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CD34 negative populations are associated with an increased relapse risk in childhood AML and harbor chemo-resistant leukemia stem cells

ABSTRACT: 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).

ORGANISM(S): Homo sapiens  

SUBMITTER: Daniel J White   Mike Griffiths  Philip Short  Stefan Meyer  Wenbin Wei  Sarah Lawson  Shaun Wilson  Khaleda Yasmeen  Katie Brown  Adam Stevens  Oliver Ziff  Jenny Jesson  A R Taylor  Victoria J Weston  Francis Mussai  Sally Jeffries  Tatjana Stankovic  Pamela Kearns  Lisa Eyre  Tracey Perry 

PROVIDER: E-GEOD-45249 | ArrayExpress | 2015-03-01



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