TY - JOUR
T1 - IL1RAP potentiates multiple oncogenic signaling pathways in AML
AU - Mitchell, Kelly
AU - Barreyro, Laura
AU - Todorova, Tihomira I.
AU - Taylor, Samuel J.
AU - Antony-Debré, Iléana
AU - Narayanagari, Swathi Rao
AU - Carvajal, Luis A.
AU - Leite, Joana
AU - Piperdi, Zubair
AU - Pendurti, Gopichand
AU - Mantzaris, Ioannis
AU - Paietta, Elisabeth
AU - Verma, Amit
AU - Gritsman, Kira
AU - Steidl, Ulrich
N1 - Funding Information:
We would like to thank all past and current members of the Steidl laboratory for their helpful suggestions and discussions and I. Kaur, R. Stanley, A. Pandolfi, I. Schulze, J. Wheat, D. Walter, M. Ferreira, T. Yatsenko, V. Thiruthuvanathan, and L. Benard for their guidance and assistance with experiments. We thank F. Aodengtuya, Y. Zhang, and J. Zhang from the AECOM Flow Cytometry Core Facility, D. Sun from the AECOM Stem Cell Isolation and Xenotransplantation Facility (funded through New York Stem Cell Science grant no. C029154), and P. Schultes from the AECOM Department of Cell Biology. We thank J. Ruthberg for help in preparing this manuscript and graphic design expertise.
Funding Information:
We would like to thank all past and current members of the Steidl laboratory for their helpful suggestions and discussions and I. Kaur, R. Stanley, A. Pandolfi, I. Schulze, J. Wheat, D. Walter, M. Ferreira, T. Yatsenko, V. Thiruthuvanathan, and L. Benard for their guidance and assistance with experiments. We thank F. Aodengtuya, Y. Zhang, and J. Zhang from the AEC OM Flow Cytometry Core Facility, D. Sun from the AEC OM Stem Cell Isolation and Xenotransplantation Facility (funded through New York Stem Cell Science grant no. C029154), and P. Schultes from the AEC OM Department of Cell Biology. We thank J. Ruthberg for help in preparing this manuscript and graphic design expertise. This work was supported by National Institutes of Health grants R01CA166429 (to U. Steidl), R01CA196973 (to K. Gritsman), and U10CA180827 (to E. Paietta), as well as research grants of the Feldstein Medical Foundation and the Leukemia & Lymphoma Society to U. Steidl. K. Mitchell was partially supported by the Training Program in Cellular and Molecular Biology and Genetics (National Institutes of Health, T32 GM007491), and S.J. Taylor was supported by the Einstein Training Program in Stem Cell Research from the Empire State Stem Cell Fund (NYS TEM; New York State Department of Health, contract C30292GG). U. Steidl is the Diane and Arthur B. Belfer Scholar in Cancer Research of the Albert Einstein College of Medicine and is a Research Scholar of the Leukemia & Lymphoma Society. The authors declare no competing financial interests. Author contributions: K. Mitchell, L. Barreyro, S.J. Taylor, I. Antony-Debr?, and U. Steidl designed the study and experiments; K. Mitchell, L. Barreyro, T.I. Todorova, S.J. Taylor, I. Antony-Debr?, and S.-R. Narayanagari performed experiments; L.A. Carvajal and K. Gritsman provided guidance with experiments and study design; I. Mantzaris, G. Pendurti, E. Paietta, and A. Verma provided primary patient specimens and diagnostic information; J. Leite and Z. Piperdi provided technical assistance; K. Mitchell, L. Barreyro, S.J. Taylor, and I. Antony-Debr? analyzed and interpreted data; K. Mitchell and U. Steidl wrote the manuscript.
Funding Information:
This work was supported by National Institutes of Health grants R01CA166429 (to U. Steidl), R01CA196973 (to K. Gritsman), and U10CA180827 (to E. Paietta), as well as research grants of the Feldstein Medical Foundation and the Leukemia & Lymphoma Society to U. Steidl. K. Mitchell was partially supported by the Training Program in Cellular and Molecular Biology and Genetics (National Institutes of Health, T32 GM007491), and S.J. Taylor was supported by the Einstein Training Program in Stem Cell Research from the Empire State Stem Cell Fund (NYSTEM; New York State Department of Health, contract C30292GG). U. Steidl is the Diane and Arthur B. Belfer Scholar in Cancer Research of the Albert Einstein College of Medicine and is a Research Scholar of the Leukemia & Lymphoma Society. The authors declare no competing financial interests.
Publisher Copyright:
© 2018 Mitchell et al.
PY - 2018/6/1
Y1 - 2018/6/1
N2 - The surface molecule interleukin-1 receptor accessory protein (IL1RAP) is consistently overexpressed across multiple genetic subtypes of acute myeloid leukemia (AML) and other myeloid malignancies, including at the stem cell level, and is emerging as a novel therapeutic target. However, the cell-intrinsic functions of IL1RAP in AML cells are largely unknown. Here, we show that targeting of IL1RAP via RNA interference, genetic deletion, or antibodies inhibits AML pathogenesis in vitro and in vivo, without perturbing healthy hematopoietic function or viability. Furthermore, we found that the role of IL1RAP is not restricted to the IL-1 receptor pathway, but that IL1RAP physically interacts with and mediates signaling and proproliferative effects through FLT3 and c-KIT, two receptor tyrosine kinases with known key roles in AML pathogenesis. Our study provides a new mechanistic basis for the efficacy of IL1RAP targeting in AML and reveals a novel role for this protein in the pathogenesis of the disease.
AB - The surface molecule interleukin-1 receptor accessory protein (IL1RAP) is consistently overexpressed across multiple genetic subtypes of acute myeloid leukemia (AML) and other myeloid malignancies, including at the stem cell level, and is emerging as a novel therapeutic target. However, the cell-intrinsic functions of IL1RAP in AML cells are largely unknown. Here, we show that targeting of IL1RAP via RNA interference, genetic deletion, or antibodies inhibits AML pathogenesis in vitro and in vivo, without perturbing healthy hematopoietic function or viability. Furthermore, we found that the role of IL1RAP is not restricted to the IL-1 receptor pathway, but that IL1RAP physically interacts with and mediates signaling and proproliferative effects through FLT3 and c-KIT, two receptor tyrosine kinases with known key roles in AML pathogenesis. Our study provides a new mechanistic basis for the efficacy of IL1RAP targeting in AML and reveals a novel role for this protein in the pathogenesis of the disease.
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U2 - 10.1084/jem.20180147
DO - 10.1084/jem.20180147
M3 - Article
C2 - 29773641
AN - SCOPUS:85048066539
SN - 0022-1007
VL - 215
SP - 1709
EP - 1727
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
IS - 6
ER -