TY - JOUR
T1 - Overexpression of IL-1 receptor accessory protein in stem and progenitor cells and outcome correlation in AML and MDS
AU - Barreyro, Laura
AU - Will, Britta
AU - Bartholdy, Boris
AU - Zhou, Li
AU - Todorova, Tihomira I.
AU - Stanley, Robert F.
AU - Ben-Neriah, Susana
AU - Montagna, Cristina
AU - Parekh, Samir
AU - Pellagatti, Andrea
AU - Boultwood, Jacqueline
AU - Paietta, Elisabeth
AU - Ketterling, Rhett P.
AU - Cripe, Larry
AU - Fernandez, Hugo F.
AU - Greenberg, Peter L.
AU - Tallman, Martin S.
AU - Steidl, Christian
AU - Mitsiades, Constantine S.
AU - Verma, Amit
AU - Steidl, Ulrich
PY - 2012/8/9
Y1 - 2012/8/9
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84865183566&partnerID=8YFLogxK
U2 - 10.1182/blood-2012-01-404699
DO - 10.1182/blood-2012-01-404699
M3 - Article
C2 - 22723552
AN - SCOPUS:84865183566
SN - 0006-4971
VL - 120
SP - 1290
EP - 1298
JO - Blood
JF - Blood
IS - 6
ER -