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leukemia MicroEnvironment

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https://www.readbyqxmd.com/read/28645939/combined-btk-and-pi3k%C3%AE-inhibition-with-acalabrutinib-and-acp-319-improves-survival-and-tumor-control-in-cll-mouse-model
#1
Carsten U Niemann, Helena I Mora-Jensen, Eman L Dadashian, Fanny Krantz, Todd Covey, Shih-Shih Chen, Nicholas- Chiorazzi, Raquel Izumi, Roger Ulrich, Brian J Lannutti, Adrian Wiestner, Sarah E M Herman
Purpose: Targeting the B-cell receptor (BCR) pathway with inhibitors of BTK and PI3K-delta is highly effective for the treatment of chronic lymphocytic leukemia (CLL). However, deep remissions are uncommon and drug resistance with single-agent therapy can occur. In vitro studies support the effectiveness of combing PI3K-delta and BTK inhibitors. <p>Experimental design: As CLL proliferation and survival depends on the microenvironment, we used murine models to assess the efficacy of the BTK inhibitor acalabrutinib combined with the PI3K-delta inhibitor ACP-319 in vivo We compared single-agent with combination therapy in TCL1-192 cell-injected mice, a model of aggressive CLL...
June 23, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28643044/pd-1-signaling-and-inhibition-in-aml-and-mds
#2
REVIEW
Faysal Haroun, Sade A Solola, Samah Nassereddine, Imad Tabbara
Acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) are clinically and molecularly heterogeneous clonal myeloid disorders with a poor prognosis especially in the relapsed refractory setting and in patients above the age of 60. While allogeneic hematopoietic stem cell transplantation (ASCT) is a potentially curative approach, high relapse, morbidity, and mortality rates necessitate the development of alternative therapies. Immune checkpoint inhibitors unmask tumoral immune tolerance and have demonstrated efficacy in the treatment of chemotherapy-resistant hematologic and solid malignancies...
June 22, 2017: Annals of Hematology
https://www.readbyqxmd.com/read/28641656/-effect-of-human-umbilical-cord-blood-derived-mesenchymal-stem-cells-on-the-proliferation-and-apoptosis-of-leukemic-cells-and-its-mechanism
#3
Ming-Ying Li, Chun-Ting Zhao, Bo-Li Cui, Shao-Ling Wu, Xiao-Dan Liu, Zhan Su, Tian-Lan Li, Ling-Jie Sun, Wei Wang, Xiao-Yan Ju
OBJECTIVE: To investigate the effects of human umbilical cord blood-derived mesenchymal stem cells(HUCMSC) on the leukemic cell line HL-60 and acute lymphoblastic leukemia cell line Jurkat as well as the role of CXCL12/CXCR4. METHODS: HL-60 cells and Jurkat cells were co-cultured with human umbilical cord blood mesenchymal stem cell (HUCMSC), and the model was treated with G-CSF, AMD3100 and their combination. The cell viability and cell cycle were measured by Cell Counting Kit-8 (CCK-8), the apoptosis and the cell-cycle analysis were assessed by flow cytometry with the Annexin V/PI double staining...
June 2017: Zhongguo Shi Yan Xue Ye Xue za Zhi
https://www.readbyqxmd.com/read/28637661/the-full-transforming-capacity-of-mll-af4-is-interlinked-with-lymphoid-lineage-commitment
#4
Shan Lin, Roger T Luo, Mahesh Shrestha, Michael J Thirman, James C Mulloy
Chromosome rearrangements involving mixed-lineage leukemia gene (MLL) create MLL-fusion proteins, which could drive both acute lymphoblastic and myeloid leukemia (ALL and AML). The lineage decision of MLL-fusion leukemia is influenced by the fusion partner and microenvironment. To investigate the interplay of fusion proteins and microenvironment in lineage choice, we transplanted human hematopoietic stem and progenitor cells (HSPC) expressing MLL-AF9 or MLL-Af4 into immunodeficient NSGS mice, which strongly promote myeloid development...
June 21, 2017: Blood
https://www.readbyqxmd.com/read/28619982/jak1-2-and-bcl2-inhibitors-synergize-to-counteract-bone-marrow-stromal-cell-induced-protection-of-aml
#5
Riikka Karjalainen, Tea Pemovska, Mihaela Popa, Minxia Liu, Komal K Javarappa, Muntasir M Majumder, Bhagwan Yadav, David Tamborero, Jing Tang, Dmitrii Bychkov, Mika Kontro, Alun Parsons, Minna Suvela, Mireia Mayoral Safont, Kimmo Porkka, Tero Aittokallio, Olli Kallioniemi, Emmet McCormack, Bjørn T Gjertsen, Krister Wennerberg, Jonathan Knowles, Caroline A Heckman
The bone marrow (BM) provides a protective microenvironment to support the survival of leukemic cells and influence their response to therapeutic agents. In acute myeloid leukemia (AML), the high rate of relapse may in part be due to the inability of current treatment to effectively overcome the protective influence of the BM niche. To better understand the impact of the BM microenvironment on drug responses in AML, we conducted a comprehensive evaluation of 304 inhibitors, including approved and investigational agents, comparing ex vivo responses of primary AML cells in BM stroma-derived and standard culture conditions...
June 15, 2017: Blood
https://www.readbyqxmd.com/read/28605336/tissue-inhibitor-of-metalloproteinase-1-timp-1-and-il-23-induced-by-polysaccharide-of-the-black-hoof-medicinal-mushroom-phellinus-linteus-agaricomycetes
#6
Soo Kyung Yoon, Soo Kyung Sung, Dong Hee Lee, Ha Won Kim
Matrix metalloproteinase-9 (MMP-9) has diverse roles associated with cell growth, migration, invasion, and angiogenesis. Tissue inhibitor of metalloproteinase-1 (TIMP-1) is known to inhibit MMP-9 by complexing with it at a 1:1 ratio. Suppressing MMP-9 activity through the overexpression of TIMP-1 allows for regulation of tumor growth and metastasis by blocking invasion and angiogenesis in the tumor microenvironment. We found that TIMP-1 and interleukin (IL)-23 are induced in RAW264.7 macrophage cells, a cell line established by Abelson leukemia virus transformation from the BALB/c mouse strain, in a dose-dependent pattern, at the transcriptional level by treatment with a crude polysaccharide fraction of Phellinus linteus (CPP) at a range of 10 to 1000 μg/mL...
2017: International Journal of Medicinal Mushrooms
https://www.readbyqxmd.com/read/28604752/tumor-cell-derived-lactate-induces-taz-dependent-upregulation-of-pd-l1-through-gpr81-in-human-lung-cancer-cells
#7
J Feng, H Yang, Y Zhang, H Wei, Z Zhu, B Zhu, M Yang, W Cao, L Wang, Z Wu
The clinical success of immunotherapy that inhibits the negative immune regulatory pathway programmed cell death protein 1/PD-1 ligand (PD-1/PD-L1) has initiated a new era in the treatment of metastatic cancer. PD-L1 expression is upregulated in many solid tumors including lung cancer and functions predominantly in lactate-enriched tumor microenvironments. Here, we provided evidence for PD-L1 induction in response to lactate stimulation in lung cancer cells. Lactate-induced PD-L1 induction was mediated by its receptor GPR81...
June 12, 2017: Oncogene
https://www.readbyqxmd.com/read/28603911/cd11c-expression-in-chronic-lymphocytic-leukemia-revisited-related-with-complications-and-survival
#8
E G Umit, M Baysal, Y Durmus, A M Demir
INTRODUCTION: Chronic lymphocytic leukemia (CLL) is a disorder of mature but dysfunctional monoclonal B cells. Microenvironment, antigenic stimulation and genetical mutations are demonstrated in etiopathogenesis. We aimed to evaluate the expression of CD11c in patients with CLL and its possible clinical significance. METHODS: Data of 259 patients with CLL between 2010 and 2016 in Trakya University Faculty of Medicine, including age at diagnosis, sex, whole blood count, stage, percentage of CLL cells in bone marrow, line of treatments, development of Richter's transformation and secondary tumors, autoimmune complications, IgG level, prognostic cytogenetic analysis, and length of survival were recorded from files...
June 12, 2017: International Journal of Laboratory Hematology
https://www.readbyqxmd.com/read/28596424/s100-a9-protein-in-exosomes-from-chronic-lymphocytic-leukemia-cells-promotes-nf-%C3%AE%C2%BAb-activity-during-disease-progression
#9
Daniel Prieto, Natalia Sotelo, Noé Seija, Sandra Sernbo, Cecilia Abreu, Rosario Durán, Magdalena Gil, Estefanía Sicco, Victoria Irigoin, Carolina Oliver, Ana Inés Landoni, Raúl Gabus, Guillermo Dighiero, Pablo Oppezzo
Chronic Lymphocytic Leukemia (CLL) is an incurable disease characterized by accumulation of clonal B lymphocytes, resulting from a complex balance between cell proliferation and apoptotic death. A continuous crosstalk between cancer cells and local/distant host environment is required for effective tumor growth. Among the main actors of this dynamic interplay between tumoral cells and their microenvironment are the nano-sized vesicles called exosomes. Emerging evidence indicates that secretion, composition, and functional capacity of the exosomes are altered as tumors progress to an aggressive phenotype...
June 8, 2017: Blood
https://www.readbyqxmd.com/read/28596280/extracellular-vesicles-of-bone-marrow-stromal-cells-rescue-chronic-lymphocytic-leukemia-b-cells-from-apoptosis-enhance-their-migration-and-induce-gene-expression-modifications
#10
Emerence Crompot, Michael Van Damme, Karlien Pieters, Marjorie Vermeersch, David Perez-Morga, Philippe Mineur, Marie Maerevoet, Nathalie Meuleman, Dominique Bron, Laurence Lagneaux, Basile Stamatopoulos
Interactions between chronic lymphocytic leukemia B-cells and the bone marrow microenvironment play a major function in the physiopathology of chronic lymphocytic leukemia. Extracellular vesicles, which are composed of exosomes and microparticles, play an important role in cell communication. However, little is known about their role in chronic lymphocytic leukemia/microenvironment interactions. In the present study, extracellular vesicles purified by ultracentrifugation from bone marrow mesenchymal stromal cell cultures were added to chronic lymphocytic leukemia B-cells...
June 8, 2017: Haematologica
https://www.readbyqxmd.com/read/28594662/patient-derived-tumor-xenografts-of-lymphoproliferative-disorders-are-they-surrogates-for-the-human-disease
#11
Marco Pizzi, Giorgio Inghirami
PURPOSE OF REVIEW: Patient-derived tumor xenografts (PDTXs) have emerged as powerful platforms in medical oncology. A plethora of PDTXs were generated to study solid cancers, but limited data are as yet available on hematological diseases. The aim of this review is to describe the state of art of lymphoma PDTXs, discussing future directions for the development of integrated/personalized cancer programs. RECENT FINDINGS: In the last decades, several PDTXs of lymphoproliferative disorders have been produced...
July 2017: Current Opinion in Hematology
https://www.readbyqxmd.com/read/28579851/transformation-of-follicular-lymphoma-to-a-high-grade-b-cell-lymphoma-with-myc-and-bcl2-translocations-and-overlapping-features-of-burkitt-lymphoma-and-acute-lymphoblastic-leukemia-a-case-report-and-literature-review
#12
Alina M Bischin, Russell Dorer, David M Aboulafia
Most commonly, histologic transformation (HT) from follicular lymphoma (FL) manifests as a diffuse large B-cell lymphoma, not otherwise specified (DLBCL, NOS). Less frequently, HT may result in a high-grade B-cell lymphoma (HGBL) with MYC and B-cell lymphoma protein 2 (BCL2) and/or BCL6 gene rearrangements, also known as "double-hit" or "triple-hit" lymphomas. In the 2016 revision of the World Health Organization (WHO) classification of lymphoid neoplasms, the category B-cell lymphoma, unclassifiable was eliminated due to its vague criteria and limiting diagnostic benefit...
2017: Clinical Medicine Insights. Blood Disorders
https://www.readbyqxmd.com/read/28577901/functional-studies-of-chronic-lymphocytic-leukemia-b-cells-expressing-%C3%AE-2-integrin-type-complement-receptors-cr3-and-cr4
#13
Barbara Uzonyi, Bernadett Mácsik-Valent, Szilvia Lukácsi, Richárd Kiss, Katalin Török, Mariann Kremlitzka, Zsuzsa Bajtay, Judit Demeter, Csaba Bödör, Anna Erdei
The expression and role of CR3 (CD11b/CD18) and CR4 (CD11c/CD18) in B cells are not yet explored in contrast to myeloid cells, where these β2-integrin type receptors are known to participate in various cellular functions, including phagocytosis, adherence and migration. Here we aimed to reveal the expression and role of CR3 and CR4 in human B cells. In B cells of healthy donors CR3 and CR4 are scarcely expressed. However, two patients with chronic lymphocytic leukemia (CLL) characterized by a peculiar immune-phenotype containing both CD5-positive and CD5-negative B cell populations made possible to study these molecules in distinct B cell subsets...
May 31, 2017: Immunology Letters
https://www.readbyqxmd.com/read/28561728/adoptive-t-cell-therapy-for-solid-tumors
#14
Oladapo Yeku, Xinghuo Li, Renier J Brentjens
Chimeric antigen receptor (CAR) T-cell therapy is an innovative form of immunotherapy wherein autologous T cells are genetically modified to express chimeric receptors encoding an antigen-specific single-chain variable fragment and various costimulatory molecules. Upon administration, these modified T cells traffic to, and recognize, cancer cells in an HLA-independent manner. CAR T-cell therapy has shown remarkable success in the treatment of CD-19-expressing B-cell acute lymphocytic leukemia. However, clinical gains to the same magnitude have not been reported in solid tumors...
2017: American Society of Clinical Oncology Educational Book
https://www.readbyqxmd.com/read/28560577/impact-of-inflammation-on-early-hematopoiesis-and-the-microenvironment
#15
REVIEW
Hitoshi Takizawa, Markus G Manz
Steady-state hematopoiesis is maintained by slowly dividing, self-renewing hematopoietic stem cells (HSCs) and their offspring, lineage-specified downstream progenitors in bone marrow (BM). It was previously thought that hematopoietic stresses such as infection or other inflammatory stimuli, are mostly recognized by terminally differentiated immune cells, i.e., front-line defenders at the local site of reaction, and that they produce factors that directly act on hematopoietic stem and progenitors (HSPCs) in BM and subsequently stimulate them to rebuild and sustain the hemato-lymphatic system...
July 2017: International Journal of Hematology
https://www.readbyqxmd.com/read/28556516/emt-and-met-related-processes-in-non-epithelial-tumors-importance-for-disease-progression-prognosis-and-therapeutic-opportunities
#16
REVIEW
Ulf D Kahlert, Justin V Joseph, Frank A E Kruyt
The epithelial-to mesenchymal (EMT) process is increasingly recognized for playing a key role in the progression, dissemination and therapy resistance of epithelial tumors. Accumulating evidence suggests that EMT inducers also lead to a gain in mesenchymal properties and promote malignancy of non-epithelial tumors. In this review we present and discuss current findings, illustrating the importance of EMT inducers in tumors originating from non-epithelial/ mesenchymal tissues, including: brain tumors, hematopoietic malignancies and sarcomas...
May 28, 2017: Molecular Oncology
https://www.readbyqxmd.com/read/28555079/muc1-inhibition-leads-to-decrease-in-pd-l1-levels-via-up-regulation-of-mirnas
#17
A R Pyzer, D Stroopinsky, J Rosenblatt, E Anastasiadou, H Rajabi, A Washington, A Tagde, J-H Chu, M Coll, A L Jiao, L T Tsai, D E Tenen, L Cole, K Palmer, A Ephraim, R K Leaf, M Nahas, A Apel, Mb-N Zommer, S Jain, M McMasters, L Mendez, J Arnason, B A Raby, F Slack, D Kufe, D Avigan
The PD-L1/PD-1 pathway is a critical component of the immunosuppressive tumor microenvironment in AML, but little is known about its regulation. We investigated the role of the MUC1 oncoprotein in modulating PD-L1 expression in AML. Silencing of MUC1 in AML cell lines suppressed PD-L1 expression without a decrease in PD-L1 mRNA levels, suggesting a post-transcriptional mechanism of regulation. We identified the microRNAs miR-200c and miR-34a as key regulators of PD-L1 expression in AML. Silencing of MUC1 in AML cells led to a marked increase in miR-200c and miR-34a levels, without changes in precursor microRNA, suggesting that MUC1 might regulate microRNA processing...
May 30, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28537457/inhibition-of-mtor-kinase-as-a-therapeutic-target-for-acute-myeloid-leukemia
#18
Yoko Tabe, Agostino Tafuri, Kazumasa Sekihara, Haeun Yang, Marina Konopleva
Acute myeloid leukemia (AML), the most common acute leukemia in adults, remains a therapeutic challenge. The phosphatidylinositol 3-kinase/AKT/mammalian target of rapamycin (PI3K/AKT/mTOR) signaling pathway is one of the key aberrant intracellular axes involved in AML. Areas covered: mTOR plays a critical role in sensing and responding to environmental determinants such as nutrient availability, stress, and growth factor concentrations; and in modulating key cellular functions such as proliferation, metabolism, and survival...
June 9, 2017: Expert Opinion on Therapeutic Targets
https://www.readbyqxmd.com/read/28526063/targeting-the-cxcr4-pathway-using-a-novel-anti-cxcr4-igg1-antibody-pf-06747143-in-chronic-lymphocytic-leukemia
#19
Manoj K Kashyap, Carlos I Amaya-Chanaga, Deepak Kumar, Brett Simmons, Nanni Huser, Yin Gu, Max Hallin, Kevin Lindquist, Rolla Yafawi, Michael Y Choi, Ale-Ali Amine, Laura Z Rassenti, Cathy Zhang, Shu-Hui Liu, Tod Smeal, Valeria R Fantin, Thomas J Kipps, Flavia Pernasetti, Januario E Castro
BACKGROUND: The CXCR4-CXCL12 axis plays an important role in the chronic lymphocytic leukemia (CLL)-microenvironment interaction. Overexpression of CXCR4 has been reported in different hematological malignancies including CLL. Binding of the pro-survival chemokine CXCL12 with its cognate receptor CXCR4 induces cell migration. CXCL12/CXCR4 signaling axis promotes cell survival and proliferation and may contribute to the tropism of leukemia cells towards lymphoid tissues and bone marrow...
May 19, 2017: Journal of Hematology & Oncology
https://www.readbyqxmd.com/read/28512625/using-murine-models-to-investigate-tumor-lymphoid-interactions-spotlight-on-chronic-lymphocytic-leukemia-and-angioimmunoblastic-t-cell-lymphoma
#20
REVIEW
Tyler A Herek, Christine E Cutucache
The role of the tumor microenvironment in leukemias and lymphomas is well established, yet the intricacies of how the malignant cells regulate and influence their non-malignant counterparts remain elusive. For example, chronic lymphocytic leukemia (CLL) is an expansion of malignant CD5(+)CD19(+) B cells, yet the non-malignant T cells play just as large of a role in disease presentation and etiology. Herein, we review the dynamic tumor cell to lymphoid repertoire interactions found in two non-Hodgkin's lymphoma subtypes: CLL and angioimmunoblastic T-cell lymphoma...
2017: Frontiers in Oncology
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