Overexpression of IL-1 receptor accessory protein in stem and progenitor cells and outcome correlation in AML and MDS
Open accessAbstract
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.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Hematological malignancies that frequently carry TET2 founding mutations, such as MDS and AML, display dependencies on IL-1 signaling.
“hematological malignancies that frequently carry TET2 founding mutations, such as MDS and AML, display dependencies on IL-1 signaling.53, 54, 55”
From Aging drives <i>Tet2</i> <i>+/−</i> clonal hematopoiesis via IL-1 signaling (2023) · cites this paper as [53]
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 Barreyro et al., 2012
Cites
Majeti, R., Chao, M. P., Alizadeh, A. A., Pang, W. W., Jaiswal, S., Gibbs, K. D., van Rooijen, N., & Weissman, I. L. (2009) · Cell · doi:10.1016/j.cell.2009.05.045 · Cited by 1,752 · see citing works
Transformation from committed progenitor to leukaemia stem cell initiated by MLL–AF9
Krivtsov, A. V., Twomey, D., Feng, Z., Stubbs, M. C., Wang, Y., Faber, J., Levine, J. E., Wang, J., Hahn, W. C., Gilliland, D. G., et al. (2006) · Nature · doi:10.1038/nature04980 · Cited by 1,513 · see citing works
Granulocyte-macrophage progenitors as candidate leukemic stem cells in blast-crisis CML
Jamieson, C. H. M., Ailles, L. E., Dylla, S. J., Muijtjens, M., Jones, C., Zehnder, J. L., Gotlib, J., Li, K., Manz, M. G., Keating, A., et al. (2004) · New England Journal of Medicine · doi:10.1056/nejmoa040258 · Cited by 1,485 · see citing works
Rambaldi, A., Torcia, M., Bettoni, S., Vannier, E., Barbui, T., Shaw, A., Dinarello, C., & Cozzolino, F. (1991) · Blood · doi:10.1182/blood.v78.12.3248.3248 · Cited by 129 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Inflammation: a key regulator of hematopoietic stem cell fate in health and disease
Pietras, E. M. (2017) · Blood · doi:10.1182/blood-2017-06-780882 · Cited by 417 · see citing works
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 · see citing works
Dual inhibition of MDMX and MDM2 as a therapeutic strategy in leukemia
Carvajal, L. A., Neriah, D. B., Senecal, A., Benard, L., Thiruthuvanathan, V., Yatsenko, T., Narayanagari, S.-R., Wheat, J. C., Todorova, T. I., Mitchell, K., et al. (2018) · Science Translational Medicine · doi:10.1126/scitranslmed.aao3003 · Cited by 249 · see citing works
Self-citationDeregulation of innate immune and inflammatory signaling in myelodysplastic syndromes
Gañán-Gómez, I., Wei, Y., Starczynowski, D. T., Colla, S., Yang, H., Cabrero-Calvo, M., Bohannan, Z. S., Verma, A., Steidl, U., & Garcia-Manero, G. (2015) · Leukemia · doi:10.1038/leu.2015.69 · Cited by 236 · see citing works
Self-citationShih, A. H., Jiang, Y., Meydan, C., Shank, K., Pandey, S., Barreyro, L., Antony-Debre, I., Viale, A., Socci, N., Sun, Y., et al. (2015) · Cancer Cell · doi:10.1016/j.ccell.2015.03.009 · Cited by 236 · see citing works
Self-citationTargeting 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 · see citing works
New IDH1 mutant inhibitors for treatment of acute myeloid leukemia
Okoye-Okafor, U. C., Bartholdy, B., Cartier, J., Gao, E. N., Pietrak, B., Rendina, A. R., Rominger, C., Quinn, C., Smallwood, A., Wiggall, K. J., et al. (2015) · Nature Chemical Biology · doi:10.1038/nchembio.1930 · Cited by 180 · see citing works
Self-citationAging drives <i>Tet2</i> <i>+/−</i> clonal hematopoiesis via IL-1 signaling
Caiado, F., Kovtonyuk, L. V., Gonullu, N. G., Fullin, J., Boettcher, S., & Manz, M. G. (2023) · Blood · doi:10.1182/blood.2022016835 · Cited by 161 · see citing works
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 · see citing works
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 · see citing works
Higa, K. C., Goodspeed, A., Chavez, J. S., De Dominici, M., Danis, E., Zaberezhnyy, V., Rabe, J. L., Tenen, D. G., Pietras, E. M., & DeGregori, J. (2021) · Journal of Experimental Medicine · doi:10.1084/jem.20200560 · Cited by 57 · see citing works
Bone marrow inflammation in haematological malignancies
de Jong, M. M. E., Chen, L., Raaijmakers, M. H. G. P., & Cupedo, T. (2024) · Nature reviews. Immunology · doi:10.1038/s41577-024-01003-x · Cited by 54 · see citing works
PU.1 is required to restrain myelopoiesis during chronic inflammatory stress
Chavez, J. S., Rabe, J. L., Niño, K. E., Wells, H. H., Gessner, R. L., Mills, T. S., Hernandez, G., & Pietras, E. M. (2023) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2023.1204160 · Cited by 14 · see citing works
“IL-1 signaling is also linked to somatic evolutionary processes that give rise to myeloid malignancy (Barreyro et al., 2012; Pietras et al., 2016; de Mooij et al., 2017; Caiado et al., 2021; Burns et al., 2022; Caiado et al., 2022).”
Background
- Authors
- Barreyro, L., Will, B., Bartholdy, B., Zhou, L., Todorova, T. I., Stanley, R. F., Ben-Neriah, S., Montagna, C., Parekh, S., Pellagatti, A., Boultwood, J., Paietta, E., Ketterling, R. P., Cripe, L., Fernandez, H. F., Greenberg, P. L., Tallman, M. S., Steidl, C., Mitsiades, C. S., Verma, A., & Steidl, U.
- Affiliations
- Departments of Cell Biology and
- Albert Einstein College of Medicine (US)
- Centre for Lymphoid Cancer, British Columbia Cancer Agency and
- John Radcliffe Hospital (GB)
- Mayo Clinic (US)
- Indiana University Health (US)
- Moffitt Cancer Center (US)
- Stanford Medicine (US)
- Memorial Sloan Kettering Cancer Center (US)
- BC Cancer Agency (CA)
- Harvard University (US)
- ORCID
- Barreyro, Laura
- Will, Britta
- Bartholdy, Boris
- Zhou, Li
- Todorova, Tihomira I.
- Stanley, Robert F.
- Montagna, Cristina
- Parekh, Samir
- Pellagatti, Andrea
- Boultwood, Jacqueline
- Paietta, Elisabeth
- Ketterling, Rhett P.
- Fernandez, Hugo F.
- Greenberg, Peter L.
- Tallman, Martin S.
- Steidl, Christian
- Mitsiades, Constantine S.
- Verma, Amit
- Steidl, Ulrich
- Venue
- Blood
- Publisher
- American Society of Hematology
- Published
- 2012-08-09
- Volume
- 120
- Issue
- 6
- Pages
- 1290-1298
- ISSN
- 0006-4971 (ISSN-L)
- 1528-0020
- PMC
- PMC3418722
- OpenAlex
- W1980521997
- Cited by
- 201
- References
- 4
- Citations by year
- 2026: 7 · 2025: 16 · 2024: 17 · 2023: 13 · 2022: 17 · 2021: 21 · 2020: 13 · 2019: 13 · 2018: 14 · 2017: 18 · 2016: 12 · 2015: 16 · 2014: 13 · 2013: 11
- FWCI
- 8.52
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Blood (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Cancer Institute (R01CA166429, U24CA114737, R00CA131503)
- National Institute of General Medical Sciences (T32GM007288)
- Topics
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinoids in leukemia and cellular processes
- Keywords
- IL-1 receptor accessory protein, acute myeloid leukemia, myelodysplastic syndrome, leukemia stem cells, hematopoietic stem cells, CFU-GM, prognostic factors, overall survival, clonogenicity, gene expression dysregulation, therapeutic target
- MeSH terms
- Hematopoietic Stem Cells, Humans, Models, Biological, Myelodysplastic Syndromes, Prognosis, Tumor Cells, Cultured, Biomarkers, Tumor, Neoplastic Stem Cells, Cohort Studies, Leukemia, Myeloid, Acute, Up-Regulation, Gene Expression Regulation, Leukemic, Survival Analysis, HL-60 Cells, Interleukin-1 Receptor Accessory Protein, Gene Knockdown Techniques
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
