| Abstract: |
Cellular and interpatient heterogeneity and the involvement of different stem and progenitor compartments in leukemogenesis are challenges for the identification of common pathways contributing to the initiation and maintenance of acute myeloid leukemia (AML). Here we used a strategy of parallel transcriptional analysis of phenotypic long-term hematopoietic stem cells (HSCs), short-term HSCs, and granulocyte-monocyte progenitors from individuals with high-risk (-7/7q-) AML and compared them with the corresponding cell populations from healthy controls. This analysis revealed dysregulated expression of 11 genes, including IL-1 receptor accessory protein (IL1RAP), in all leukemic stem and progenitor cell compartments. IL1RAP protein was found to be overexpressed on the surface of HSCs of AML patients, and marked cells with the -7/7q- anomaly. IL1RAP was also overexpressed on HSCs of patients with normal karyotype AML and high-risk myelodysplastic syndrome, 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 (P = 2.2 × 10-7). Knockdown of IL1RAP decreased clonogenicity and increased cell death ofAML cells. Our study identified genes dysregulated in stem and progenitor cells in -7/7q- AML, and suggests that IL1RAP may be a promising therapeutic and prognostic target in AML and high-risk myelodysplastic syndrome. © 2012 by The American Society of Hematology. |
| Keywords: |
clinical article; controlled study; survival analysis; acute granulocytic leukemia; human cell; overall survival; leukemia, myeloid, acute; cancer patient; flow cytometry; protein localization; protein analysis; phenotype; cell death; cell compartmentalization; gene overexpression; cohort studies; gene expression; models, biological; tumor markers, biological; cohort analysis; tumor cells, cultured; cell population; high risk patient; stem cell; myelodysplastic syndrome; fluorescence in situ hybridization; bone marrow biopsy; neoplastic stem cells; nucleotide sequence; leukemia cell; hematopoietic stem cells; hematopoietic stem cell; monocyte; up-regulation; karyotype; gene knockdown techniques; granulocyte; myelodysplastic syndromes; gene expression regulation, leukemic; cell surface; immune dysregulation; hl-60 cells; interleukin 1 receptor accessory protein; interleukin-1 receptor accessory protein
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