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Selective killing of candidate AML stem cells by antibody targeting of IL1RAP
Abstract
IL1RAP, a co-receptor for interleukin (IL)-1 and IL-33 receptors, was previously found to be highly upregulated on candidate chronic myeloid leukemia stem cells, allowing for leukemia-selective killing using IL1RAP-targeting antibodies. We analyzed IL1RAP expression in a consecutive series of 29 patients with acute myeloid leukemia (AML) and, based on the level of expression in mononuclear cells (MNCs), we divided the samples into 3 groups: IL1RAP low (n = 6), IL1RAP intermediate (n = 11), and IL1RAP high (n = 12). Within the CD34+CD38- population, the intermediate and high groups expressed higher levels of IL1RAP than did corresponding normal cells. With the aim to target AML stem cells, an anti-IL1RAP monoclonal antibody was generated followed by isotype switching for improved antibody-dependent, cell-mediated cytotoxicity activity. Using this antibody, we achieved selective killing of AML MNC, CD34+CD38+, and CD34+CD38- cells. Our findings demonstrate that IL1RAP is a promising new therapeutic target in AML.
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Aberrant signaling via IL-1 and the downstream IRAK/TRAF pathway shared by IL-1R and TLRs has been implicated as a driver of survival and/or expansion of MDS and myeloid leukemia stem cells.
“Aberrant signaling via IL-1 and the downstream IL-1 receptor associated kinase/TNF receptor associated factor pathway shared by IL-1R and TLRs has been implicated as a driver of survival and/or expansion of MDS and myeloid leukemia stem cells (Ågerstam et al., 2016; Askmyr et al., 2013; Barreyro et al., 2012; Carey et al., 2017; Muto et al., 2020; Smith et al., 2019; Zhang et al., 2016).”
From PU.1 enforces quiescence and limits hematopoietic stem cell expansion during inflammatory stress (2021) · cites this paper as Askmyr et al., 2013
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Immunological and inflammatory functions of the interleukin-1 family
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Research works printed but not linked: 9
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Carey, A., Edwards, D. K., Eide, C. A., Newell, L., Traer, E., Medeiros, B. C., Pollyea, D. A., Deininger, M. W., Collins, R. H., Tyner, J. W., et al. (2017) · Cell Reports · doi:10.1016/j.celrep.2017.03.018 · Cited by 270
Targeting microglia for the treatment of Alzheimer’s Disease
Wes, P. D., Sayed, F. A., Bard, F., & Gan, L. (2016) · Glia · doi:10.1002/glia.22988 · Cited by 185
Ramanan, V. K., Risacher, S. L., Nho, K., Kim, S., Shen, L., McDonald, B. C., Yoder, K. K., Hutchins, G. D., West, J. D., Tallman, E. F., et al. (2015) · Brain · doi:10.1093/brain/awv231 · Cited by 133
PU.1 enforces quiescence and limits hematopoietic stem cell expansion during inflammatory stress
Chavez, J. S., Rabe, J. L., Loeffler, D., Higa, K. C., Hernandez, G., Mills, T. S., Ahmed, N., Gessner, R. L., Ke, Z., Idler, B. M., et al. (2021) · Journal of Experimental Medicine · doi:10.1084/jem.20201169 · Cited by 91
Metadata
- Authors
- Askmyr, M., Ågerstam, H., Hansen, N., Gordon, S., Arvanitakis, A., Rissler, M., Juliusson, G., Richter, J., Järås, M., & Fioretos, T.
- Affiliations
- Lund University (SE)
- ORCID
- Venue
- Blood
- Publisher
- American Society of Hematology
- Published
- 2013-05-02
- Volume
- 121
- Issue
- 18
- Pages
- 3709-3713
- ISSN
- 0006-4971 (ISSN-L)
- 1528-0020
- OpenAlex
- W2074711837
- Cited by
- 127
- References
- 2
- Citations by year
- 2026: 3 · 2025: 11 · 2024: 9 · 2023: 10 · 2022: 16 · 2021: 15 · 2020: 10 · 2019: 7 · 2018: 8 · 2017: 13 · 2016: 5 · 2015: 10 · 2014: 6 · 2013: 3
- FWCI
- 5.74
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Blood (publishedVersion)
- PubMed (publishedVersion)
- Lund University Publications (Lund University) (submittedVersion)
- Topics
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Life Sciences › Immunology and Microbiology › Immunology › Monoclonal and Polyclonal Antibodies Research
- Health Sciences › Medicine › Hematology › Chronic Myeloid Leukemia Treatments
- Keywords
- IL1RAP, acute myeloid leukemia, leukemia stem cells, antibody targeting, IL-33 receptor, monoclonal antibodies, antibody-dependent cellular cytotoxicity, CD34+CD38- cells, therapeutic target, selective killing
- MeSH terms
- Adult, Aged, Aged, 80 and over, Antibodies, Antibody Specificity, Cells, Cultured, Cytotoxicity, Immunologic, Female, Humans, Immunotherapy, Male, Middle Aged, Neoplastic Stem Cells, Leukemia, Myeloid, Acute, Interleukin-1 Receptor Accessory Protein, Molecular Targeted Therapy
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