Transformation from committed progenitor to leukaemia stem cell initiated by MLL–AF9
Abstract
Leukaemias and other cancers possess a rare population of cells capable of the limitless self-renewal necessary for cancer initiation and maintenance. Eradication of these cancer stem cells is probably a critical part of any successful anti-cancer therapy, and may explain why conventional cancer therapies are often effective in reducing tumour burden, but are only rarely curative. Given that both normal and cancer stem cells are capable of self-renewal, the extent to which cancer stem cells resemble normal tissue stem cells is a critical issue if targeted therapies are to be developed. However, it remains unclear whether cancer stem cells must be phenotypically similar to normal tissue stem cells or whether they can retain the identity of committed progenitors. Here we show that leukaemia stem cells (LSC) can maintain the global identity of the progenitor from which they arose while activating a limited stem-cell- or self-renewal-associated programme. We isolated LSC from leukaemias initiated in committed granulocyte macrophage progenitors through introduction of the MLL-AF9 fusion protein encoded by the t(9;11)(p22;q23). The LSC were capable of transferring leukaemia to secondary recipient mice when only four cells were transferred, and possessed an immunophenotype and global gene expression profile very similar to that of normal granulocyte macrophage progenitors. However, a subset of genes highly expressed in normal haematopoietic stem cells was re-activated in LSC. LSC ca…
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PU.1 haploinsufficiency causes subtle changes in hematopoietic differentiation but is not sufficient to induce leukemia.
“PU.1 halpoinsufficiency causes subtle changes in hematopoietic differentiation, but is not sufficient to induce leukemia3, 9, 11, 13, 14.”
From Minimal PU.1 reduction induces a preleukemic state and promotes development of acute myeloid leukemia (2015) · cites this paper as [11]
Loss or near-complete loss of PU.1 induces acute myeloid leukemia in mice.
“Although loss or near-complete loss of the hematopoietic transcription factor PU.1 induces acute myeloid leukemia (AML) in mice”
From Minimal PU.1 reduction induces a preleukemic state and promotes development of acute myeloid leukemia (2015) · cites this paper as [11]
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“But a stem-like phenotype is not a necessary feature of TPCs: even cells that do not express stem cell markers or exhibit multipotent differentiation can propagate tumors (Krivtsov et al., 2006; Peacock et al., 2007).”
BackgroundHuman topoisomerases and their roles in genome stability and organization
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“…profiling of Jak2+/VF LSKs demonstrated a robust enrichment of myeloid progenitor differentiation signatures including those derived from MEP (Krivtsov et al., 2006) and Pre-CFU-E cells (Pronk et al., 2007), respectively, indicating that Jak2V617F instructs HSC differentiation, consistent…”
BackgroundInfluentialSelf-citationCancer stem cells – old concepts, new insights
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“RESULTS Adrenergic Signals Regulate AML We transduced Lin c-KitSca-1 (LSK) cells with the MLL-AF9 oncogene and clonally propagated transduced LSK cells in methylcellulose as preleukemic cells (Krivtsov et al., 2006).”
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“MEF2C has been implicated in human oncogenesis: in myeloid leukemias of MLL-AF9 transgenic mice, Mef2c has been identified as a HoxA9 target gene that regulates self- 494 Cancer Cell 19, 484–497, April 12, 2011 ª2011 Elsevier Inc. renewal of leukemic stem cells (Krivtsov et al., 2006).”
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“Follow-up, median (IQR), mo 9 (3-27) 17 (7-73) 25 (10-55) 10 (2-22)”
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“Although Hoxa and Meis1 expression is induced by MLL oncoproteins (Krivtsov et al., 2006) and required for initiation of MLL leukemia (Ayton and Cleary, 2003; So et al.”
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“As MLL-AF9 cells are EZH2-dependent and manifest differentiation blockade due to epigenetic deregulation 34 , we monitored the impact of SAH-EZH2-mediated disruption of PRC2 activity on the morphology of treated cells.”
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“The finding of telomerase activity in all MA9 clones suggests that the initiation of a self-renewal program by MA9, as demonstrated by others (Krivtsov et al., 2006), includes this critical enzyme.”
BackgroundPharmacologic inhibition of the menin-MLL interaction blocks progression of MLL leukemia in vivo
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“Leukemia can be initiated by introducing MLL fusion oncogenes into committed progenitors (Cozzio et al., 2003; Krivtsov et al., 2006; Somervaille and Cleary, 2006), suggesting that the reactivation of such a self-renewal program by MLL fusion oncogenes can occur in progenitors.”
BackgroundMicroRNA miR-125a controls hematopoietic stem cell number
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“Representative fields from primary (1) and secondary (2) cultures.”
BackgroundSelf-citationHOXA9 is required for survival in human MLL-rearranged acute leukemias.
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Self-citationCell state-specific metabolic dependency in hematopoiesis and leukemogenesis
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“BCR-ABL induces a stem cell-based disease (Takahashi et al., 1998) and MLL-AF9 induces a myeloid progenitor (GMP) disease (Krivtsov et al., 2006).”
Self-citationA Myc enhancer cluster regulates normal and leukaemic haematopoietic stem cell hierarchies
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“Moreover, the mechanisms governing self-renewal are largely unknown and are now just beginning to emerge for diseases in which cancer stem cells have been identified (Krivtsov et al. 2006).”
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- Authors
- 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., Golub, T. R., & Armstrong, S. A.
- Affiliations
- Boston Children's Hospital (US)
- Broad Institute (US)
- Brigham and Women's Hospital (US)
- Corresponding author
- Armstrong, Scott A.
- ORCID
- Venue
- Nature
- Published
- 2006-07-16
- Volume
- 442
- Issue
- 7104
- Pages
- 818-822
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2109336877
- Cited by
- 1,513
- References
- 0
- Citations by year
- 2026: 37 · 2025: 45 · 2024: 66 · 2023: 70 · 2022: 60 · 2021: 65 · 2020: 66 · 2019: 73 · 2018: 70 · 2017: 75 · 2016: 85 · 2015: 83 · 2014: 77 · 2013: 79 · 2012: 92
- FWCI
- 59.70
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Damon Runyon Cancer Research Foundation
- National Institutes of Health
- Topics
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Keywords
- leukemia stem cells, committed progenitors, MLL-AF9 fusion, CFU-GM, self-renewal, cancer stem cells, hematopoietic stem cells, gene expression profiling, oncogenic transformation, targeted cancer therapy
- MeSH terms
- Animals, Cell Differentiation, Cell Division, Cell Line, Cell Transformation, Neoplastic, Granulocytes, Humans, Leukemia, Macrophages, Neoplasm Transplantation, Neoplastic Stem Cells, Leukemia, Myelomonocytic, Acute, Oncogene Proteins, Fusion, Survival Rate, Cell Lineage, Mice, Myeloid-Lymphoid Leukemia Protein
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