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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 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]
In the citing paper
“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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“Recently, it has been demonstrated that expression of an MLL fusion gene (MLL-AF9) in granulocyte/macrophage progenitors (GMPs) induces a ‘‘HSC stem cell-like’’ signature that includes various HOX genes (Krivtsov et al., 2006).”
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“In support of this, it has been reported that leukemic stem cells can be generated from committed hematopoietic progenitors through expression of the MLL-AF9 fusion protein (Krivtsov et al., 2006).”
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“We then analyzed the gene expression data using gene set enrichment analysis (GSEA; Krivtsov et al., 2006; Subramanian et al., 2005), a computational method that determines if a defined gene set shows differential expression between two biological states (http://www.broad.mit. edu/gsea/).”
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BackgroundCharafe-Jauffret, E., Ginestier, C., Iovino, F., Wicinski, J., Cervera, N., Finetti, P., Hur, M., Diebel, M. E., Monville, F., Dutcher, J., et al. (2009) · Cancer Research · doi:10.1158/0008-5472.can-08-2741 · Cited by 1,210
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“It is thus interesting that direct introduction of the MLL–AF9 fusion gene (which is seen in some patients with AML) into mouse GMPs can produce a mouse leukaemia without an apparent alteration of the cell surface markers or gene expression profile of the target cell”
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“To test the role of ME in MLL-AF9 leukemogenesis, we infected bone marrow cells fromMEmice,(8) which bear a lacZ insertion in exon 1 ofMds1 (Figure 1A) and lack MDS1 and ME but express normal levels of EVI1, and performed a serial replating assay.(13-16) AlthoughMLL-AF9 induced wild-type (WT) cells to form colonies at…”
Hypoxia-Inducible Factors, Stem Cells, and Cancer
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“…lacking the ability to selfrenew , more recent evidence suggests that in many cancers the cancer stem cells arise from progenitor cells that have gained the ability to self-renew (Cozzio et al. 2003, Huntly et al. 2004, Krivtsov et al. 2006, Lavau et al. 1997, So et al. 2004, Wagner et al. 2006).”
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BackgroundInfluentialStem cell concepts renew cancer research
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“However, human leukemias often express more complex combinations of modules that are not observed in normal samples, including HSPC modules, as has been reported in murine models of leukemia (Krivtsov et al., 2006).”
Self-citationTackling the cancer stem cells — what challenges do they pose?
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MLL-Rearranged Leukemia Is Dependent on Aberrant H3K79 Methylation by DOT1L
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“In addition we correlated histone modification profiles with previously published gene expression profiles for these same populations (Krivtsov et al., 2006).”
InfluentialSelf-citationStems Cells and the Pathways to Aging and Cancer
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“Interestingly, expression profiling of LSCs generated through transformation of committed progenitors by ectopic expression of the MLL-AF9 oncogene revealed that the expression signature of the parental progenitors was more or less retained, whereas the self-renewing leukemic clones had acquired a gene expression sign…”
BackgroundTumour-initiating cells: challenges and opportunities for anticancer drug discovery
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“For example, by gaining certain epigenetic programmes or losing certain combinations of tumour suppressor genes, progenitor cells could gain the capacity for self-renewal and become malignan”
BackgroundThe Wnt/β-Catenin Pathway Is Required for the Development of Leukemia Stem Cells in AML
Wang, J. Y., Krivtsov, A. V., Sinha, A. U., North, T. E., Goessling, W., Feng, Z., Zon, L. I., & Armstrong, S. A. (2010) · Science · doi:10.1126/science.1186624 · Cited by 777
Self-citationMurat, A., Migliavacca, E., Gorlia, T., Lambiv, W. L., Shay, T., Hamou, M., de Tribolet, N., Regli, L., Wick, W., Kouwenhoven, M., et al. (2008) · Journal of Clinical Oncology · doi:10.1200/jco.2007.15.7164 · Cited by 741
“As an independent predictive factor of resistance, we have identified a HOX-dominated gene cluster, evocative of a self-renewal signature recently described for leukemia.(9) Strong HOXA10 expression of glioblastoma-derived neurospheres is in line with a role of HOX genes in the glioma stem-like cell compartment.”
BackgroundResultInfluentialModule Map of Stem Cell Genes Guides Creation of Epithelial Cancer Stem Cells
Wong, D. J., Liu, H. W., Ridky, T. W., Cassarino, D. S., Segal, E., & Chang, H. Y. (2008) · Cell stem cell · doi:10.1016/j.stem.2008.02.009 · Cited by 717
“Because previous studies in leukemia stem cells have demonstrated reactivation of HSC transcriptional programs (Krivtsov et al., 2006), reactivation of tissue-specific, adult stem cell programs may have been predicted to underlie cancer stem cells from different epithelial cancers.”
BackgroundMetastasis: recent discoveries and novel treatment strategies
Eccles, S. A., & Welch, D. R. (2007) · The Lancet · doi:10.1016/s0140-6736(07)60781-8 · Cited by 737
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“The ability of oncogenic mutations to increase the self-renewal capacity of lineage-restricted progenitors has also been demonstrated in the hematopoietic system (Cozzio et al., 2003; Krivtsov et al., 2006).”
Targeting FTO Suppresses Cancer Stem Cell Maintenance and Immune Evasion
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“To test this, we conducted in vitro and in vivo limiting dilution assays (Krivtsov et al., 2006; Li et al., 2015; Weng et al., 2018).”
Pronk, C. J. H., Rossi, D. J., Månsson, R., Attema, J. L., Norddahl, G. L., Chan, C. K. F., Sigvardsson, M., Weissman, I. L., & Bryder, D. (2007) · Cell Stem Cell · doi:10.1016/j.stem.2007.07.005 · Cited by 671
“The critical requirement of appropriate control of such factors in oligopotent—but normally not self-renewing—progenitors has been highlighted by the development of leukemias arising as a consequence of the misappropriate expression of such transcriptional regulators (Cozzio et al., 2003; Krivtsov et al., 2006).”
BackgroundCoexistence of LMPP-like and GMP-like leukemia stem cells in acute myeloid leukemia.
Goardon, N., Marchi, E., Atzberger, A., Quek, L., Schuh, A., Soneji, S., Woll, P., Mead, A., Alford, K., Rout, R., et al. (2011) · Cancer Cell · doi:10.1016/j.ccr.2010.12.012 · Cited by 671
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“MLL-associated leukemia models in mice have served as platforms for purifying and examining the gene expression profiles of leukemia stem cells (LSCs, also called leukemia-initiating cells) (Krivtsov et al., 2006).”
BackgroundSchüller, U., Heine, V., Mao, J., Kho, A., Dillon, A. K., Han, Y.-G., Huillard, E., Sun, T., Ligon, A., Qian, Y., et al. (2008) · Cancer Cell · doi:10.1016/j.ccr.2008.07.005 · Cited by 656
“This also raises the possibility of a ‘‘dedifferentiation’’ pathway that produces tumors with mixed multipotent and unipotent features, as has been suggested for certain leukemia stem cells (Krivtsov et al., 2006).”
Beyond tumorigenesis: cancer stem cells in metastasis
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Non-genetic mechanisms of therapeutic resistance in cancer
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Hematopoietic Stem Cell Quiescence Promotes Error-Prone DNA Repair and Mutagenesis
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“…advantage(s) either by inheriting mutations from the HSC compartment (as observed with BCR/ABL1 during CML progression) (Jamieson et al., 2004) or by directly acquiring leukemia-associated fusion genes with major ‘‘reprogramming’’ activity, such as MLL translocations (Krivtsov et al., 2006).”
BackgroundIdentification and characterization of leukemia stem cells in murine MLL-AF9 acute myeloid leukemia
Somervaille, T. C. P., & Cleary, M. L. (2006) · Cancer Cell · doi:10.1016/j.ccr.2006.08.020 · Cited by 582
H3K79 methylation profiles define murine and human MLL-AF4 leukemias
Krivtsov, A., Feng, Z.-H., Lemieux, M., Faber, J., Vempati, S., Sinha, A., Xia, X.-B., Jesneck, J., Bracken, A., Silverman, L., et al. (2008) · Cancer Cell · doi:10.1016/j.ccr.2008.10.001 · Cited by 573
“This analysis identified a number of genes previously associated with MLLrearranged leukemias, including HOXA genes, MEIS1, RUNX2, PROM1, and FLT3 (Figures 6C and 6D; Figure S6B) (Armstrong et al., 2002, 2003; Krivtsov and Armstrong, 2007; Krivtsov et al., 2006; Rozovskaia et al., 2001).”
BackgroundMethodSelf-citationThe histone demethylase KDM1A sustains the oncogenic potential of MLL-AF9 leukemia stem cells
Harris, W. J., Huang, X., Lynch, J. T., Spencer, G. J., Hitchin, J. R., Li, Y., Ciceri, F., Blaser, J. G., Greystoke, B. F., Jordan, A. M., et al. (2012) · Cancer Cell · doi:10.1016/j.ccr.2012.03.014 · Cited by 566
“, 2009), FACS-purified KIT cell populations, which are enriched for LSCs (Somervaille and Cleary, 2006; Krivtsov et al., 2006), expressed higher levels of Kdm1a than did their downstream KIT progeny (Figure S1C), suggesting downregulation of expression upon LSC differentiation.”
BackgroundMethodHijacked in cancer: the KMT2 (MLL) family of methyltransferases
Rao, R. C., & Dou, Y. (2015) · Nature reviews. Cancer · doi:10.1038/nrc3929 · Cited by 680
BET inhibitor resistance emerges from leukaemia stem cells
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“These findings suggest that localization to GAT may be dependent on both the leukemia cell of origin (i.e., HSC versus GMP) and the specific oncogenes that drive the malignant transformation process.”
MethodSykes, D. B., Kfoury, Y. S., Mercier, F. E., Wawer, M. J., Law, J. M., Haynes, M. K., Lewis, T. A., Schajnovitz, A., Jain, E., Lee, D., et al. (2016) · Cell · doi:10.1016/j.cell.2016.08.057 · Cited by 500
“These differentiation changes were accompanied by a loss of phenotypic leukemia stem cells (Figure 7F), as previously defined (Krivtsov et al., 2006), as well as a decrease in colony formation (Figure 7G).”
The Wnt signaling pathway in cancer
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“limitless self-renewal through oncogenic transformation leading to the activation of a stem cell like gene expression program.(2) These observations raise questions about the origin of leukemia stem cells that is beyond the scope of this review, but cumulative data”
BackgroundSelf-citationHox genes in hematopoiesis and leukemogenesis
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“Support for this hypothesis comes from multiple murine studies demonstrating that purified committed hematopoietic progenitors, with limited self-renewal capacities, engineered to overexpress the Hox gene regulators MLL-AF9 (Krivtsov et al., 2006), MLL-ENL (Cozzio et al.”
BackgroundDNA methylation protects hematopoietic stem cell multipotency from myeloerythroid restriction
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“To test this hypothesis, we transduced Lin − bone marrow cells with a retrovirus expressing MLL-AF9 , a prototype human oncogene in which the MLL and AF9 (officially known as MLLT3 ) genes are fused by a t(9;11)(p22;q23) translocatio”
MethodStein, E. M., Garcia-Manero, G., Rizzieri, D. A., Tibes, R., Berdeja, J. G., Savona, M. R., Jongen-Lavrenic, M., Altman, J. K., Thomson, B., Blakemore, S. J., et al. (2018) · Blood · doi:10.1182/blood-2017-12-818948 · Cited by 461
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“Although it has been widely assumed that relatively undifferentiated tissue stem cells may be the target progenitor cell of neoplastic transformation in solid organ tumors, it is also likely that cells partially differentiated along a particular lineage (committed progenitor cells or transit-amplifying cells) can beco…”
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“Another case of resistant CSCs was reported for myelodysplasia carrying a 5q deletion.”
InfluentialRb Regulates Interactions between Hematopoietic Stem Cells and Their Bone Marrow Microenvironment
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“Our understanding of the normal regulation of self-renewal will also provide insight into tumorigenesis, where self-renewal pathways are thought to be active (Krivtsov et al., 2006).”
Humanized mouse models for immuno-oncology research
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Musashi-2 regulates normal hematopoiesis and promotes aggressive myeloid leukemia
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Self-citationImplications of the Cancer Stem-Cell Hypothesis for Breast Cancer Prevention and Therapy
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“Overexpression of the MLL fusion gene in hematopoietic progenitors results in production of leukemias, which are driven by cells that acquire stem-cell properties.(21) Interestingly, these progenitors acquire the expression of self-renewal genes normally expressed in hematopoietic stem cells.”
BackgroundNormal and Leukemic Stem Cell Niches: Insights and Therapeutic Opportunities
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Identification of CD15 as a Marker for Tumor-Propagating Cells in a Mouse Model of Medulloblastoma
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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).”
MethodSelf-citationHomminga, I., Pieters, R., Langerak, A. W., de Rooi, J. J., Stubbs, A., Verstegen, M. M. A., Vuerhard, M., Buijs-Gladdines, J. G. C. A. M., Kooi, C., Klous, P., et al. (2011) · Cancer Cell · doi:10.1016/j.ccr.2011.02.008 · Cited by 391
“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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Self-citationGlioma Stem Cells: A Midterm Exam
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Targeted disruption of the EZH2–EED complex inhibits EZH2-dependent cancer
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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.”
Clinical and Therapeutic Implications of Cancer Stem Cells
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Microenvironment Determines Lineage Fate in a Human Model of MLL-AF9 Leukemia
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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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“These effects were accompanied by reduced c-kit (CD117) expression, a marker associated with leukemia stem Cancer Cell 27, 589–6 cells (LSCs) (Krivtsov et al., 2006; Somervaille and Cleary, 2006) (Figures S2J and S2K).”
BackgroundSelf-citationUnique and Independent Roles for MLL in Adult Hematopoietic Stem Cells and Progenitors
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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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Cyclin-dependent protein kinases and cell cycle regulation in biology and disease
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“These findings suggest that LSCs from AML and CML in chronic phase have different capacity of producing ROS.”
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Effects of RAS on the genesis of embryonal rhabdomyosarcoma
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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).”
Backgroundle Viseur, C., Hotfilder, M., Bomken, S. N., Wilson, K., Röttgers, S., Schrauder, A., Rosemann, A., Irving, J. A. E., Stam, R. W., Shultz, L. D., et al. (2008) · Cancer Cell · doi:10.1016/j.ccr.2008.05.015 · Cited by 293
“Similarly, in some murine leukemia models, a very high frequency of 1:6 leukemic stem cells can be found (Krivtsov et al., 2006).”
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Acute myeloid leukemia stem cells and CD33-targeted immunotherapy
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Isolation and Molecular Characterization of Cancer Stem Cells in MMTV-Wnt-1 Murine Breast Tumors
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Metadata
- 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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