Unknown,Transcriptomics,Genomics,Proteomics

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Microarray analyses of ESAM positive cells in the CD34(+) CD38(-) fraction of collagenase-treated bones

ABSTRACT: We previously identified endothelial cell-selective adhesion molecule (ESAM) as a novel functional marker of hematopoietic stem cells (HSCs) in mice. To examine ESAM expression in human, we analyzed diverse HSC sources using flow cytometry. From mononuclear cells of collagenase-treated human hip bones, we obtained two ESAM positive populations in CD34(+) CD38(-) fraction, referred to as ESAM(High) and ESAM(Bright). Then we conducted microarray analyses comparing gene expression signatures between these two populations. Trabecular tissues of the femora were treated with collagenase IV and DNase. Mononuclear cells were collected, and CD34(+) CD38(-) ESAM(High) or ESAM(Bright) cells were sorted.

ORGANISM(S): Homo sapiens

SUBMITTER: Tomohiko Ishibashi

PROVIDER: E-GEOD-63877 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Differences in chemo-sensitivity of subpopulations of AML stem cells could have important clinical implications. Using in vitro cytotoxicity, xenograft models and colony forming assays, we compared chemotherapy sensitivity between Lineage (Lin-)CD34-CD38-, Lin-CD34-CD38+, Lin-CD34+CD38- and Lin-CD34+CD38+ populations from 26 primary AMLs (19 paediatric and 7 adult). We identified a common recurring pattern of chemo-response associated with a poor clinical outcome: In each of 16/26 (62%) AMLs, Lin-CD34-CD38- cells were the most chemoresistant of the four subpopulations to daunorubicin in vitro. Cytarabine-resistant colonies formed only from Lin-CD34-CD38- populations following tertiary passages through both NOG mice and methylcellulose in these AMLs The presence of chemo-resistant Lin-CD34-CD38- populations was signficantly associated with reduced relapse-free survival in childhood AML. Consistently, CD34 negativity was significantly associated with an increased risk of relapse in a larger retropsective cohort (n=89). Samples enriched for chemo-resistant Lin-CD34-CD38- LSCs with a stem cell profile and an undifferentiated genotype revealed pathways likely to confer chemo-resistance, These strongly indicated dependence of chemo-resistant Lin-CD34-CD38- LSCs on their niche environment as well as deregulated DNA damage responses, lipid and Notch1 signalling, Our findings have major implications for the risk stratification of childhood AML and could lead to the development of novel therapeutic approaches. 3 subpopulations of leukemia stem cells from 9 patients with primary childhood AML were analysed. We compared gene expression profiles of Lin-CD34+CD38- (Q1), Lin-CD34+CD38+ (Q2) and Lin-CD34-CD38- (Q3) cells between 3 AMLs in which the CD34+ cells were most chemo-resistant (AML-1P, AML-6P and AML-10P) and the same cells from the remaining AMLs in which the Lin-CD34-CD38- cells were the most chemo-resistant population. We also compared the gene expression profiles of Lin-CD34-CD38- (Q3) cells in the 3 samples with the highest LC50 values (AML-15P, AML-17P and AML-19P) with that of the 3 AMLs exhibiting the lowest LC50 values (AML-2P, AML-5P and AML-11P).

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Microarray analyses of ESAM positive cells in the CD34(+) CD38(-) fraction of collagenase-treated bones

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