Molecular and functional characterization of stem and progenitor cells in acute myeloid leukemia

Abstract

Acute myeloid leukemia (AML) is a hematological disorder characterized by improper production of mature blood cells. Experimental evidence suggests that AML originates from hematopoietic stem and progenitor cells (HSPC) following the acquisition of multiple genetic or epigenetic changes, giving rise leukemia stem cells (LSC). LSC are quiescent cells that are not completely eradicated with current chemotherapy regimens, leading to disease relapse and death. LSC should be eradicated to achieve lasting cures. To find molecular characteristics of LSC that can be used as therapeutic targets to eradicate these cells, we employed parallel transcriptional analysis of multiple phenotypic HSPC populations in distinct subtypes of AML.;By comparing the gene expression in HSPC compartments in AML with identically sorted compartments from age-matched healthy controls, we found Interleukin 1 receptor accessory protein (IL1RAP) significantly upregulated in HSPC in all examined subtypes of AML with very low expression levels in healthy HSPC. IL1RAP expression marked cells with the -7/7q-anomaly in AML patients with monosomy 7. IL1RAP was also overexpressed on HSC of patients with high-risk MDS, suggesting a pervasive role in different disease subtypes. High IL1RAP expression was independently associated with poor overall survival in 3 independent cohorts of AML patients, suggesting a prognostic value for this molecule. Experimental downregulation of IL1RAP led to changes in phosphorylation of several kinases, decreased clonogenicity in AML cell lines and MDS primary patient samples, increased cell death of AML cells in vitro and reduced infiltration of hematopoietic organs in vivo. Interactions of IL1RAP with tyrosine kinase receptors KIT and FLT3 in AML suggest its participation in multiple signaling pathways and targeting of IL1RAP with peptides or antibodies is currently being tested.;Our study provides a map of dysregulated transcripts across multiple fractionated stem and progenitor cell types from patients with AML, and identifies IL1RAP as a putative new therapeutic and prognostic target in stem cells in AML and MDS. Comparative analysis of sorted, tissue-specific stem and progenitor cells in cancer versus healthy controls may be applicable for the identification of novel targets for stem cell-directed therapy in other type of cancers with a suspected stem cell origin.