scholarly journals MLL-rearranged acute lymphoblastic leukaemia stem cell interactions with bone marrow stroma promote survival and therapeutic resistance that can be overcome with CXCR4 antagonism

2013 ◽  
Vol 160 (6) ◽  
pp. 785-797 ◽  
Author(s):  
Edward Allan R. Sison ◽  
Rachel E. Rau ◽  
Emily McIntyre ◽  
Li Li ◽  
Donald Small ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Acute Lymphoblastic Leukaemia ◽  
Lymphoblastic Leukaemia ◽  
Cell Interactions ◽  
Therapeutic Resistance ◽  
Bone Marrow Stroma ◽  
Marrow Stroma

scholarly journals Enhanced T-lineage acute lymphoblastic leukaemia cell survival on bone marrow stroma requires involvement of LFA-1 and ICAM-1

2001 ◽  
Vol 115 (4) ◽  
pp. 862-871 ◽  
Author(s):  
Stuart S. Winter ◽  
Jill J. Sweatman ◽  
Michael B. Lawrence ◽  
Torre H. Rhoades ◽  
Anita L. Hart ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Lymphoblastic Leukaemia ◽  
Cell Survival ◽  
Lymphoblastic Leukaemia ◽  
Bone Marrow Stroma ◽  
Leukaemia Cell ◽  
Marrow Stroma

Antibodies to CD44 enhance adhesion of normal CD34+cells and acute myeloblastic but not lymphoblastic leukaemia cells to bone marrow stroma

1997 ◽  
Vol 98 (4) ◽  
pp. 828-837 ◽  
Author(s):  
Linda J Bendall ◽  
Jason Kirkness ◽  
Amy Hutchinson ◽  
Alessandra Bianchi ◽  
Vicki Makrynikola ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Lymphoblastic Leukaemia ◽  
Bone Marrow Stroma ◽  
Cd34 Cells ◽  
Marrow Stroma

MDS Marrow Stroma Is Characterized by Distinct Epigenetic Alterations

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3635-3635 ◽  
Author(s):  
Tushar D Bhagat ◽  
Emily Spaulding ◽  
Davendra Sohal ◽  
Yongkai Mo ◽  
Mario Marcondes ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Bone Marrow Microenvironment ◽  
Whole Genome ◽  
Healthy Controls ◽  
Bone Marrow Stroma ◽  
Epigenetic Alterations ◽  
Dnmt Inhibitor ◽  
Dnmt Inhibitors ◽  
Marrow Stroma

Abstract The bone marrow microenvironment plays an important role in the pathogenesis and perpetuation of stem cell defects in Myelodysplastic Syndrome (MDS). However, while distinct cytogenetic alterations have been described in the stem cell compartment in MDS, the bone marrow stroma has never been shown to be part of the clone. Thus, aberrant epigenetic alterations may be responsible for altered function of bone marrow stroma in MDS. DNA methyl transferase (DNMT) inhibitors, which are therapeutically effective in MDS, affect both hematopoietic cells and the stroma, providing further rationale for studying DNA methylation profiles of bone marrow stroma in this disease. To accomplish this aim, bone marrow mononuclear cells from MDS patients and controls were grown to form adherent cell layers and then depleted for hematopoietic elements by immunomagnetic CD45 negative selection. CD45 negative adherent cells were subsequently expanded and then used for whole genome methylation studies using a recently described novel method, the HELP assay (HpaII tiny fragment Enrichment by Ligation-mediated PCR; Khulan et al, Genome Res. 2006 Aug;16(8)) which uses differential methylation-specific digestion by HpaII and MspI followed by amplification, two color labeling and hybridization to quantify individual promoter CpG island methylation. A custom whole genome human promoter array (Roche-Nimblegen) was used to determine the level of methylation of 25626 gene promoters by calculating HpaII/MspI cut fragment intensity ratio. Global epigenetic profiling revealed that MDS stroma (n=6) was epigenetically distinct from normal bone marrow stroma (n=4) (ANOVA, P<0.0001). Many novel genes that were differentially methylated in MDS stroma, though majority were found to be hypomethylated when compared to normal controls. Growth regulators and transcription factors such as BMP-9, PAX-4, EIF2B1, and BATF-1, were mot significantly hypomethylated. These genes were grouped into functional pathways by Ingenuity Pathway architect and encoded for Cancer related pathways with Hepatocyte nuclear factor- alpha as their central node. In subsequent studies, we profiled stroma from another set of MDS patients who had been treated with the DNMT inhibitor, 5-Azacytidine (n=4). In contrast to untreated MDS patients, there were no significant epigenetic differences between these 5-Azacytidine treated MDS patients and healthy controls (p = NS). These 5-Azacytidine exposed stroma cells did not demonstrate global hypomethylation (as hypothesized after DNMT inhibitor treatment) and were characterized by both hyper- and hypo-methylated loci similar to healthy controls. Thus our results reveal that MDS is characterized by widespread aberrant epigenetic changes in the bone marrow microenvironment. Our results also demonstrate that DNMT inhibitors can alter the epigenomic profiles of stromal cells, and we hypothesize that those stroma effects contribute in part to their clinical efficacy. Overall, these studies underscore the importance of studying the entire bone marrow, including the microenvironment, if we are to improve our understanding of the pathophysiology of MDS and further improve therapy.

scholarly journals Human Non-Hematopoietic CD271pos/CD140alow/neg Bone Marrow Stroma Cells Fulfill Stringent Stem Cell Criteria in Serial Transplantations

2016 ◽  
Vol 25 (21) ◽  
pp. 1652-1658 ◽  
Author(s):  
Roshanak Ghazanfari ◽  
Hongzhe Li ◽  
Dimitra Zacharaki ◽  
Hooi Ching Lim ◽  
Stefan Scheding
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Bone Marrow Stroma ◽  
Marrow Stroma ◽  
Bone Marrow Stroma Cells

Hematopoietic stem cell deficiency resulting from cytomegalovirus infection of bone marrow stroma

1992 ◽  
Vol 64 (S1) ◽  
pp. A125-A127 ◽  
Author(s):  
M. J. Reddehase ◽  
L. Dreher-Stumpp ◽  
P. Angele ◽  
M. Balthesen ◽  
M. Šuša
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Hematopoietic Stem Cell ◽  
Cytomegalovirus Infection ◽  
Bone Marrow Stroma ◽  
Hematopoietic Stem ◽  
Marrow Stroma

BMP4 Induces Changes in Jagged 1 Expression in Bone Marrow Stroma: Association with Induction of Notch Regulated Genes in CD34+Cells.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1388-1388
Author(s):  
Sara R. Fagerlie ◽  
Mineo Iwata ◽  
Lynn Graf ◽  
Beverly Torok-Storb
Keyword(s):  
Gene Expression ◽  
Bone Marrow ◽  
Stem Cell ◽  
Cell Fate ◽  
Stromal Cell ◽  
Bone Marrow Stroma ◽  
Stem Cell Fate ◽  
Cd34 Cells ◽  
Marrow Stroma ◽  
Induced Changes

Abstract In a previous report we identified gene products that may be associated with stem cell maintenance by comparative transcriptome analysis of 2 functionally distinct stromal cell lines: HS-27a which supports primitive hematopoietic progenitor cells and HS-5 which stimulates differentiation. Since the ability of stromal cells to maintain stem cells is lost as the percentage of monocytes in stromal cultures increases, monokine-induced changes in HS-27a gene expression were also determined. An algorithm that combined these datasets was developed and used to identify factors produced by stroma that could be hypothesized to influence hematopoietic stem cell fate. Bone Morphogenetic protein 4 (BMP4) was identified and selected for study. Real time quantitative PCR confirmed that BMP4 gene expression was 9 fold higher in HS-27a than HS-5 and suppressed 6-fold by IL-1β. BMP4 protein secretion followed a similar pattern: HS-27a cells secreted 70 pg/ml BMP4 protein and treatment with IL-1β resulted in a 3 fold suppression; no BMP-4 secretion was detected from HS-5 cells. BMP4 is a critical factor for regulating hematopoietic development during embryogenesis and is involved in the regulation of T-cell differentiation by thymic stroma. However, relatively little is known about the role of bone marrow stromal derived BMP4 in adult hematopoiesis. BMP4 has been implicated in Notch signaling in muscle development. Since the Notch pathway is a key determinant of stem cell fate in hematopoiesis and the Notch ligand, Jagged 1, is differentially expressed in HS-5 and HS-27a cells, we investigated the effect of BMP4 on stromal expression of Jagged 1. We exposed HS-5 cells to BMP4 and assayed for Jagged 1 expression by western blot analysis. BMP4 induced both expression and modification of Jagged 1 in HS-5 cells. To determine if changes in Jagged 1 expression altered signaling between stroma and CD34+ cells, we exposed HS-5 cells to BMP4 for 24 hours. The medium was subsequently removed and replaced with fresh medium that did not contain BMP4. CD34+ cells were then added to the HS-5 cells and incubated at 37° for 2 to 24 hours. CD34+ cells were collected for RNA extraction and whole cell protein extracts were made from the HS-5 cells to verify changes in Jagged 1 expression. Pre-incubation of HS-5 cells with BMP4 prior to co-culture with CD34+ cells resulted in a consistent increase (1.4 to 2.0 fold) in gene expression of the notch regulated genes, Hey1 and Hes1. Although other, as yet undefined, BMP4 induced changes in marrow stroma may be responsible for this induction, we hypothesize that BMP4-induced changes in stromal Jagged 1 expression increases Hey 1 and Hes 1 gene expression via ligand engagement and activation of Notch signaling. Taken together, these studies suggest that BMP4 acts indirectly on progenitor cells via bone marrow stroma through a previously undescribed mechanism whereby BMP4 induces changes in stromal cell expression of the Notch ligand, Jagged1.

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