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leukemia MicroEnvironment

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https://www.readbyqxmd.com/read/28807161/phytochemical-modulation-of-apoptosis-and-autophagy-strategies-to-overcome-chemoresistance-in-leukemic-stem-cells-in-the-bone-marrow-microenvironment
#1
Helen C Owen, Sandra Appiah, Noor Hasan, Lucy Ghali, Ghada Elayat, Celia Bell
Advances in scientific research and targeted treatment regimes have improved survival rates for many cancers over the past few decades. However, for some types of leukemia, including acute lymphoblastic and acute myeloid leukemia, mortality rates have continued to rise, with chemoresistance in leukemic stem cells (LSCs) being a major contributing factor. Most cancer drug therapies act by inducing apoptosis in dividing cells but are ineffective in targeting quiescent LSCs. Niches in the bone marrow, known as leukemic niches, behave as "sanctuaries" where LSCs acquire drug resistance...
2017: International Review of Neurobiology
https://www.readbyqxmd.com/read/28802664/cytokines-and-soluble-hla-g-levels-in-bone-marrow-stroma-and-their-association-with-the-survival-rate-of-patients-exhibiting-childhood-t-cell-acute-lymphoblastic-leukemia
#2
Renata Dos Santos Almeida, Alessandra Maria de Luna Ramos, Carlos Feitosa Luna, Francisco Pedrosa, Eduardo Antônio Donadi, Norma Lucena-Silva
Leukemic cells can induce defective expression of soluble factors and change marrow cytokine profile, leading to aberrant cell signaling, cell fixation and cell proliferation in bone marrow. T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive disorder which accounts for 15% of pediatric ALL. To evaluate the contribution of immunological factors on T-ALL survival, we measured Th1, Th2, Th17 cytokines and soluble HLA-G (sHLA-G) levels in bone marrow from 32 Brazilian children at diagnosis (D0), after induction (D19) and after consolidation (D49) of the chemotherapy phase...
August 9, 2017: Cytokine
https://www.readbyqxmd.com/read/28775118/chronic-lymphocytic-leukemia-cells-are-active-participants-in-microenvironmental-cross-talk
#3
Martijn Ha van Attekum, Eric Eldering, Arnon P Kater
The importance of the tumor microenvironment in chronic lymphocytic leukemia is widely accepted. Yet, the understanding of the complex interplay between the various types of bystander cells and chronic lymphocytic leukemia cells is incomplete. Whereas numerous studies have indicated that bystander cells provide chronic lymphocytic leukemia-supportive functions, it has also become clear that chronic lymphocytic leukemia cells actively engage in the formation of a supportive tumor microenvironment by engaging in several cross-talk mechanisms...
August 3, 2017: Haematologica
https://www.readbyqxmd.com/read/28767666/mismatch-repair-deficient-hematopoietic-stem-cells-are-preleukemic-stem-cells
#4
Yulan Qing, Stanton L Gerson
Whereas transformation events in hematopoietic malignancies may occur at different developmental stages, the initial mutation originates in hematopoietic stem cells (HSCs), creating a preleukemic stem cell (PLSC). Subsequent mutations at either stem cell or progenitor cell levels transform the PLSC into lymphoma/leukemia initiating cells (LIC). Thymic lymphomas have been thought to develop from developing thymocytes. T cell progenitors are generated from HSCs in the bone marrow (BM), but maturation and proliferation of T cells as well as T-lymphomagenesis depends on both regulatory mechanisms and microenvironment within the thymus...
2017: PloS One
https://www.readbyqxmd.com/read/28758974/immunotherapeutic-concepts-to-target-acute-myeloid-leukemia-focusing-on-the-role-of-monoclonal-antibodies-hypomethylating-agents-and-the-leukemic-microenvironment
#5
REVIEW
Olumide Babajide Gbolahan, Amer M Zeidan, Maximilian Stahl, Mohammad Abu Zaid, Sherif Farag, Sophie Paczesny, Heiko Konig
Intensive chemotherapeutic protocols and allogeneic stem cell transplantation continue to represent the mainstay of acute myeloid leukemia (AML) treatment. Although this approach leads to remissions in the majority of patients, long-term disease control remains unsatisfactory as mirrored by overall survival rates of approximately 30%. The reason for this poor outcome is, in part, due to various toxicities associated with traditional AML therapy and the limited ability of most patients to tolerate such treatment...
July 31, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28753604/socs1-function-in-bcr-abl-mediated-myeloproliferative-disease-is-dependent-on-the-cytokine-environment
#6
Özlem Demirel, Olivier Balló, Pavankumar N G Reddy, Olesya Vakhrusheva, Jing Zhang, Astrid Eichler, Ramona Fernandes, Susanne Badura, Hubert Serve, Christian Brandts
Treatment with tyrosine kinase inhibitors is the standard of care for Philadelphia chromosome positive leukemias. However the eradication of leukemia initiating cells remains a challenge. Circumstantial evidence suggests that the cytokine microenvironment may play a role in BCR-ABL mediated leukemogenesis and in imatinib resistance. Gene expression analyses of BCR-ABL positive ALL long-term cultured cells revealed strong reduction of SOCS mRNA expression after imatinib treatment, thereby demonstrating a strong inhibition of cytokine signaling...
2017: PloS One
https://www.readbyqxmd.com/read/28708600/tumor-trp53-status-and-genotype-affect-the-bone-marrow-microenvironment-in-acute-myeloid-leukemia
#7
Rodrigo Jacamo, R Eric Davis, Xiaoyang Ling, Sonali Sonnylal, Wencai Ma, Min Zhang, Peter Ruvolo, Vivian Ruvolo, Rui-Yu Wang, Scott Lowe, Johannes Zuber, Steven M Kornblau, Marina Konopleva, Michael Andreeff
The genetic heterogeneity of acute myeloid leukemia (AML) and the variable responses of individual patients to therapy suggest that different AML genotypes may influence the bone marrow (BM) microenvironment in different ways. We performed gene expression profiling of bone marrow mesenchymal stromal cells (BM-MSC) isolated from normal C57BL/6 mice or mice inoculated with syngeneic murine leukemia cells carrying different human AML genotypes, developed in mice with Trp53 wild-type or nullgenetic backgrounds...
July 6, 2017: Oncotarget
https://www.readbyqxmd.com/read/28703283/wnt-signaling-pathways-in-chronic-lymphocytic-leukemia-and-b-cell-lymphomas
#8
REVIEW
Pavlína Janovská, Vítězslav Bryja
In this review, we discuss the intricate roles of the WNT signaling network in the development and progression of mature B cell-derived hematological malignancies, with a focus on chronic lymphocytic leukemia (CLL) and related B cell lymphomas. We review the current literature and highlight the differences between the β-catenin-dependent and independent branches of WNT signaling. Special attention is paid to the role of the non-canonical WNT/Planar cell polarity (PCP) pathway, mediated by the WNT5-ROR1-Dishevelled (DVL) signaling axis in CLL...
July 12, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/28691927/ubiquitination-of-tumor-suppressor-pml-regulates-prometastatic-and-immunosuppressive-tumor-microenvironment
#9
Ya-Ting Wang, Jocelyn Chen, Chou-Wei Chang, Jayu Jen, Tzu-Yu Huang, Chun-Ming Chen, Roger Shen, Suh-Yuen Liang, I-Cheng Cheng, Shuenn-Chen Yang, Wu-Wei Lai, Kuang-Hung Cheng, Tao-Shih Hsieh, Ming-Zong Lai, Hung-Chi Cheng, Yi-Ching Wang, Ruey-Hwa Chen
The tumor microenvironment plays an important role in tumor growth and metastasis. However, the mechanism by which tumor cells regulate the cell and non-cell constituents of surrounding stroma remains incompletely understood. Promyelocytic leukemia (PML) is a pleiotropic tumor suppressor, but its role in tumor microenvironment regulation is poorly characterized. PML is frequently downregulated in many cancer types, including lung cancer. Here, we identify a PML ubiquitination pathway that is mediated by WD repeat 4-containing cullin-RING ubiquitin ligase 4 (CRL4WDR4)...
August 1, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28680761/the-splenic-marginal-zone-shapes-the-phenotype-of-leukemia-b-cells-and-facilitates-their-niche-specific-retention-and-survival
#10
Vanessa Stache, Lydia Verlaat, Marcel Gätjen, Kristina Heinig, Jörg Westermann, Armin Rehm, Uta E Höpken
Microenvironmental regulation in lymphoid tissues is essential for the development of chronic lymphocytic leukemia. We identified cellular and molecular factors provided by the splenic marginal zone (MZ), which alter the migratory and adhesive behavior of leukemic cells. We used the Cxcr5(-/-)Eµ-Tcl1 leukemia mouse model, in which tumor cells are excluded from B cell follicles and instead accumulate within the MZ. Genes involved in MZ B cell development and genes encoding for adhesion molecules were upregulated in MZ-localized Cxcr5(-/-)Eµ-Tcl1 cells...
2017: Oncoimmunology
https://www.readbyqxmd.com/read/28679949/aml-induced-osteogenic-differentiation-in-mesenchymal-stromal-cells-supports-leukemia-growth
#11
V Lokesh Battula, Phuong M Le, Jeffrey C Sun, Khoa Nguyen, Bin Yuan, Ximin Zhou, Sonali Sonnylal, Teresa McQueen, Vivian Ruvolo, Keith A Michel, Xiaoyang Ling, Rodrigo Jacamo, Elizabeth Shpall, Zhiqiang Wang, Arvind Rao, Gheath Al-Atrash, Marina Konopleva, R Eric Davis, Melvyn A Harrington, Catherine W Cahill, Carlos Bueso-Ramos, Michael Andreeff
Genotypic and phenotypic alterations in the bone marrow (BM) microenvironment, in particular in osteoprogenitor cells, have been shown to support leukemogenesis. However, it is unclear how leukemia cells alter the BM microenvironment to create a hospitable niche. Here, we report that acute myeloid leukemia (AML) cells, but not normal CD34+ or CD33+ cells, induce osteogenic differentiation in mesenchymal stromal cells (MSCs). In addition, AML cells inhibited adipogenic differentiation of MSCs. Mechanistic studies identified that AML-derived BMPs activate Smad1/5 signaling to induce osteogenic differentiation in MSCs...
July 6, 2017: JCI Insight
https://www.readbyqxmd.com/read/28673395/mechanisms-of-resistance-to-flt3-inhibitors-and-the-role-of-the-bone-marrow-microenvironment
#12
REVIEW
Gabriel Ghiaur, Mark Levis
The presence of FLT3 mutations in acute myeloid leukemia (AML) carries a particularly poor prognosis, making the development of FLT3 inhibitors an imperative goal. The last decade has seen an abundance of clinical trials using these drugs alone or in combination with chemotherapy. This culminated with the recent approval by the US Food and Drug Administration of Midostaurin for the treatment of FLT3-mutated AML. Initial success has been followed by the emergence of clinical resistance. Although novel FLT3 inhibitors are being developed, studies into mechanisms of resistance raise hope of new strategies to prevent emergence of resistance and eliminate minimal residual disease...
August 2017: Hematology/oncology Clinics of North America
https://www.readbyqxmd.com/read/28659338/high-throughput-profiling-of-signaling-networks-identifies-mechanism-based-combination-therapy-to-eliminate-microenvironmental-resistance-in-acute-myeloid-leukemia
#13
Zhihong Zeng, Wenbin Liu, Twee Tsao, YiHua Qiu, Yang Zhao, Ismael Samudio, Dos D Sarbassov, Steven M Kornblau, Keith A Baggerly, Hagop M Kantarjian, Marina Konopleva, Michael Andreeff
The bone marrow microenvironment is known to provide a survival advantage to residual acute myeloid leukemia cells, possibly contributing to disease recurrence. The mechanisms by which stroma in the microenvironment regulates leukemia survival remain largely unknown. Using reverse phase-protein array technology, we profiled 53 key protein molecules in 11 signaling pathways in 20 primary acute myeloid leukemia samples and two cell lines, aiming to understand stroma-mediated signaling modulation in response to the targeted agents temsirolimus (MTOR), ABT737 (BCL2/BCL-XL), and Nutlin-3a (MDM2), and to identify the effective combination therapy targeting acute myeloid leukemia in the context of the leukemia microenvironment...
June 28, 2017: Haematologica
https://www.readbyqxmd.com/read/28654259/new-inhibitor-targeting-signal-transducer-and-activator-of-transcription-5-stat5-signaling-in-myeloid-leukemias
#14
Ludovic Juen, Marie Brachet-Botineau, Cécile Parmenon, Jérôme Bourgeais, Olivier Hérault, Fabrice Gouilleux, Marie-Claude Viaud-Massuard, Gildas Prié
Signal transducers and activators of transcription 5 (STAT5s) are crucial effectors of tyrosine kinase oncogenes in myeloid leukemias. Inhibition of STAT5 would contribute to reducing the survival of leukemic cells and also tackling their chemoresistance. In a first screening experiment, we identified hit 13 as able to inhibit STAT5 phosphorylation and leukemic cell growth. The synthesis of 18 analogues of 13 allowed us to identify one compound, 17f, as having the most potent antileukemic effect. 17f inhibited the growth of acute and chronic myeloid leukemia cells and the phosphorylation and transcriptional activity of STAT5...
July 27, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28652130/tal1-as-a-master-oncogenic-transcription-factor-in-t-cell-acute-lymphoblastic-leukemia
#15
REVIEW
Takaomi Sanda, Wei Zhong Leong
In hematopoietic cell development, the transcriptional program is strictly regulated in a lineage- and stage-specific manner that requires a number of transcription factors to work in a cascade or in a loop, in addition to interactions with nonhematopoietic cells in the microenvironment. Disruption of the transcriptional program alters the cellular state and may predispose cells to the acquisition of genetic abnormalities. Early studies have shown that proteins that promote cell differentiation often serve as tumor suppressors, whereas inhibitors of those proteins act as oncogenes in the context of acute leukemia...
June 24, 2017: Experimental Hematology
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
#16
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
#17
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...
September 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
#18
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
#19
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
#20
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 a result of the inability of current treatment to effectively overcome the protective influence of the BM niche. To better understand the effect 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...
August 10, 2017: Blood
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