minden
Acute myeloid leukemia (AML) is a complex, heterogeneous disease with variable outcomes following curative intent chemotherapy. AML with inv(3) is a genetic subgroup characterized by a very low response rate to current induction type chemotherapy and thus has among the worst long-term survivorship of the AMLs. Here, we describe OCI-AML-20, a new AML cell line with inv(3) and deletion of chromosome 7; the latter is a common co-occurrence in inv(3) AML. In OCI-AML-20, CD34 expression is maintained and required for repopulation in vitro and in vivo...
October 22, 2018: Experimental Hematology
Hima V Vangapandu, Varsha Gandhi
Extracellular flux assays are conducted using seahorse XF96 analyzer. They are used to calculate oxygen consumption rate which is to determine mitochondrial oxidative phosphorylation and extracellular acidification rate which is a measure of glycolysis. Collectively, these assays are used to assess the metabolic phenotype of a cell. Up to four drugs can be loaded and tested in the XF cartridges used in the assay and their effect on cells could be determined. While adherent cell lines are easy to use for this assay, suspension cultures or primary cells are difficult to use...
2019: Methods in Molecular Biology
J Rao, M Ruan, B H Yu, X Q Li, W T Yang, R H Shui
Objective: To investigate the clinicopathologic features and differential diagnosis of breast lymphoma in core needle biopsy. Methods: Seventy-two cases of breast lymphoma in core needle biopsy between 2011 and 2016 were extracted from the pathology database of Fudan University Shanghai Cancer Center. The clinicopathologic features were analyzed. The histological diagnosis of the tumors was based on the WHO classifications of tumors of hematopoietic and lymphoid tissues. Immunohistochemistry and molecular methods were performed to detect related antigens and genes...
October 8, 2018: Zhonghua Bing Li Xue za Zhi Chinese Journal of Pathology
Federica Portale, Giulia Cricrì, Silvia Bresolin, Monica Lupi, Stefania Gaspari, Daniela Silvestri, Barbara Russo, Noemi Marino, Paolo Ubezio, Fabio Pagni, Patrizia Vergani, Geertruy Te Kronnie, Maria Grazia Valsecchi, Franco Locatelli, Carmelo Rizzari, Andrea Biondi, Erica Dander, Giovanna D'Amico
B-cell precursor-Acute Lymphoblastic Leukemia modulates the bone marrow niche to become leukemia-supporting and chemoprotective by reprogramming the stromal microenvironment. New therapies targeting the leukemia/stroma interplay can be instrumental to improve disease outcome. We identified ActivinA, a TGF-β family member, with a well-described promoting role in several solid malignancies, as a new potentially targetable leukemia-favoring factor. ActivinA resulted overexpressed in the leukemic bone marrow and its production was strongly induced in mesenchymal stromal cells after culture with leukemic cells...
September 27, 2018: Haematologica
Paulina Podszywalow-Bartnicka, Agata Kominek, Magdalena Wolczyk, Marta D Kolba, Julian Swatler, Katarzyna Piwocka
The unique bone marrow microenvironment is created by stromal cells and such physical conditions as hypoxia. Both hypoxia and interactions with stromal cells have a significant impact on the biology of leukemia cells, changing their sensitivity to antileukemic therapies. Thus, it is crucial to introduce biological systems, which enable the investigation of leukemia-stroma cross-talk and verification of novel therapies effectiveness under such bone marrow niche-mimicking conditions. Here, we have established an experimental setup based on the hypoxic co-culture of stromal cells with different cell lines derived from various leukemia patients...
July 2018: Cytometry. Part A: the Journal of the International Society for Analytical Cytology
Belen Lopez-Millan, Rafael Diaz de la Guardia, Heleia Roca-Ho, Eduardo Anguita, Abul B M M K Islam, Damia Romero-Moya, Cristina Prieto, Francisco Gutierrez-Agüera, Jose Antonio Bejarano-Garcia, Jose Antonio Perez-Simon, Paula Costales, Montse Rovira, Pedro Marín, Silvia Menendez, Mar Iglesias, Jose Luis Fuster, Alvaro Urbano-Ispizua, Fernando Anjos-Afonso, Clara Bueno, Pablo Menendez
Treatment for acute myeloid leukemia (AML) remains suboptimal and many patients remain refractory or relapse upon standard chemotherapy based on nucleoside analogs plus anthracyclines. The crosstalk between AML cells and the BM stroma is a major mechanism underlying therapy resistance in AML. Lenalidomide and pomalidomide, a new generation immunomodulatory drugs (IMiDs), possess pleiotropic anti-leukemic properties including potent immune-modulating effects and are commonly used in hematological malignances associated with intrinsic dysfunctional BM such as myelodysplastic syndromes and multiple myeloma...
2018: Oncoimmunology
Lu Ding, Wan Zhang, Lili Yang, Helene Pelicano, Kaiwen Zhou, Ran Yin, Ruibin Huang, Junyi Zeng
Background: The bone marrow microenvironment constitutes a sanctuary for leukemia cells. Recent evidence indicates that environment-mediated drug resistance arises from a reciprocal influence between tumor cells and the surrounding stroma. The present study aimed to investigate the effect of chronic lymphocytic leukemia (CLL) cells on the metabolism of bone marrow stroma, to determine the role of this metabolic change in the stroma in vorinostat resistance of CLL cells, and thus to assess a novel strategy to target stroma and achieve the maximum therapeutic effect of vorinostat...
2018: OncoTargets and Therapy
Weihuan Wang, Gurnoor Majihail, Cui Lui, Lan Zhou
Osteoblasts are bone marrow endosteum-lining niche cells playing important roles in the regulation of hematopoietic stem cells by secreting factors and cell adhesion molecules. Characterization of primary osteoblasts has been achieved through culture of outgrowth of collagenase treated bone. Immunophenotyping and flow-based analysis of long bone osteoblasts offer a simplified and rapid approach to characterize osteoblasts. We describe a modified procedure of isolating mouse bone marrow osteoblastic cells based on cell surface immunophenotyping...
May 20, 2018: Bio-protocol
N B Paramonova, E A Kogan, A V Kolotovkina, O V Burmenskaya
OBJECTIVE: To study endometrial receptivity in infertile women with external genital endometriosis (EGE). SUBJECTS AND METHODS: Clinical, morphological, immunohistochemical, and molecular genetic examinations of endometrial aspiration pipelle biopsy specimens obtained on days 22-24 of the menstrual cycle from 94 infertile women with endometriosis: 50 women with Stage I-II EGE and 44 women with ovarian endometrioid cysts (OEC). A control group consisted of 54 women with tubal peritoneal factor of infertility (TPFI) and a successful attempt at IVF...
2018: Arkhiv Patologii
Leona Matsumoto, Yasushi Hirota, Tomoko Saito-Fujita, Norihiko Takeda, Tomoki Tanaka, Takehiro Hiraoka, Shun Akaeda, Hidetoshi Fujita, Ryoko Shimizu-Hirota, Shota Igaue, Mitsunori Matsuo, Hirofumi Haraguchi, Mayuko Saito-Kanatani, Tomoyuki Fujii, Yutaka Osuga
Although it has been reported that hypoxia inducible factor 2 α (Hif2a), a major transcriptional factor inducible by low oxygen tension, is expressed in the mouse uterus during embryo implantation, its role in pregnancy outcomes remains unclear. This study aimed to clarify functions of uterine HIF using transgenic mouse models. Mice with deletion of Hif2a in the whole uterus (Hif2a-uKO mice) showed infertility due to implantation failure. Supplementation with progesterone (P4) and leukemia inhibitory factor (LIF) restored decidual growth arrest and aberrant position of implantation sites in Hif2a-uKO mice, respectively, but did not rescue pregnancy failure...
July 2, 2018: Journal of Clinical Investigation
Kyle Crassini, Tahni Pyke, Yandong Shen, William S Stevenson, Richard I Christopherson, Stephen P Mulligan, Oliver Giles Best
The Raf-1 kinase inhibitory protein (RKIP) is an important regulatory element in multiple signaling pathways, including MAPK-ERK1/2. We investigated whether targeted disruption of RKIP is a therapeutic option for chronic lymphocytic leukemia (CLL). The RKIP inhibitor locostatin-induced apoptosis of CLL cells, irrespective of poor prognostic indications or treatment history. Locostatin down-regulated MAPK-ERK1/2 and AKT phosphorylation, decreased expression of the chemokine receptor CXCR4 (p = .04) and reduced the migratory capacity of CLL cells toward stroma-derived factor 1α (SDF-1α, p = ...
June 18, 2018: Leukemia & Lymphoma
Hima V Vangapandu, Brandon Alston, Joshua Morse, Mary L Ayres, William G Wierda, Michael J Keating, Joseph R Marszalek, Varsha Gandhi
Blood cells from patients with chronic lymphocytic leukemia (CLL) are replicationally quiescent but transcriptionally, translationally, and metabolically active. Recently, we demonstrated that oxidative phosphorylation (OxPhos) is a predominant pathway in CLL for energy production and is further augmented in the presence of the stromal microenvironment. Importantly, CLL cells from patients with poor prognostic markers showed increased OxPhos. From these data, we theorized that OxPhos can be targeted to treat CLL...
May 18, 2018: Oncotarget
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