Overexpression of IL-1 receptor accessory protein in stem and progenitor cells and outcome correlation in AML and MDS.
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 of AML 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.
Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Laura
L
Barreyro
Britta
B
Will
Boris
B
Bartholdy
Li
L
Zhou
Tihomira I
TI
Todorova
Robert F
RF
Stanley
Susana
S
Ben-Neriah
Cristina
C
Montagna
Samir
S
Parekh
Andrea
A
Pellagatti
Jacqueline
J
Boultwood
Elisabeth
E
Paietta
Rhett P
RP
Ketterling
Larry
L
Cripe
Hugo F
HF
Fernandez
Peter L
PL
Greenberg
Martin S
MS
Tallman
Christian
C
Steidl
Constantine S
CS
Mitsiades
Amit
A
Verma
Ulrich
U
Steidl
D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D015331:Cohort Studies; D015973:Gene Expression Regulation, Leukemic; D055785:Gene Knockdown Techniques; D018922:HL-60 Cells; D006412:Hematopoietic Stem Cells / Q000378:metabolism / Q000473:pathology; D006801:Humans; D053577:Interleukin-1 Receptor Accessory Protein / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D015470:Leukemia, Myeloid, Acute / Q000175:diagnosis* / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D008954:Models, Biological; D009190:Myelodysplastic Syndromes / Q000175:diagnosis* / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D011379:Prognosis; D016019:Survival Analysis; D014407:Tumor Cells, Cultured; D015854:Up-Regulation / Q000235:genetics
D014408:Biomarkers, Tumor; C507765:IL1RAP protein, human; D053577:Interleukin-1 Receptor Accessory Protein