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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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Items 301–400 of 1,002
Recurrence cancer stem cells – Made by cell fusion?
Dittmar, T., Nagler, C., Schwitalla, S., Reith, G., Niggemann, B., & Zänker, K. S. (2009) · Medical Hypotheses · doi:10.1016/j.mehy.2009.05.044 · Cited by 100
“Evidences exist for both possibilities, whereby data published in the past 2–3 years strongly suggest that progenitor cells, which have regained self-renewal activity, are most likely the precursors to CSCs [5–7].”
BackgroundSilencing of LINE-1 retrotransposons is a selective dependency of myeloid leukemia
Gu, Z., Liu, Y., Zhang, Y., Cao, H., Lyu, J., Wang, X., Wylie, A., Newkirk, S. J., Jones, A. E., Lee, M., et al. (2021) · Nature Genetics · doi:10.1038/s41588-021-00829-8 · Cited by 111
Tsang, J. C. H., Yu, Y., Burke, S., Buettner, F., Wang, C., Kolodziejczyk, A. A., Teichmann, S. A., Lu, L., & Liu, P. (2015) · Genome biology · doi:10.1186/s13059-015-0739-5 · Cited by 112
“[44] as associated with HSC and leukemic stem cell self-renewal (Additional file 3).”
BackgroundMusashi2 sustains the mixed-lineage leukemia–driven stem cell regulatory program
Park, S.-M., Gönen, M., Vu, L., Minuesa, G., Tivnan, P., Barlowe, T. S., Taggart, J., Lu, Y., Deering, R. P., Hacohen, N., et al. (2015) · Journal of Clinical Investigation · doi:10.1172/jci78440 · Cited by 110
“Among these pathways, we identified that MSI2’s direct RNA targets were associated with the MLL-AF9 self-renewal signature that is shared between leukemic granulocyte monocyte progenitors (GMPs) and HSCs (29).”
InfluentialOncogene-induced plasticity and cancer stem cells
Rapp, U. R., Ceteci, F., & Schreck, R. (2008) · Cell Cycle · doi:10.4161/cc.7.1.5203 · Cited by 88
IKZF2 Drives Leukemia Stem Cell Self-Renewal and Inhibits Myeloid Differentiation
Park, S.-M., Cho, H., Thornton, A. M., Barlowe, T. S., Chou, T., Chhangawala, S., Fairchild, L., Taggart, J., Chow, A., Schurer, A., et al. (2019) · Cell Stem Cell · doi:10.1016/j.stem.2018.10.016 · Cited by 97
“Studies have shown that AMLs induced by MLL-AF9 are organized in a cellular hierarchy with phenotypically distinct progenitor-like leukemia stem cells (LSCs) at the apex that selfrenew to generate more LSCs and also give rise to differentiated progeny cells (Krivtsov et al., 2006; Somervaille and Cleary, 2006).”
BackgroundSelf-citationGröschel, S., Schlenk, R. F., Engelmann, J., Ročková, V., Teleanu, V., Kühn, M. W. M., Eiwen, K., Erpelinck-Verschueren, C. A. J., Havermans, M., Lübbert, M., et al. (2012) · Journal of Clinical Oncology · doi:10.1200/jco.2011.41.5505 · Cited by 110
IL1RAP potentiates multiple oncogenic signaling pathways in AML
Mitchell, K., Barreyro, L., Todorova, T. I., Taylor, S. J., Antony-Debré, I., Narayanagari, S.-R., Carvajal, L. A., Leite, J., Piperdi, Z., Pendurti, G., et al. (2018) · Journal of Experimental Medicine · doi:10.1084/jem.20180147 · Cited by 97
“c-Kit+ cells have been shown to contain the leukemia-initiating population in the MLL-AF9 retroviral model (Krivtsov et al., 2006).”
BackgroundMouse models of MLL leukemia: recapitulating the human disease.
Milne, T. (2017) · Blood · doi:10.1182/blood-2016-10-691428 · Cited by 95
“In an attempt to more directly target specific cell types, viral transduction ofMLL-AF9 into highly purified granulocyte/macrophage progenitors (GMPs) was used to produce a transplantable AML that is phenotypically downstream from a normal GMP.(33,34) Earlier work had already established that highly purified lineage(2…”
MethodGLI2 inhibition abrogates human leukemia stem cell dormancy
Sadarangani, A., Pineda, G., Lennon, K. M., Chun, H.-J. E., Shih, A. Y., Schairer, A., Court, A., Goff, D., Prashad, S., Geron, I., et al. (2015) · Journal of Translational Medicine · doi:10.1186/s12967-015-0453-9 · Cited by 95
“In advanced human myeloid malignancies that progress from antecedent hematologic malignancies, such as blast crisis (BC) CML, LSC have a proclivity for becoming dormant in protective niches [2,5,7,11,15-18].”
BackgroundRunx2 induces acute myeloid leukemia in cooperation with Cbfbeta-SMMHC in mice.
Kuo, Y.-H., Zaidi, S. K., Gornostaeva, S., Komori, T., Stein, G., & Castilla, L. (2009) · Blood · doi:10.1182/blood-2008-06-162248 · Cited by 95
Pei, S.-S., Shelton, I. T., Gillen, A. E., Stevens, B. M., Gasparetto, M., Wang, Y.-N., Liu, L., Liu, J., Brunetti, T. M., Engel, K. L., et al. (2022) · bioRxiv · doi:10.1101/2022.12.04.519036 · Cited by 94
“5E), suggesting that in certain patients the developmental hierarchy of m-LSC-driven AMLs can be shallower than others (e.g., AML-16).”
ResultInfluentialSelf-citationAkinduro, O., Weber, T., Ang, H. Y.-K., Haltalli, M. L. R., Ruivo, N., Duarte, D., Rashidi, N. M., Hawkins, E. D., Duffy, K. R., & Celso, C. L. (2018) · Nature Communications · doi:10.1038/s41467-017-02376-5 · Cited by 97
NCAM1 (CD56) promotes leukemogenesis and confers drug resistance in AML.
Sasca, D., Szybinski, J., Schüler, A., Shah, V., Heidelberger, J. B., Haehnel, P. S., Dolnik, A., Kriege, O., Fehr, E.-M., Gebhardt, W., et al. (2019) · Blood · doi:10.1182/blood-2018-12-889725 · Cited by 93
JUN is a key transcriptional regulator of the unfolded protein response in acute myeloid leukemia
Zhou, C., Martı́nez, E., Marcantonio, D. D., Solanki-Patel, N., Aghayev, T., Peri, S., Ferraro, F., Skórski, T., Scholl, C., Fröhling, S., et al. (2016) · Leukemia · doi:10.1038/leu.2016.329 · Cited by 105
Setbp1 promotes the self-renewal of murine myeloid progenitors via activation of Hoxa9 and Hoxa10
Oakley, K., Han, Y., Vishwakarma, B. A., Chu, S., Bhatia, R., Gudmundsson, K. O., Keller, J. R., Chen, X., Vasko, V. V., Jenkins, N. A., et al. (2012) · Blood · doi:10.1182/blood-2011-10-388710 · Cited by 99
Csnk1a1 inhibition has p53-dependent therapeutic efficacy in acute myeloid leukemia
Järås, M., Miller, P. G., Chu, L. P., Puram, R. V., Fink, E. C., Schneider, R. K., Al-Shahrour, F., Peña, P., Breyfogle, L. J., Hartwell, K. A., et al. (2014) · Journal of Experimental Medicine · doi:10.1084/jem.20131033 · Cited by 92
“To examine whether Csnk1a1 is essential for primary mouse MLL-AF9 leukemia cells in vivo, we used lentiviruses that coexpress individual shRNAs with GFP to transduce MLL-AF9 AML cells that were enriched for leukemia stem cells (LSCs) by sorting for c-Kithigh cells (Krivtsov et al., 2006).”
InfluentialDifferentiation and transdifferentiation potentials of cancer stem cells
Huang, Z., Wu, T., Liu, A. Y., & Ouyang, G. (2015) · Oncotarget · doi:10.18632/oncotarget.6098 · Cited by 100
“Transducing MLLAF9 fusion protein into myeloid progenitors gives rise to leukemia in vivo, indicating that progenitors can convert to leukemia stem cells [14].”
BackgroundWojiski, S. A., Guibal, F. C., Kindler, T., Lee, B. H., Jesneck, J. L., Fabian, A. J., Tenen, D. G., & Gilliland, D. G. (2009) · Leukemia · doi:10.1038/leu.2009.63 · Cited by 87
Self-citationMyocyte enhancer factor 2C in hematopoiesis and leukemia
Canté-Barrett, K., Pieters, R., & Meijerink, J. P. P. (2013) · Oncogene · doi:10.1038/onc.2013.56 · Cited by 94
Arsenic, Stem Cells, and the Developmental Basis of Adult Cancer
Tokar, E. J., Qu, W., & Waalkes, M. P. (2010) · Toxicological Sciences · doi:10.1093/toxsci/kfq342 · Cited by 93
“, 2001; Visvader and Lindeman, 2008), and the ‘‘U-shaped’’ expression trend in self-renewal genes is not specific to arsenic as a similar trend has been seen during the progression of other malignancies (Krivtsov et al., 2006).”
BackgroundResultKrauter, J., Wagner, K., Schäfer, I., Marschalek, R., Meyer, C., Heil, G., Schaich, M. A., Ehninger, G., Niederwieser, D. W., Krahl, R., et al. (2009) · Journal of Clinical Oncology · doi:10.1200/jco.2008.16.7981 · Cited by 101
Consistent deregulation of gene expression between human and murine MLL-rearrangement leukemias
Li, Z.-J., Luo, R., Mi, S.-L., Sun, M., Chen, P., Bao, J.-Y., Neilly, M. B., Jayathilaka, N., Johnson, D. S., Wang, L.-L., et al. (2009) · Cancer Research · doi:10.1158/0008-5472.can-08-3381 · Cited by 90
Self-citationDual inhibition of EZH1/2 breaks the quiescence of leukemia stem cells in acute myeloid leukemia
Fujita, S., Honma, D., Adachi, N., Araki, K., Takamatsu, E., Katsumoto, T., Yamagata, K., Akashi, K., Aoyama, K., Iwama, A., et al. (2018) · Leukemia · doi:10.1038/leu.2017.300 · Cited by 89
Kurscheid, S., Bady, P., Sciuscio, D., Samaržija, I., Shay, T., Vassallo, I., Criekinge, W. V., Daniel, R. T., van den Bent, M. J., Marosi, C., et al. (2015) · Genome biology · doi:10.1186/s13059-015-0583-7 · Cited by 100
“In 2006, Krivtsov and colleagues first described the inappropriate expression of a HOX gene signature in acute myeloid leukemia (AML) [13].”
BackgroundCancer: The root of the problem
Abbott, A. (2006) · Nature · doi:10.1038/442742a · Cited by 89
In vitro models of cancer stem cells and clinical applications
Franco, S. S., Szczęsna, K., Iliou, M. S., Al-Qahtani, M. H., Mobasheri, A., Kobolák, J., & Dinnyés, A. (2016) · BMC Cancer · doi:10.1186/s12885-016-2774-3 · Cited by 92
“Moreover, some groups suggest that CSCs could also originate from more committed progenitors that acquire stemness-related features as an effect of accumulation of epigenetic and/or genetic changes [34, 35].”
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Leukemogenic mechanisms and targets of a NUP98/HHEX fusion in acute myeloid leukemia.
Jankovic, D., Gorello, P., Liu, T., Ehret, S., la Starza, R., Desjobert, C., Baty, F., Brutsche, M., Jayaraman, P.-S., Santoro, A., et al. (2008) · Blood · doi:10.1182/blood-2007-09-108175 · Cited by 88
van Gils, N., Denkers, F., & Smit, L. (2021) · Frontiers in Oncology · doi:10.3389/fonc.2021.659253 · Cited by 108
“Moreover, reactivation of a self-renewal-associated transcriptional signature was shown to be an important characteristic of the transformation of normal progenitors into LSCs (35).”
BackgroundHein, N., Cameron, D. P., Hannan, K. M., Nguyen, N.-Y. N., Fong, C. Y., Sornkom, J., Wall, M., Pavy, M., Cullinane, C. M., Diesch, J., et al. (2017) · Blood · doi:10.1182/blood-2016-05-718171 · Cited by 98
“In M/A9 mouse transplantation models, these LICs are a committed progenitor population characterized by aberrant self-renewal capacity and the ability to initiate disease.(18) Although the relative frequency of LICs is still a matter of scientific discussion, it has been reported to account for ;25% to 30% of the tumo…”
BackgroundMethodInfluentialCytoprotective autophagy maintains leukemia-initiating cells in murine myeloid leukemia
Sumitomo, Y., Koya, J., Nakazaki, K., Kataoka, K., Tsuruta-Kishino, T., Morita, K., Sato, T., & Kurokawa, M. (2016) · Blood · doi:10.1182/blood-2015-12-684696 · Cited by 89
SETBP1 mutations drive leukemic transformation in ASXL1-mutated MDS
Inoue, D., Kitaura, J., Matsui, H., Hou, H.-A., Chou, W.-C., Nagamachi, A., Kawabata, K. C., Togami, K., Nagase, R., Horikawa, S., et al. (2014) · Leukemia · doi:10.1038/leu.2014.301 · Cited by 92
Cancer stem cells: Models, mechanisms and implications for improved treatment
Zhou, J.-B., & Zhang, Y. (2008) · Cell Cycle · doi:10.4161/cc.7.10.5953 · Cited by 86
Metabolic regulation of somatic stem cells in vivo
Meacham, C. E., DeVilbiss, A. W., & Morrison, S. J. (2022) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-022-00462-1 · Cited by 85
Bruedigam, C., Bagger, F., Heidel, F. H., Kuhn, C. P., Guignes, S., Song, A., Austin, R., Vu, T., Lee, E. M., Riyat, S., et al. (2014) · Cell Stem Cell · doi:10.1016/j.stem.2014.11.010 · Cited by 85
“LSCs are defined functionally by having the ability to initiate, maintain, and serially propagate AML and differentiate into committed progeny that lack this ability (Bonnet and Dick, 1997; Krivtsov et al., 2006; Lane and Gilliland, 2010).”
Self-citationEsposito, M. T., & So, C. W. E. (2014) · Chromosoma · doi:10.1007/s00412-014-0482-9 · Cited by 88
“TheMLL gene on chromosomal 11q23 can fuse to more than 50 partner genes (Krivtsov and Armstrong 2007; Yip and So 2013) resulting in potent oncoproteins that confer self-renewal activity and activate a leukemogenic program even in committed hematopoietic progenitors (Krivtsov et al. 2006).”
BackgroundThe theoretical basis of cancer‐stem‐cell‐based therapeutics of cancer: can it be put into practice?
Sánchez-Garcı́a, I., Vicente‐Dueñas, C., & Cobaleda, C. (2007) · BioEssays · doi:10.1002/bies.20679 · Cited by 78
“This has been experimentally shown in the mouse for several types of human translocations, suggesting that, in human cancers, stemness can be a newly generated attribute conferred by the oncogene to more mature cells: some oncogenes, like MOZ-TIF2,((36)) MLL-AF9,((37,38)) MLL-ENL((39)) or MLL-GAS7,((40)) must be able…”
BackgroundChromatin modifiers and the promise of epigenetic therapy in acute leukemia
Greenblatt, S. M., & Nimer, S. D. (2014) · Leukemia · doi:10.1038/leu.2014.94 · Cited by 83
The hematopoietic stem cell niche—home for friend and foe?
Krause, D. S., Scadden, D. T., & Preffer, F. I. (2012) · Cytometry Part B Clinical Cytometry · doi:10.1002/cyto.b.21066 · Cited by 96
“MLL-AF9þ Lin- c-Kitþ CD34þ FccRþ (104,105); CD11bþ (105) (Mo) CALM-AF10þ B220þ CD11b- Gr-1 (106) (Mo) Over-expressed HoxA9/Meis1; Bmi-1 (107) ND (Mo)”
Gilbertson, R. J. (2011) · Cell · doi:10.1016/j.cell.2011.03.019 · Cited by 103
“The leukemic stem cells in this model retain a GMP-like gene expression profile, but they also acquire an aberrant self-renewal signature and self-renewal capacity, normally seen only in HSCs (Krivtsov et al., 2006).”
BackgroundInfluentialChromosomes and Expression in Human Testicular Germ‐Cell Tumors
Looijenga, L. H. J., Gillis, A., Stoop, H., Hersmus, R., & Oosterhuis, J. W. (2007) · Annals of the New York Academy of Sciences · doi:10.1196/annals.1411.000 · Cited by 76
FOXM1 regulates leukemia stem cell quiescence and survival in MLL-rearranged AML
Sheng, Y., Yu, C., Liu, Y., Hu, C., Ma, R., Lu, X.-Y., Ji, P., Chen, J., Mizukawa, B., Huang, Y., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-14590-9 · Cited by 83
MLL2, not MLL1, Plays a Major Role in Sustaining MLL-rearranged Acute Myeloid Leukemia
Chen, Y.-F., Anastassiadis, K., Kranz, A., Stewart, A., Arndt, K., Waskow, C., Yokoyama, A., Jones, K. L., Neff, T., Lee, Y., et al. (2017) · Cancer Cell · doi:10.1016/j.ccell.2017.05.002 · Cited by 83
“…affect leukemia stem cells (LSCs), revealed only upon secondary transplantation, so we sorted viable, YFP+/Lin /c-Kit+ cells (LSC-enriched [Krivtsov et al., 2006; Somervaille and Cleary, 2006]) from TAM-treated primary recipients and engrafted them at limiting numbers to secondary…”
MLL-AF9– and HOXA9-mediated acute myeloid leukemia stem cell self-renewal requires JMJD1C
Zhu, N., Chen, M., Eng, R., DeJong, J., Sinha, A. U., Rahnamay, N. F., Koche, R. P., Al‐Shahrour, F., Minehart, J. C., Chen, C.-W. D., et al. (2016) · Journal of Clinical Investigation · doi:10.1172/jci82978 · Cited by 87
“(D) Left panel: heat map of microarray geneexpression data (14) on MLL-AF9 target genes (28).”
BackgroundMethodInfluentialSelf-citationProstate cancer stem cells and their potential roles in metastasis
Li, H., & Tang, D. G. (2011) · Journal of Surgical Oncology · doi:10.1002/jso.21806 · Cited by 72
Diverse roles of GSK-3: Tumor promoter–tumor suppressor, target in cancer therapy
McCubrey, J. A., Davis, N. M., Abrams, S. L., Montalto, G., Cervello, M., Bäsecke, J., Libra, M., Nicoletti, F., Cocco, L., Martelli, A. M., et al. (2013) · Advances in Biological Regulation · doi:10.1016/j.jbior.2013.09.013 · Cited by 85
Fujioka, N., Fritz, V. A., Upadhyaya, P., Kassie, F., & Hecht, S. S. (2016) · Molecular Nutrition & Food Research · doi:10.1002/mnfr.201500889 · Cited by 84
“Cancer stem cells are believed to originate from either transformed adult tissue-specific stem cells [47] or from de-differentiated progenitor cells [48].”
Reddy, D., Kumavath, R., Barh, D., Azevedo, V., & Ghosh, P. (2020) · Molecules · doi:10.3390/molecules25163596 · Cited by 99
“The apoptosis by peruvoside in AML is due to the cell cycle arrest at the G2/M phase, which is one of the basic properties of CGs to induce apoptosis.”
BackgroundInfluentialOrlovsky, K., Kalinkovich, A., Rozovskaia, T., Shezen, E., Itkin, T., Alder, H., Özer, H. G., Carramusa, L., Avigdor, A., Volinia, S., et al. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1103154108 · Cited by 69
Lymphoma stem cells: enough evidence to support their existence?
Martinez-Climent, J. A., Fontán, L., Gascoyne, R. D., Siebert, R., & Prósper, F. (2010) · Haematologica · doi:10.3324/haematol.2009.013318 · Cited by 69
“as was demonstrated by Krivtsov and colleagues in an MLL-AF9 transgenic model.(83) In BCP-ALL, oncogenic fusions may similarly awaken stem-cell properties in com-”
BackgroundEffects of Low Confluency, Serum Starvation and Hypoxia on the Side Population of Cancer Cell Lines
Tavaluc, R. T., Hart, L. S., Dicker, D., & El-Deiry, W. (2007) · Cell Cycle · doi:10.4161/cc.6.20.4911 · Cited by 81
Stem cell-like cancer cells in cancer cell lines
Kondo, T. (2007) · Cancer Biomarkers · doi:10.3233/cbm-2007-34-508 · Cited by 81
“Finally, both stem cells and precursor cells, which are transformed with oncogenic genes, have been shown to as developing cancer in vivo [4,13,14,25,28,44,50].”
Neurofibromin and suppression of tumorigenesis: beyond the GAP
Mo, J., Moye, S. L., McKay, R. M., & Le, L. Q. (2022) · Oncogene · doi:10.1038/s41388-021-02156-y · Cited by 95
“Aberrant transcription factor activity is frequently observed in numerous cancer types, for example GABP in glioblastoma [241], RUNX2 in breast cancer [242], STAT1 and RUNX2 in melanoma [243, 244], and MYC in lymphoma [245] by regulating stem cell properties [246], EMT [247], replicative immortality [241], and immune…”
BackgroundMullally, A., Poveromo, L., Schneider, R., Al-Shahrour, F., Lane, S., & Ebert, B. (2012) · Blood · doi:10.1182/blood-2012-01-402396 · Cited by 80
Aberrant cytokine signaling in leukemia
Etten, R. A. V. (2007) · Oncogene · doi:10.1038/sj.onc.1210758 · Cited by 108
“, 2003), MLL-AF9 (Krivtsov et al., 2006) and MOZ-TIF2 (Huntly et al.”
BackgroundInfluentialA molecular switch between mammalian MLL complexes dictates response to Menin-MLL inhibition
Soto-Feliciano, Y. M., Sánchez-Rivera, F. J., Perner, F., Barrows, D., Kastenhuber, E., Ho, Y.-J., Carroll, T. S., Xiong, Y.-J., Anand, D., Soshnev, A., et al. (2022) · bioRxiv · doi:10.1101/2021.10.22.465184 · Cited by 79
“Mouse MLL-AF9 leukemia cells were kindly shared by David Chen (Chun-Wei Chen, City of Hope) and were originally generated by the transformation of female mouse bone marrow Lin-Sca1+cKit+ (LSK) cells with an MSCV-IRES-GFP (pMIG) retrovirus expressing the human MLL–AF9 fusion protein and transplanted into sublethally ir…”
MethodSelf-citationThe Cancer Stem Cell Hypothesis: A Guide to Potential Molecular Targets
Allegra, A., Alonci, A., Penna, G., Innao, V., Gerace, D. G., Rotondo, F., & Musolino, C. (2014) · Cancer Investigation · doi:10.3109/07357907.2014.958231 · Cited by 107
Glioblastoma cancer stem cells: Biomarker and therapeutic advances
Pointer, K. B., Clark, P. A., Zorniak, M., Alrfaei, B. M., & Kuo, J. S. (2014) · Neurochemistry International · doi:10.1016/j.neuint.2014.03.005 · Cited by 82
“Expression of oncogenes driven by stem cell-specific promoters, such as nestin in brain tumors, results in recapitulated human tumors in mice (28, 29); however, progenitor cells that are more differentiated have also been shown to recapitulate other cancers in a similar manner (30, 31).”
ResultHoming and invasiveness of MLL/ENL leukemic cells is regulated by MEF2C
Schwieger, M., Schüler, A., Forster, M., Engelmann, A., Arnold, M., Delwel, R., Valk, P. J. M., Löhler, J., Slany, R. K., Olson, E. N., et al. (2009) · Blood · doi:10.1182/blood-2008-05-158196 · Cited by 73
shRNA screening identifies JMJD1C as being required for leukemia maintenance
Sroczyńska, P., Cruickshank, V. A., Bukowski, J., Miyagi, S., Bagger, F. O., Walfridsson, J., Schuster, M. B., Porse, B. T., & Helin, K. (2014) · Blood · doi:10.1182/blood-2013-08-522094 · Cited by 83
The cell of origin and the leukemia stem cell in acute myeloid leukemia
Chopra, M., & Bohlander, S. K. (2019) · Genes Chromosomes and Cancer · doi:10.1002/gcc.22805 · Cited by 95
Koide, S., Oshima, M., Takubo, K., Yamazaki, S., Nitta, E., Saraya, A., Aoyama, K., Kato, Y., Miyagi, S., Nakajima‐Takagi, Y., et al. (2016) · Blood · doi:10.1182/blood-2016-01-694810 · Cited by 87
“To test the role of Setdb1 in cancer stem cells, we used a myeloid leukemiamodel induced by the leukemic fusion geneMLL-AF9.(18)We purified GMPs from Cre-ERT control and Cre-ERT;Setdb1 mice and transduced them with an MLL-AF9 retrovirus (Figure 2A).”
MethodCells of origin for cancer: an updated view from prostate cancer
Xin, L. (2012) · Oncogene · doi:10.1038/onc.2012.541 · Cited by 83
Insco, M. L., Bailey, A. S., Kim, J. J., Olivares, G. H., Wapinski, O. L., Tam, C., & Fuller, M. (2012) · Cell Stem Cell · doi:10.1016/j.stem.2012.08.012 · Cited by 77
“The mechanisms that limit the number of TA divisions and initiate terminal differentiation thus may provide tumor suppressor function, and defects may contribute to progression toward cancer in adult stem cell lineages (Clarke and Fuller, 2006; Jamieson et al., 2004; Krivtsov et al., 2006).”
klumpfuss distinguishes stem cells from progenitor cells during asymmetric neuroblast division
Qi, X., Komori, H., & Lee, C. (2012) · Development · doi:10.1242/dev.081687 · Cited by 71
“Failure to properly downregulate stem cell determinants in presumptive progenitor cells might allow them to acquire stem cell-like functional properties, and can perturb tissue homeostasis and contribute to tumor formation (Krivtsov et al., 2006; Wei et al., 2008).”
BackgroundImplications of understanding cancer stem cell (CSC) biology in head and neck squamous cell cancer.
Sayed, S. I., Dwivedi, R. C., Katna, R., Garg, A., Pathak, K., Nutting, C., Rhys-Evans, P., Harrington, K., & Kazi, R. (2011) · Oral Oncology · doi:10.1016/j.oraloncology.2011.02.009 · Cited by 77
Haining, W. N., Ebert, B. L., Subrmanian, A., Wherry, E. J., Eichbaum, Q. G., Evans, J., Mak, R. H., Rivoli, S., Pretz, J. L., Angelosanto, J., et al. (2008) · The Journal of Immunology · doi:10.4049/jimmunol.181.3.1859 · Cited by 69
“GSEA has proven a powerful analytic tool to evaluate coordinately regulated patterns of genes occurring in cellular differentiation in stem cell biology (38), and immunology (31, 32).”
MethodSelf-citationMLLT3 regulates early human erythroid and megakaryocytic cell fate.
Pina, C., May, G., Soneji, S., Hong, D., & Enver, T. (2008) · Cell Stem Cell · doi:10.1016/j.stem.2008.01.013 · Cited by 77
Melanoma stem cells and metastasis: mimicking hematopoietic cell trafficking?
Lee, N., Barthel, S. R., & Schatton, T. (2013) · Laboratory Investigation · doi:10.1038/labinvest.2013.116 · Cited by 77
The Implications of Cancer Stem Cells for Cancer Therapy
Jiang, W., Peng, J., Zhang, Y., Cho, W., & Jin, K. (2012) · International Journal of Molecular Sciences · doi:10.3390/ijms131216636 · Cited by 59
“For example, leukemia stem cells can be transformed from granulocyte-macrophage progenitors with the assistance of MLL-AF9 fusion protein [72].”
BackgroundLeukemia stem cells in 2010: current understanding and future directions.
Becker, M. W., & Jordan, C. (2011) · Blood reviews · doi:10.1016/j.blre.2010.11.001 · Cited by 75
Goldstein, A. S., Stoyanova, T. I., & Witte, O. N. (2010) · Molecular Oncology · doi:10.1016/j.molonc.2010.06.009 · Cited by 75
“Much evidence in the general cancer literature supports primitive cells as efficient targets for transformation [56–59], although evidence also supports a role for cells with a more mature status in oncogenesis [60–62].”
BackgroundInfluentialMolecular Mechanisms Underlying FIP1L1-PDGFRA–Mediated Myeloproliferation
Buitenhuis, M., Verhagen, L. P., Cools, J., & Coffer, P. J. (2007) · Cancer Research · doi:10.1158/0008-5472.can-06-4183 · Cited by 70
“Although retaining their normal GMP phenotype, the self-renewal capacity of these cells was induced on the expression of MLL-AF9, suggesting that reactivation of selfrenewal in committed progenitors is both possible and sufficient to induce leukemia (26).”
BackgroundZeng, A. G. X., Iacobucci, I., Shah, S., Mitchell, A., Wong, G., Bansal, S., Chen, D., Gao, Q., Kim, H., Kennedy, J. A., et al. (2025) · Blood Cancer Discovery · doi:10.1158/2643-3230.bcd-24-0342 · Cited by 126
“…a primitive identity in most patients (57, 74–77), but within a subset of patients with AML (usually containing KMT2A rearrangements or NRAS/KRAS mutations), LSCs seem to be phenotypically committed and can be non-quiescent (28, 78–83); in some cases, these have been shown to co-exist (28, 83, 84).”
Agger, K., Miyagi, S., Pedersen, M. H., Kooistra, S., Johansen, J., & Helin, K. (2016) · Genes & Development · doi:10.1101/gad.280495.116 · Cited by 74
Overexpression of sPRDM16 coupled with loss of p53 induces myeloid leukemias in mice
Shing, D. C., Trubia, M., Marchesi, F., Radaelli, E., Belloni, E., Tapinassi, C., Scanziani, E., Mecucci, C., Crescenzi, B., Lahortiga, I., et al. (2007) · Journal of Clinical Investigation · doi:10.1172/jci32390 · Cited by 68
Developmental signaling pathways in brain tumor‐derived stem‐like cells
Clark, P. A., Treisman, D. M., Ebben, J. D., & Kuo, J. S. (2007) · Developmental Dynamics · doi:10.1002/dvdy.21381 · Cited by 65
“Canonical, or WNT/ -catenin, signaling is the most thoroughly studied WNT pathway, but the molecule has also been shown to function through two other pathways: the WNT/Ca2 and planar cell polarity (PCP; Kuhl et al., 2000; Strutt, 2003; Ille and Sommer, 2005).”
BackgroundCommon themes of dedifferentiation in somatic cell reprogramming and cancer.Preprint
Daley, G. Q. (2008) · Cold Spring Harbor Symposia on Quantitative Biology · doi:10.1101/sqb.2008.73.041 · Cited by 74
“…the MLL-AF9 oncogene associated with AML represents another model wherein expression in GMPs induces a self-renewal gene expression signature typical of hematopoietic stem cells, meaning that the tissue progenitors assume the replicative properties of the tissue stem cells (Krivtsov et al. 2006).”
BackgroundLyu, T., Wang, Y.-N., Li, D., Yang, H., Qin, B., Zhang, W.-L., Li, Z., Cheng, C., Zhang, B.-L., Guo, R.-Q., et al. (2021) · Experimental Hematology & Oncology · doi:10.1186/s40164-021-00220-7 · Cited by 73
“Previous studies have revealed that LSCs can produce leukemic progenitor cells, which differentiate into primitive leukemic cells that are blocked at different stages of the cell cycle [8].”
BackgroundSelf-citationKaushik, S., Liu, F., Veazey, K. J., Gao, G., Das, P., Neves, L., Li, K., Zhong, Y., Lu, Y., Giuliani, V., et al. (2017) · Leukemia · doi:10.1038/leu.2017.206 · Cited by 73
“To determine whether the arginine methyltransferase PRMT5 modifies MLL-AF9 leukemia, we first introduced MLL-AF9 into PRMT5 flox/flox and PRMT5 flox/flox ER-Cre bone marrow hematopoietic stem/progenitor cells with a retrovirus marked with green fluorescent protein (GFP) (MLL-AF9-IRESGFP) (29).”
BackgroundMethodThe GM-CSF receptor family: Mechanism of activation and implications for disease
Hercus, T., Broughton, S., Ekert, P., Ramshaw, H., Perugini, M., Grimbaldeston, M., Woodcock, J., Thomas, D., Pitson, S., Hughes, T., et al. (2012) · Growth Factors · doi:10.3109/08977194.2011.649919 · Cited by 73
“A number of studies suggest that AML stem cells arise from myeloid progenitor cells that adopt self-renewal properties (Cozzio et al. 2003; Krivtsov et al. 2006).”
BackgroundCD133 expression in chemo-resistant Ewing sarcoma cells
Jiang, X., Gwye, Y., Russell, D., Cao, C., Douglas, D., Hung, L. T., Kovar, H., Triche, T., & Lawlor, E. (2010) · BMC Cancer · doi:10.1186/1471-2407-10-116 · Cited by 73
“These cells exist as a minority population within the tumor, possess the stem cell properties of self-renewal and multi-lineage differentiation capacity and are proposed to be the root cells from which tumors are derived and maintained [4-10].”
BackgroundTargeting chromatin complexes in fusion protein-driven malignancies
Brien, G. L., Stegmaier, K., & Armstrong, S. A. (2019) · Nature reviews. Cancer · doi:10.1038/s41568-019-0132-x · Cited by 84
Self-citationDifferential regulation of myeloid leukemias by the bone marrow microenvironment
Krause, D. S., Fulzele, K. S., Catic, A., Sun, C. C., Dombkowski, D., Hurley, M. P., Lezeau, S., Attar, E. C., Wu, J. Y., Lin, H. Y.-F., et al. (2013) · Nature Medicine · doi:10.1038/nm.3364 · Cited by 261
“For the daily subcutaneous injections (intermittent dosing regimen), we administered human PTH (1-34) or saline at 80 μg per kg body weight per day.”
MethodTCR-dependent transformation of mature memory phenotype T cells in mice
Wang, X., Werneck, M. B. F., Wilson, B. G., Kim, H. J., Kluk, M., Thom, C. S., Wischhusen, J. W., Evans, J. A., Jesneck, J. L., Nguyen, P., et al. (2011) · Journal of Clinical Investigation · doi:10.1172/jci37210 · Cited by 82
Kustikova, O. S., Schiedlmeier, B., Brugman, M. H., Stahlhut, M., Bartels, S., Li, Z., & Baum, C. (2009) · Molecular Therapy · doi:10.1038/mt.2009.134 · Cited by 67
BERNASCONI, P. P. (2008) · British Journal of Haematology · doi:10.1111/j.1365-2141.2008.07245.x · Cited by 76
“Their significant impact on leukemia pathogenesis is further strengthened by a recent study that isolated LSC from leukemias initiated in committed granulocyte macrophage progenitors through the introduction of the MLL-MLLT3 fusion (Kristov et al, 2006).”
BackgroundLeukemia Stem Cells in Acute Myeloid Leukemia
Chan, W.-I., & Huntly, B. J. P. (2008) · Seminars in Oncology · doi:10.1053/j.seminoncol.2008.04.003 · Cited by 75
Strehl, S., Nebral, K., König, M., Harbott, J., Strobl, H., Ratei, R., Struski, S., Bielorai, B., Lessard, M., Zimmermann, M., et al. (2008) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-07-4022 · Cited by 83
Selective Inhibition of HDAC1 and HDAC2 as a Potential Therapeutic Option for B-ALL
Stubbs, M. C., Kim, W.-I., Bariteau, M. A., Davis, T. N., Vempati, S., Minehart, J. C., Witkin, M. D., Qi, J., Krivtsov, A. V., Bradner, J. E., et al. (2015) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-14-1290 · Cited by 82
“Lentiviruses were produced as described previously (27).”
Self-citationPolycomb-group proteins in hematopoietic stem cell regulation and hematopoietic neoplasms
Radulović, V., de Haan, G., & Klauke, K. (2012) · Leukemia · doi:10.1038/leu.2012.368 · Cited by 62
Dynamics of Mutant Cells in Hierarchical Organized Tissues
Werner, B., Dingli, D., Lenaerts, T., Pacheco, J. M., & Traulsen, A. (2011) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1002290 · Cited by 69
“and normal properties in all the other upstream compartments. This would be the special case described by equation (16), and can be understood as a mutation that enables a cell to reacquire stem cell-like renewal capacities again. Such a behavior can explain the origin of various subtypes of acute leukemia as has been…”
BackgroundBmi1 is essential for leukemic reprogramming of myeloid progenitor cells
Yuan, J., Takeuchi, M., Negishi, M., Oguro, H., Ichikawa, H., & Iwama, A. (2011) · Leukemia · doi:10.1038/leu.2011.85 · Cited by 86
Role of Epigenetics in Cancer Initiation and Progression
Chik, F., Szyf, M., & Rabbani, S. A. (2011) · Advances in experimental medicine and biology · doi:10.1007/978-1-4614-0254-1_8 · Cited by 74
Stem Cells in Normal Development and Cancer
D'Angelo, R. C., & Wicha, M. S. (2010) · Progress in molecular biology and translational science · doi:10.1016/b978-0-12-385071-3.00006-x · Cited by 68
Wang, W.-T., Chen, T.-Q., Zeng, Z., Pan, Q., Huang, W., Han, C., Fang, K., Sun, L.-Y., Yang, Q.-Q., Wang, D., et al. (2020) · Journal of Hematology & Oncology · doi:10.1186/s13045-020-00909-y · Cited by 70
Chan, A., & Chen, C.-W. D. (2019) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2019.00081 · Cited by 83
The multifaceted functions of C/EBPα in normal and malignant haematopoiesis
Ohlsson, E., Schuster, M. B., Hasemann, M. S., & Porse, B. T. (2015) · Leukemia · doi:10.1038/leu.2015.324 · Cited by 84
Pandolfi, A., Barreyro, L., & Steidl, U. G. (2013) · Stem Cells Translational Medicine · doi:10.5966/sctm.2012-0109 · Cited by 66
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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