Interconversion between Tumorigenic and Differentiated States in Acute Myeloid Leukemia
Open accessAbstract
Tumors are composed of phenotypically heterogeneous cancer cells that often resemble various differentiation states of their lineage of origin. Within this hierarchy, it is thought that an immature subpopulation of tumor-propagating cancer stem cells (CSCs) differentiates into non-tumorigenic progeny, providing a rationale for therapeutic strategies that specifically eradicate CSCs or induce their differentiation. The clinical success of these approaches depends on CSC differentiation being unidirectional rather than reversible, yet this question remains unresolved even in prototypically hierarchical malignancies, such as acute myeloid leukemia (AML). Here, we show in murine and human models of AML that, upon perturbation of endogenous expression of the lineage-determining transcription factor PU.1 or withdrawal of established differentiation therapies, some mature leukemia cells can de-differentiate and reacquire clonogenic and leukemogenic properties. Our results reveal plasticity of CSC maturation in AML, highlighting the need to therapeutically eradicate cancer cells across a range of differentiation states.
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A wide array of myeloid leukemia-associated oncogenic lesions can interfere with PU.1 expression or function, including PML/RARA, AML1-ETO, NPM1c, CEBPA, and mitogenic kinase mutations in BCR/ABL and Flt3ITD.
“a wide array of myeloid leukemia–associated oncogenic lesions can interfere with PU.1 expression or function, including PML/RARA, AML1-ETO, NPM1c, CEBPA, and mitogenic kinase mutations in BCR/ABL and Flt3ITD (Gerloff et al., 2015; McKenzie et al., 2019; Mueller et al., 2006; Noguera et al., 2016; Vangala et al., 2003; Yang et al., 2012).”
From PU.1 enforces quiescence and limits hematopoietic stem cell expansion during inflammatory stress (2021) · cites this paper as McKenzie et al., 2019
The only passage returned from our copy is an unlabelled list of links, with no discussion of PU.1 or the named oncogenic lesions. Searches for PU.1, the listed lesions, and related terms found no passage addressing whether they interfere with PU.1 expression or function. (LLM, conf=0.72)
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Cites
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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
“On the other hand, loss-of function mutations in PU.1 itself are rarely observed in hematological malignancy, though a wide array of myeloid leukemia-associated oncogenic lesions can interfere with PU.1 expression or function, including PML/RARA, AML1-ETO, NPM1c, and mitogenic kinase mutations in BCR/ABL and Flt3ITD (…”
BackgroundSelf-citationSurface antigen-guided CRISPR screens identify regulators of myeloid leukemia differentiation
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- Authors
- McKenzie, M. D., Ghisi, M., Oxley, E. P., Ngo, S., Cimmino, L., Esnault, C., Liu, R., Salmon, J. M., Bell, C. C., Ahmed, N., Erlichster, M., Witkowski, M. T., Liu, G. J., Chopin, M., Dakic, A., Simankowicz, E., Pomilio, G., Vu, T., Krsmanovic, P., Su, S., Tian, L., Baldwin, T. M., Zalcenstein, D. A., DiRago, L., Wang, S., Metcalf, D., Johnstone, R. W., Croker, B. A., Lancaster, G. I., Murphy, A. J., Naik, S. H., Nutt, S. L., Pospisil, V., Schroeder, T., Wall, M., Dawson, M. A., Wei, A. H., de Thé, H., Ritchie, M. E., Zuber, J., & Dickins, R. A.
- Affiliations
- Walter and Eliza Hall Institute of Medical Research (AU)
- Monash University (AU)
- New York University (US)
- Centre National de la Recherche Scientifique (FR)
- The University of Melbourne (AU)
- ETH Zurich (CH)
- The Alfred Hospital (AU)
- Charles University (CZ)
- Boston Children's Hospital (US)
- Baker Heart and Diabetes Institute (AU)
- Research Institute of Molecular Pathology (AT)
- Corresponding author
- Dickins, Ross A.
- ORCID
- Ghisi, Margherita
- Oxley, Ethan P.
- Ngo, Steven
- Cimmino, Luisa
- Esnault, Cécile
- Liu, Ruijie
- Salmon, Jessica M.
- Bell, Charles C.
- Ahmed, Nouraiz
- Erlichster, Michael
- Witkowski, Matthew T.
- Liu, Grace J.
- Dakic, Aleksandar
- Krsmanovic, Pavle
- Su, Shian
- Tian, Luyi
- Baldwin, Tracey M.
- DiRago, Ladina
- Wang, Shu
- Johnstone, Ricky W.
- Croker, Ben A.
- Lancaster, Graeme I.
- Murphy, Andrew J.
- Naik, Shalin H.
- Nutt, Stephen L.
- Schroeder, Timm
- Wall, Meaghan
- Dawson, Mark A.
- Wei, Andrew H.
- Zuber, Johannes
- Dickins, Ross A.
- Venue
- Cell Stem Cell
- Publisher
- Elsevier BV
- Published
- 2019-08
- Volume
- 25
- Issue
- 2
- Pages
- 258-272.e9
- ISSN
- 1875-9777 (ISSN-L)
- 1934-5909
- OpenAlex
- W2965242241
- Cited by
- 91
- References
- 11
- Citations by year
- 2026: 4 · 2025: 17 · 2024: 11 · 2023: 12 · 2022: 13 · 2021: 20 · 2020: 12 · 2019: 2
- FWCI
- 8.20
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell stem cell (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- Funders
- Gabrielle’s Angel Foundation for Cancer Research
- Veski
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
- Boehringer Ingelheim
- Australian Research Council
- Leukaemia Foundation
- Sylvia and Charles Viertel Charitable Foundation
- National Health and Medical Research Council
- Topics
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
- Keywords
- acute myeloid leukemia, cancer stem cells, dedifferentiation, tumor heterogeneity, PU.1, clonogenicity, leukemia relapse
- MeSH terms
- Cell Plasticity, Proto-Oncogene Protein Spi-1, Animals, Cell Differentiation, Cells, Cultured, Humans, Proto-Oncogene Proteins, Tretinoin, Neoplastic Stem Cells, Leukemia, Myeloid, Acute, Trans-Activators, Mice, Cell Transdifferentiation, Carcinogenesis
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