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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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Self-citationColon cancer stem cells: Controversies and perspectives
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“Funding: This work was supported by funds from Human Frontier Science Program (LT-000601); Alex’s Lemonade Stand Foundation (19-16679); The Leukemia & Lymphoma Society and The Leukemia & Lymphoma Society of Canada (3404-21); Portuguese Foundation for Science and Technology (SFRH/BD/136200/2018); Princess Margaret Canc…”
MethodSelf-citationMEF2 and the tumorigenic process, hic sunt leones
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Self-citationMEF2C phosphorylation is required for chemotherapy resistance in acute myeloid leukemia
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Self-citationThe MADS transcription factor Mef2c is a pivotal modulator of myeloid cell fate
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“Another hypothesis states that malignant progenitor cells or differentiated cells can be induced to acquire stem cell properties through additional gene activation or mutation (67,68).”
SCL, LMO1 and Notch1 Reprogram Thymocytes into Self-Renewing Cells
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“committed progenitors can induce a stem cell gene signature [8], leading to the reprogramming of non-self-renewing progenitors into pre-leukemic stem cells (pre-LSCs) [9,10].”
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“clear cell sarcoma, are similar to leukemias in which related translocations switch committed hematopoietic progenitors back to a stem cell state (7).”
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BackgroundSelf-citationProstate cancer and metastasis initiating stem cells
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MEF2C is activated by multiple mechanisms in a subset of T-acute lymphoblastic leukemia cell lines
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“Many of the same transcription factors required for progenitor self renewal and specification are involved in malignant transformation (Krivtsov et al., 2006).”
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“Leukemia stem cells can thus be generated from committed progenitors without widespread reprogramming of gene expression, and a leukemia self-renewal–associated signature is activated in the process.(35) Thus, some cancer stem cells may originate from a normal progenitor by reactivating the self-renewal programmer and…”
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The commonality of plasticity underlying multipotent tumor cells and embryonic stem cells
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Murine Models of Acute Myeloid Leukaemia
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“2006 MLL-AF9 pMSCV-IRES-GFP GMP Transplantation of transduced cells propagated in MC resulted in AML in vivo [115]”
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“This is consistent with a model in which leukemic cells originated from GMPs [4].”
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“HoxA9 overexpression frequently occurs in association with rearrangements of the Mixed Lineage Leukemia locus at 11q23 (MLL) [5,6], but is also associated with trisomy 8 AML [7] and the t(7;11) (p15;p15) translocation which fuses NUP98 to HoxA9 [8].”
BackgroundIdentification of Full and Partial Class Relevant Genes
Zhu, Z., Ong, Y., & Żurada, J. (2010) · IEEE/ACM Transactions on Computational Biology & Bioinformatics · doi:10.1109/tcbb.2008.105 · Cited by 62
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“[12] found that myeloid progenitors with limited replicative potential could be transformed into selfrenewing leukemia stem cells upon viral transduction with the MLL:AF9 fusion gene.”
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“2-(2-Cyano-5-((4-((6-(2,2,2-trifluoroethyl)thieno[2,3-d]-pyrimidin-4yl)amino)piperidin-1-yl)methyl)-1H-indol-1-yl)-propanamide (8)—Similar procedure as for 7 but starting with 50 mg (0.”
MethodVitali, C., Bassani, C., Chiodoni, C., Fellini, E., Guarnotta, C., Miotti, S., Sangaletti, S., Fuligni, F., Cecco, L. D., Piccaluga, P. P., et al. (2015) · Cancer Research · doi:10.1158/0008-5472.can-14-3625 · Cited by 66
“MEF2Chas similar expression pattern of SOCS2 in normalHSC (35) and is ectopically expressed in MLL-rearranged AML (36).”
BackgroundMorisot, S., Wayne, A., Bohana‐Kashtan, O., Kaplan, I., Gocke, C., Hildreth, R., Stetler-Stevenson, M., Walker, R., Davis, S., Meltzer, P., et al. (2010) · Leukemia · doi:10.1038/leu.2010.184 · Cited by 61
Chromatin maps, histone modifications and leukemia
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Self-citationFull-intensity and reduced-intensity allogeneic stem cell transplantation in AML
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“Within MRD, leukemic cells with self-renewal capacity and stem cell features, referred to as leukemic stem cells (LSCs), are responsible for the initiation of relapse [12].”
BackgroundSalt-inducible kinase inhibition suppresses acute myeloid leukemia progression in vivo
Tarumoto, Y., Lin, S., Wang, J., Milazzo, J. P., Xu, Y., Lu, B., Yang, Z., Wei, Y., Polyanskaya, S. A., Wunderlich, M., et al. (2019) · Blood · doi:10.1182/blood.2019001576 · Cited by 77
Self-citationThe variety of leukemic stem cells in myeloid malignancy
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DNA Damage Response and Inflammatory Signaling Limit the MLL-ENL-Induced Leukemogenesis In Vivo
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“Mixedlineage leukemia (MLL) fusion oncogenes can transform committed progenitors to LSCs by reactivation of a selfrenewal-associated transcription program (Cozzio et al., 2003; Krivtsov et al., 2006).”
BackgroundResultIdentification of HIF2α as an important STAT5 target gene in human hematopoietic stem cells
Fátrai, S., Wierenga, A. T. J., Daenen, S. M. G. J., Vellenga, E., & Schuringa, J. J. (2011) · Blood · doi:10.1182/blood-2010-08-303669 · Cited by 70
Cancer Stem Cells: Lessons From Melanoma
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Ito, H., Nakamae, I., Kato, J., & Yoneda‐Kato, N. (2021) · Journal of Clinical Investigation · doi:10.1172/jci141529 · Cited by 70
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“Many signaling pathways appear to be common in both CSCs and normal stem cells (Dzobo et al., 2015; Hsu et al., 2016; Jamieson et al., 2004; Krivtsov et al., 2006; Leon et al., 2016; Pece et al., 2010; Shen et al., 2016; Wang et al., 2010).”
Novel agents for the treatment of childhood acute leukemia
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Activation of the vascular niche supports leukemic progression and resistance to chemotherapy
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“Analysis of the cell surface phenotype of expanded leukemic cells revealed ECs fostered the expansion of subsets of leukemic cells that had higher expression of cKit, CD34, and CD16/32, markers associated with primitive LICs (Figure B-E) [33].”
BackgroundRegulation of self‐renewal in normal and cancer stem cells
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MLL-AF9 initiates transformation from fast-proliferating myeloid progenitors
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“Flow cytometric analysis revealed that IDH2/R140Q-deleted EGFP+ AML cells were retained, but the populations of these cells that expressed LSC markers (MSCFR, L-GMP, cKit+Gr1-, and CD34) (29-31) were dramatically reduced in tamoxifen-treated mice (Figs 3I and S2B).”
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Self-citationAcute Myeloid Leukemia: Aging and Epigenetics
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“[46] demonstrated that LICs isolated from progenitor-derived leukemia presented with a reactivated self-renewal-associated gene expression program.”
BackgroundDirect and Indirect Targeting of HOXA9 Transcription Factor in Acute Myeloid Leukemia
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“Direct HOXA9 Targeting Protein/protein interaction HOX/PBX interaction HXR9 Phase I [70,75,248,249] HTL-001 Phase I (end 2019) [250] HTL-002 Preclinical Stage [HOX Therapeutics Ltd.”
BackgroundInfluentialA transcription factor addiction in leukemia imposed by the MLL promoter sequence
Lu, B., Klingbeil, O., Tarumoto, Y., Somerville, T., Huang, Y.-H., Wei, Y.-L., Wai, D. C. C., Low, J., Milazzo, J. P., Wu, X.-L. S., et al. (2018) · Cancer Cell · doi:10.1016/j.ccell.2018.10.015 · Cited by 58
“The key target genes of MLL fusion proteins include HOXA9, MEIS1, and MEF2C, which encode leukemogenic transcription factors (Armstrong et al., 2002; Krivtsov et al., 2006).”
BackgroundDanis, E. P., Yamauchi, T., Echanique, K. A., Zhang, X., Haladyna, J. N., Riedel, S. S., Zhu, N., Xie, H., Orkin, S. H., Armstrong, S. A., et al. (2016) · Cell Reports · doi:10.1016/j.celrep.2016.01.064 · Cited by 64
“Both gene sets clustered murine LSKs, GMPs, and megakaryocyte-erythroid progenitors (MEPs) with 100% accuracy, based on published expression data (Krivtsov et al., 2006, 2013) (Figure S4A).”
BackgroundSelf-citationDietrich, P. A., Yang, C., Leung, H. H. L., Lynch, J. R., Gonzales‐Aloy, E., Liu, B., Haber, M., Norris, M. D., Wang, J., & Wang, J. Y. (2014) · Blood · doi:10.1182/blood-2013-10-532523 · Cited by 63
“In addition to the Wnt/β-catenin signaling, we show that GPR84 overexpression also activates an oncogenic transcription program including the induction of MLL-fusion target genes, which are known to be key components of the aberrant self-renewal-associated signature identified in MLL LSCs.(17) Among those target genes…”
BackgroundMethodInfluentialSelf-citationMLL fusion proteins link transcriptional coactivators to previously active CpG-rich promoters
Okuda, H., Kawaguchi, M., Kanai, A., Matsui, H., Kawamura, T., Inaba, T., Kitabayashi, I., & Yokoyama, A. (2014) · Nucleic Acids Research · doi:10.1093/nar/gkt1394 · Cited by 58
“Posterior HOXA genes are hematopoietic stem cell (HSC) program genes (4) that promote the self-renewal of HSCs/immature progenitors (5).”
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“However, experimental cancer models have clearly determined that CSCs are not necessarily derived from normal stem cells [20].”
Common and Overlapping Oncogenic Pathways Contribute to the Evolution of Acute Myeloid Leukemias
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“Cancer Res; 71(12) June 15, 2011 Cancer Research 4122”
InfluentialSelf-citationSteiner, Q., Otten, L., Hicks, J. M., Kaya, G., Grosjean, F., Säuberli, E., Lavanchy, C., Beermann, F., McClain, K. L., & Acha‐Orbea, H. (2007) · Blood · doi:10.1182/blood-2007-06-097576 · Cited by 54
Bone marrow niche ATP levels determine leukemia-initiating cell activity via P2X7 in leukemic models
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“Moreover, the frequencies of the Lin–CD127–Sca-1–c-Kit+ CD34+CD16/32+ P2x7-null L-GMP cells, which is a population that has been indicated to be more highly enriched in immunophenotypic LICs (50), were also much lower than those of WT control cells (Supplemental Figure 3, F–H).”
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Clustering by fast search and merge of local density peaks for gene expression microarray data
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Diagnosis of Partial Body Radiation Exposure in Mice Using Peripheral Blood Gene Expression Profiles
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“To date, few reports have indicated that fusion genesmay cause the transformation of stem cells in malignancies, including leukemia (32, 33) and lung cancer (34).”
BackgroundMLL1 and MLL1 fusion proteins have distinct functions in regulating leukemic transcription program
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Hematopoietic stem cells are intrinsically protected against MLL-ENL-mediated transformation.
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“Recent studies on both murine cells and primary human samples proposed that gene-expression signatures imposed upon the LICs at transformation share commonalities with normal HSCs (Eppert et al., 2011; Krivtsov et al., 2006; Zhang et al., 2013).”
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“Such cancercausing mutations are also able to strike more developmentally advanced, although still immature, progenitor cells [22, 23].”
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Bone marrow inflammation in haematological malignancies
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“Transfer of transduced cells in recipient mice induces AML 227 .”
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miR-99 regulates normal and malignant hematopoietic stem cell self-renewal
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Dual Function of Histone H3 Lysine 36 Methyltransferase ASH1 in Regulation of Hox Gene Expression
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“Expression of MLL-AF9 translocation products in murine myeloid precursor cells has been shown to induce leukaemia in association with altered expression patterns of ‘‘stem cell genes’’[28,29].”
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“Leukaemogenesis is a complex, multi-step process that involves transformation of a haematopoietic progenitor cell through the induction of several types of chromosomal aberrations and gene mutations followed by clonal expansion (1,2).”
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JAM3 maintains leukemia-initiating cell self-renewal through LRP5/AKT/&bgr;-catenin/CCND1 signaling
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“mid (32) and a pCL-ECO packaging plasmid were transfected into”
BackgroundMethodLeukaemia cell of origin identified by chromatin landscape of bulk tumour cells
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Dynamic Interactions Between Cancer Stem Cells and Their Stromal Partners
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“Restricted leukemia progenitors can reexpress a CSC phenotype via the reactivation of selfrenewal programs [49].”
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Self-citationLoss of Kat2a enhances transcriptional noise and depletes acute myeloid leukemia stem-like cells
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“A better understanding of the molecular landscape of AML and the biology of LSCs may, therefore, aid the design of much more targeted therapies for AML.”
BackgroundInfluentialCombined MEK and JAK inhibition abrogates murine myeloproliferative neoplasm
Kong, G., Wunderlich, M., Yang, D. T., Ranheim, E. A., Young, K. H., Wang, J., Chang, Y., Du, J., Liu, Y., Tey, S.-R., et al. (2014) · Journal of Clinical Investigation · doi:10.1172/jci74182 · Cited by 52
Self-citationConcise Review: Multidimensional Regulation of the Hematopoietic Stem Cell State
Oh, I., & Humphries, R. K. (2011) · Stem Cells · doi:10.1002/stem.776 · Cited by 50
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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