ENAapplication/xmlftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR102/048/SRR10219148/SRR10219148_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR102/052/SRR10219152/SRR10219152_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR102/052/SRR10219152/SRR10219152_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR102/050/SRR10219150/SRR10219150_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR102/047/SRR10219147/SRR10219147_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR102/053/SRR10219153/SRR10219153_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR102/049/SRR10219149/SRR10219149_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR102/050/SRR10219150/SRR10219150_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR102/047/SRR10219147/SRR10219147_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR102/051/SRR10219151/SRR10219151_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR102/053/SRR10219153/SRR10219153_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR102/048/SRR10219148/SRR10219148_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR102/051/SRR10219151/SRR10219151_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR102/049/SRR10219149/SRR10219149_2.fastq.gzprimaryOK200GenomicsIrwin D Bernstein, Clinical Research Division, Fred Hutchinson Cancer Research Centerhttps://www.ebi.ac.uk/ena/browser/view/PRJNA575538Homo sapiensAlthough chemotherapy can successfully induce remission in FLT3/ITD positive acute myeloid leukemia (AML) patients, many, especially those with a high ratio of the FLT3/ITD versus wild type allele (FLT3-AR), exhibit a high relapse rate, requiring hematopoietic stem cell (HSC) transplantation to increase the chance of long-term remission. As the bone marrow tumor microenvironment (TME) has been implicated in drug resistance, we reasoned that AML-TME interactions might be critical for leukemic precursor survival and drug resistance, and that targeting AML-TME interactions might be crucial to improving survival in FLT3/ITD AML patients. In this study, we demonstrate that endothelial cells (ECs), a component of the TME, and the Notch pathway plays a critical role in the protection of FLT3/ITD positive progenitors against AC220 in AML patient samples with high FLT3-AR. We have previously shown that high FLT3-AR disease is distinguished by the presence of the mutation in the least mature CD34+CD33- precursors, where leukemic stem cells (LSCs) reside. Here, we demonstrate that inhibiting Notch signaling overcomes the TME-mediated drug resistance of the LSC-enriched CD34+CD33- precursors, raising the possibility that Notch may serve as a therapeutic target for eradicating LSCs that are thought to be responsible for relapse in this high-risk AML subset. Overall design: A total of 3 primary AML samples were analyzed. Each sample was treated with either AC220 or DMSO control in endothelial cell co-culture in duplicate prior to RNA-seq analysis. Reads from technical duplicates were pooled before edgeR analysis consisting of 3 AML samples as biological replicates per treatment group.xref:PubMed:32513964ENAfalseDifferential expression analysis of primary AML cells treated with AC220 vs DMSO in endothelial cell co-culture.Differential expression analysis of primary AML cells treated with AC220 vs DMSO in endothelial cell co-culture.2025-09-242019-10-05PRJNA575538GSE138340960632513964