scholarly journals Notch signaling in acute lymphoblastic leukemia: any role for stromal microenvironment?

Blood ◽  
2011 ◽  
Vol 118 (25) ◽  
pp. 6506-6514 ◽  
Author(s):  
Armel Hervé Nwabo Kamdje ◽  
Mauro Krampera
Keyword(s):  
Bone Marrow ◽  
Acute Lymphoblastic Leukemia ◽  
B Cell ◽  
Notch Signaling ◽  
Cell Survival ◽  
Stromal Cells ◽  
Bone Marrow Stromal Cells ◽  
Lymphoblastic Leukemia ◽  
Leukemia Cell ◽  
Marrow Stromal Cells

Abstract Notch signaling pathway regulates many different events of embryonic and adult development; among them, Notch plays an essential role in the onset of hematopoietic stem cells and influences multiple maturation steps of developing lymphoid and myeloid cells. Deregulation of Notch signaling determines several human disorders, including cancer. In the last decade it became evident that Notch signaling plays pivotal roles in the onset and development of T- and B-cell acute lymphoblastic leukemia by regulating the intracellular molecular pathways involved in leukemia cell survival and proliferation. On the other hand, bone marrow stromal cells are equally necessary for leukemia cell survival by preventing blast cell apoptosis and favoring their reciprocal interactions and cross-talk with bone marrow microenvironment. Quite surprisingly, the link between Notch signaling pathway and bone marrow stromal cells in acute lymphoblastic leukemia has been pointed out only recently. In fact, bone marrow stromal cells express Notch receptors and ligands, through which they can interact with and influence normal and leukemia T- and B-cell survival. Here, the data concerning the development of T- and B-cell acute lymphoblastic leukemia has been critically reviewed in light of the most recent findings on Notch signaling in stromal microenvironment.

scholarly journals Support of acute lymphoblastic leukemia cells by nonmalignant bone marrow stromal cells

2019 ◽  
Author(s):  
Sana Usmani ◽  
Urmila Sivagnanalingam ◽  
Olena Tkachenko ◽  
Leti Nunez ◽  
Jessica Shand ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Lymphoblastic Leukemia ◽  
Stromal Cells ◽  
Bone Marrow Stromal Cells ◽  
Lymphoblastic Leukemia ◽  
Marrow Stromal Cells ◽  
Leukemia Cells

Acute Lymphoblastic Leukemia Blast Cells Stimulate the Autocrine Production of CCL2 and IL-8 in Bone Marrow Stromal Cells

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2429-2429
Author(s):  
Jaira Ferreira de Vasconcellos ◽  
Nilson Ivo Tonin Zanchin ◽  
Angelo A. Cardoso ◽  
Silvia Regina Brandalise ◽  
José Andrés Yunes
Keyword(s):  
Bone Marrow ◽  
Acute Lymphoblastic Leukemia ◽  
Cell Survival ◽  
Stromal Cells ◽  
Neutralizing Antibodies ◽  
Positive Impact ◽  
Lymphoblastic Leukemia ◽  
Leukemia Cell ◽  
Pediatric All

Abstract The interactions of Acute Lymphoblastic Leukemia (ALL) blasts with bone marrow (BM) stromal cells have a positive impact on leukemia cell survival and resistance to chemotherapy. ALL stimulates BM stromal cells, which reciprocally promotes leukemia cell survival. To identify molecules critically involved in leukemia–microenvironment crosstalk, we performed gene expression profiling analyses of primary BM endothelial cells (BMEC) and BM mesenchymal stem cells (BMMSC) following stimulation by primary ALL cells. Leukemia stimulation of BM stromal cells upregulates the expression of several inflammatory chemokines, including CCL2 and IL-8/CXCL8. Secretion of these molecules was confirmed by ELISA assays of in vitro co-culture experiments and in BM plasma samples from pediatric ALL patients. Most primary ALL samples were found to express mRNA for CCR2 and CXCR1/CXCR2, which are the cognate receptors for CCL2 and IL-8, respectively. Primary ALL cells expressing at least one myeloid marker (CD13, CD15 or CD33) exhibited increased mRNA expression of CCR2 (p = 0.02). Leukemia cells from most patients express CCL2 and IL-8 chemokines (ELISA test) but at lower levels than that of BMEC and BMMSC. In vitro functional studies revealed that the proliferation, survival and migration of primary ALL cells co-cultured with BM stromal cells were not affected by addition of CCL2, IL-8 or of neutralizing antibodies to these chemokines. On the other hand, both chemokines were found to enhance BMEC and BMMSC survival in serum-free medium and to increase their proliferation in serum-starved conditions. Interestingly, CCL2 and IL-8 affected endothelial morphogenesis as shown in Matrigel assays. Since CCL2 and IL-8 have suppressive effects in normal hematopoiesis but do not seem to affect primary ALL cells, it is possible that these chemokines may contribute to the establishment of survival/proliferative selective advantage for ALL cells in the leukemic BM microenvironment. In addition, CCL2 and IL-8 seems indirectly to contribute to ALL cell survival by stimulating the supporting BM stromal cells. Finally, preliminary results showed that standard risk pediatric ALL patients with BM plasma levels below 577pg/ml have better survival rates than those with higher CCL2 levels (p = 0.08). In conclusion, this work suggests a significant role for the chemokines CCL2 and IL-8 in the leukemia/microenvironment crosstalk in human ALL, and suggests that these molecules may represent valuable targets for therapeutic intervention in this cancer. Supported by: CNPq, FAPESP.

Screening Small Molecule Inhibitors of VLA-5 to Block the Interaction Between Acute Lymphoblastic Leukemia with Ph+ and Their Microenvironment.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1027-1027
Author(s):  
Zhongbo Hu ◽  
Xiaomiao Li ◽  
David Ostrov ◽  
William Slayton
Keyword(s):  
Bone Marrow ◽  
Acute Lymphoblastic Leukemia ◽  
Small Molecules ◽  
Small Molecule ◽  
Stromal Cells ◽  
Bone Marrow Stromal Cells ◽  
Lymphoblastic Leukemia ◽  
Marrow Stromal Cells ◽  
Leukemia Cells ◽  
Human Fibronectin

Abstract Abstract 1027 Integrin VLA-5 (α5β1, CD49e/CD29) plays an important role in hematopoietic cells functioning as well as in promoting tumor angiogenesis and tumor metastasis. Molecules targeting VLA-5 can be rapidly developed into anti-inflammatory and anti-tumor pharmaceuticals. VLA-5 is highly expressed on Ph+ leukemia cells and VLA-5 inhibitory antibodies can significantly inhibit the adhesion of Ph+ leukemia cells to human fibronectin. We generated an atomic homology model of VLA-5 based on the crystal structure of the extracellular segment of integrin αVβ3 in complex with a cyclic peptide presenting the Arg-Gly-Asp sequence and utilized this structure-based approach to identify VLA-5 binding drug-like small molecules. We selected the Arg-Gly-Asp binding residues and the epitopes of VLA-5 antibody as the target for small molecule binding using SPHERE_SELECT in DOCK6. The grid-based scoring system was used for scoring with the non-bonded force field energy function. The 100 highest scoring small molecules were assayed in an in vitro adhesion assay using leukemia cell lines and solid phase assay. This approach identified several leading small-molecule compounds, V10, V20, V37 and L4. Their IC50 are respectively 22.5μM, 23.7μM, 32.0μM and 28.9μM. These compounds can inhibit the adhesion of VLA-5 expressing Philadelphia chromosome positive leukemia to both human fibronectin and bone marrow stromal cells. Compounds V10 and V20 also significantly inhibited the growth of Ph+ leukemia cells. These compounds can enhance the effect of imatinib and dasatinib to kill Ph+ leukemia cells when cultured contacting with bone marrow stromal cells. We are currently testing the synergistic effect of these compounds with tyrosine kinase inhibitors to treat the Ph+ acute lymphoblastic leukemia in NOD/SCID animal model. Disclosures: No relevant conflicts of interest to declare.

Interactions between acute lymphoblastic leukemia and bone marrow stromal cells influence response to therapy

2012 ◽  
Vol 36 (3) ◽  
pp. 299-306 ◽  
Author(s):  
Yordanos Tesfai ◽  
Jette Ford ◽  
Kim W. Carter ◽  
Martin J. Firth ◽  
Rebecca A. O’Leary ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Lymphoblastic Leukemia ◽  
Stromal Cells ◽  
Bone Marrow Stromal Cells ◽  
Lymphoblastic Leukemia ◽  
Response To Therapy ◽  
Marrow Stromal Cells

scholarly journals Metabolic reprogramming of bone marrow stromal cells by leukemic extracellular vesicles in acute lymphoblastic leukemia

Blood ◽  
2016 ◽  
Vol 128 (3) ◽  
pp. 453-456 ◽  
Author(s):  
Suzanne M. Johnson ◽  
Clare Dempsey ◽  
Amy Chadwick ◽  
Stephanie Harrison ◽  
Jizhong Liu ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Lymphoblastic Leukemia ◽  
Extracellular Vesicles ◽  
Stromal Cells ◽  
Bone Marrow Stromal Cells ◽  
Lymphoblastic Leukemia ◽  
Marrow Stromal Cells ◽  
Metabolic Reprogramming

scholarly journals A Method for Measurement of Drug Sensitivity of Myeloma Cells Co-Cultured with Bone Marrow Stromal Cells

2013 ◽  
Vol 18 (6) ◽  
pp. 637-646 ◽  
Author(s):  
Kristine Misund ◽  
Katarzyna A. Baranowska ◽  
Toril Holien ◽  
Christoph Rampa ◽  
Dionne C. G. Klein ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Cell Survival ◽  
Stromal Cells ◽  
Bone Marrow Stromal Cells ◽  
Large Scale ◽  
Stromal Cell ◽  
Marrow Stromal Cells ◽  
Cell Nuclei ◽  
Myeloma Cells

The tumor microenvironment can profoundly affect tumor cell survival as well as alter antitumor drug activity. However, conventional anticancer drug screening typically is performed in the absence of stromal cells. Here, we analyzed survival of myeloma cells co-cultured with bone marrow stromal cells (BMSC) using an automated fluorescence microscope platform, ScanR. By staining the cell nuclei with DRAQ5, we could distinguish between BMSC and myeloma cells, based on their staining intensity and nuclear shape. Using the apoptotic marker YO-PRO-1, the effects of drug treatment on the viability of the myeloma cells in the presence of stromal cells could be measured. The method does not require cell staining before incubation with drugs, and less than 5000 cells are required per condition. The method can be used for large-scale screening of anticancer drugs on primary myeloma cells. This study shows the importance of stromal cell support for primary myeloma cell survival in vitro, as half of the cell samples had a marked increase in their viability when cultured in the presence of BMSC. Stromal cell–induced protection against common myeloma drugs is also observed with this method.

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