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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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A progenitor cell origin of myeloid malignancies
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“These cell surface markers had been shown to be CSC surface markers in previous studies, and are believed to act as adhesive molecules with various signaling functions [13-17].”
BackgroundMonk, M., Hitchins, M. P., & Hawes, S. M. (2008) · Molecular Human Reproduction · doi:10.1093/molehr/gan025 · Cited by 58
“Although these observations have been interpreted to mean that cancer stem cells arise directly from pre-existing stem cells in the body, no causal relationship has been shown and it is possible that cancer stem cells also arise by deprogramming of more differentiated progenitor cells to the stem cell phenotype and he…”
BackgroundAubrey, B. J., Cutler, J. A., Bourgeois, W., Donovan, K. A., Gu, S. S., Hatton, C., Perlee, S. C., Perner, F., Rahnamoun, H., Theall, A. C. P., et al. (2022) · Nature Cancer · doi:10.1038/s43018-022-00366-1 · Cited by 58
Self-citationEpigenetic regulators and their impact on therapy in acute myeloid leukemia
Pastore, F., & Levine, R. L. (2016) · Haematologica · doi:10.3324/haematol.2015.140822 · Cited by 49
“Combinations of HOXA9 and MEIS1 as well as of the MLL fusion MLL-AF9 result in leukemic transformation of murine HSC and progenitor cells.(93) Several studies have shown that the H3K79 methyltransferase DOT1L is crucial for the initiation and maintenance of MLL-AF9 rearranged AML.”
BackgroundNiwa, O., Barcellos‐Hoff, M. H., Globus, R. K., Harrison, J. D., Hendry, J. H., Jacob, P., Martin, M. T., Seed, T. M., Shay, J. W., Story, M. D., et al. (2015) · Annals of the ICRP · doi:10.1177/0146645315595585 · Cited by 91
“In addition, progenitor cells have been shown to become leukaemia stem cells by direct introduction of a fusion oncogene, mixed-lineage leukaemia-acute lymphoblastic leukaemia 1 fused gene from chromosome 9 protein (MLL-AF9) (Krivtsov et al., 2006).”
BackgroundPotts, M. B., Wang, D., & Cameron, S. (2009) · Developmental Biology · doi:10.1016/j.ydbio.2009.02.022 · Cited by 50
“, 2004), and increased activity of particular Hox genes mediate important aspects of MLL action in humans and in mouse models (Armstrong et al., 2002; Drabkin et al., 2002; Ferrando et al., 2003; Krivtsov et al., 2006; Rozovskaia et al., 2003; Somervaille and Cleary, 2006; Yeoh et al., 2002).”
BackgroundLessons from microRNA mutants in worms, flies and mice
Smibert, P., & Lai, E. C. (2008) · Cell Cycle · doi:10.4161/cc.7.16.6454 · Cited by 50
Transcription factors, chromatin and cancer
Thorne, J. L., Campbell, M. J., & Turner, B. M. (2008) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2008.08.029 · Cited by 54
Nuclear NAD + homeostasis governed by NMNAT1 prevents apoptosis of acute myeloid leukemia stem cells
Shi, X. E., Jiang, Y., Kitano, A., Hu, T., Murdaugh, R. L., Li, Y., Hoegenauer, K. A., Chen, R., Takahashi, K., & Nakada, D. (2021) · Science Advances · doi:10.1126/sciadv.abf3895 · Cited by 55
“Corroborating the importance of the NAD+ biosynthesis in AML, we found that NAD+ is more abundant in L-GMPs, the LSC population in the MLL-AF9–induced AML murine model (22), than normal in GMPs (Fig.”
BackgroundLy, S., Anand, V., El-Dana, F., Nguyen, K., Cai, Y., Cai, S., Piwnica-Worms, H. M., Tripathy, D., Şahin, A. A., Andreeff, M., et al. (2021) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2020-001197 · Cited by 50
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“Failure to attenuate the function of self-renewal factors may contribute to the creation of tumor-initiating cells (Krivtsov et al., 2006; Wei et al., 2008; Liu et al., 2011; Haenfler et al., 2012; Xiao et al., 2012; Schwitalla et al., 2013).”
BackgroundDual roles for MEF2A and MEF2D during human macrophage terminal differentiation and c-Jun expression
Aude‐Garcia, C., Collin‐Faure, V., Bausinger, H., Hanau, D., Rabilloud, T., & Lemercier, C. (2010) · Biochemical Journal · doi:10.1042/bj20100131 · Cited by 58
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Stem cells and cancer: a deadly mix
Alison, M. R., Murphy, G., & Leedham, S. J. (2007) · Cell and Tissue Research · doi:10.1007/s00441-007-0510-7 · Cited by 45
“Introduction of the MLL-AF9 fusion protein can also generate leukaemic stem cells from GMPs (Krivtsov et al. 2006); furthermore, these cells maintain the gene expression profile of normal GMPs with the exception of a subset of self-renewal genes found in normal HSCs, indicating that widespread reprogramming is not req…”
BackgroundInfluentialYBX1 mediates translation of oncogenic transcripts to control cell competition in AML
Perner, F., Schnoeder, T. M., Xiong, Y., Jayavelu, A. K., Mashamba, N., Santamaría, N. T., Huber, N., Todorova, K. A., Hatton, C., Perner, B., et al. (2021) · Leukemia · doi:10.1038/s41375-021-01393-0 · Cited by 60
Self-citationEmerging roles of transit‐amplifying cells in tissue regeneration and cancer
Zhang, B., & Hsu, Y. (2017) · Wiley Interdisciplinary Reviews Developmental Biology · doi:10.1002/wdev.282 · Cited by 47
“Consistent with this change, genome-wide profiling approaches also suggest that upon oncogenic transformation, several self-renewal genes normally only expressed in HSCs, including Bmi1, Sox4, Hoxa9, and Meis1, are now upregulated in MPPs and myeloid progenitors.(94,97,98) These changes in gene expression might enable…”
BackgroundZhao, J., Chen, X., Song, G., Zhang, J., Liu, H., & Liu, X. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1612967114 · Cited by 57
“(30) were enriched in WT HSPCs but not Uhrf1-deficient HSPCs (Fig.”
BackgroundLaszlo, G., Alonzo, T., Gudgeon, C., Harrington, K. H., Kentsis, A., Gerbing, R., Wang, Y.-C., Ries, R., Raimondi, S., Hirsch, B., et al. (2015) · Journal of Hematology & Oncology · doi:10.1186/s13045-015-0215-4 · Cited by 48
“Functional studies using mouse leukemia models demonstrate that Mef2c is a potent oncogene, causing fully penetrant AML in cooperation with SOX4 [11, 22, 23].”
BackgroundSelf-citationEGFRAmplification and Glioblastoma Stem-Like Cells
Liffers, K., Lamszus, K., & Schulte, A. (2015) · Stem Cells International · doi:10.1155/2015/427518 · Cited by 43
A SALL4/MLL/HOXA9 pathway in murine and human myeloid leukemogenesis
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Self-renewal related signaling in myeloid leukemia stem cells
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SOCS2 is part of a highly prognostic 4-gene signature in AML and promotes disease aggressiveness
Nguyen, C. H., Glüxam, T., Schlerka, A., Bauer, K., Grandits, A. M., Hackl, H., Dovey, O. M., Zöchbauer‐Müller, S., Cooper, J. L., Vassiliou, G. S., et al. (2019) · Scientific Reports · doi:10.1038/s41598-019-45579-0 · Cited by 53
PBX3 is essential for leukemia stem cell maintenance in MLL‐rearranged leukemia
Guo, H.-D., Chu, Y., Wang, L., Chen, X., Chen, Y., Cheng, H., Zhang, L., Zhou, Y., Yang, F.-C., Cheng, T., et al. (2017) · International Journal of Cancer · doi:10.1002/ijc.30739 · Cited by 47
“We analyzed the expression of Pbx3 in LSCs (defined as L-GMP, or K(1)G, c-Kit(1)Gr-1)(22,35) from quaternary recipient AML mice and compared these LSCs with normal LSK (murine lineageSca-1(1)c-Kit(1)) and GMP (Linc-Kit(1)IL-7RSca1FcgRII/III(1)CD34(1)) cells enriched for normal HSPCs and normal granulocyte/macrophage p…”
BackgroundStem Cells, Cancer Stem-Like Cells, and Natural Products
Efferth, T. (2012) · Planta Medica · doi:10.1055/s-0031-1298540 · Cited by 47
Wu, Y., Dey, R., Han, A., Jayathilaka, N., Philips, M. A., Ye, J., & Chen, L. (2010) · Journal of Molecular Biology · doi:10.1016/j.jmb.2010.01.067 · Cited by 47
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“This idea correlates with the hypothesis defended by many authors in which cancer stem cells can be derived from differentiated cells in vivo [136] (Fig.”
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Cross talk between Wnt/β-catenin and Irf8 in leukemia progression and drug resistance
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Cellular reprogramming and cancer development
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“Cancer cells frequently express progenitor-related genes that are exclusively expressed in the tissue-specific stem/progenitor cells of the originated tissue.(98) The hypothesis that cancer arises from tissue-specific stem/progenitor cells suggests that the undifferentiated properties of cancer cells may be consequenc…”
BackgroundH2.0-like Homeobox Regulates Early Hematopoiesis and Promotes Acute Myeloid Leukemia
Kawahara, M., Pandolfi, A., Bartholdy, B., Barreyro, L., Will, B., Roth, M. E., Okoye-Okafor, U. C., Todorova, T. I., Figueroa, M. E., Melnick, A. M., et al. (2012) · Cancer Cell · doi:10.1016/j.ccr.2012.06.027 · Cited by 52
“Transcriptional analysis of purified stem and progenitor populations has recently been utilized as a powerful tool to identify critical regulators of stem and progenitor cell function and transformation to leukemia-initiating cells (Krivtsov et al., 2006; Majeti et al., 2009; Passegué et al., 2004; Saito et al., 2010;…”
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“For example, uncontrolled selfrenewal is a hallmark of cancer (Krivtsov et al. 2006), while a failure to maintain proliferation is often equally detrimental (Kauffman et al. 2003).”
BackgroundCancer stem cells in multiple myeloma
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“However, it is unclear whether all human cancers arise from normal self-renewing cells since studies in chronic myeloid leukemia and model systems of AML have demonstrated that specific genetic or epigenetic alterations may induce self-renewal in more differentiated cells that normally have limited replicative potenti…”
BackgroundStem cells: The root of prostate cancer?
Kasper, S. (2008) · Journal of Cellular Physiology · doi:10.1002/jcp.21489 · Cited by 46
“Basal cells were absent but the grafts contained luminal and neuroendocrine cells, demonstrating that p63 was essential for basal but not for luminal and neuroendocrine cell differentiation (Kurita et al., 2004).”
BackgroundCommon Molecular Mechanisms of Mammary Gland Development and Breast Cancer
Molyneux, G., Regan, J. L., & Smalley, M. J. (2007) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-007-7391-5 · Cited by 53
High-resolution characterization of gene function using single-cell CRISPR tiling screen
Yang, L., Chan, A. K. N., Miyashita, K., Delaney, C. D., Wang, X., Li, H., Pokharel, S. P., Li, S., Li, M., Xu, X., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-24324-0 · Cited by 45
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CD97 is a critical regulator of acute myeloid leukemia stem cell function
Martin, G. H., Roy, N., Chakraborty, S., Desrichard, A., Chung, S. S., Woolthuis, C. M., Hu, W., Berezniuk, I., Garrett-Bakelman, F. E., Hamann, J., et al. (2019) · The Journal of Experimental Medicine · doi:10.1084/jem.20190598 · Cited by 47
“…WT and CD97-deficient (CD97 − / − ) mice (Wang et al., 2007; Veninga et al., 2008) and transduced them with the leukemogenic oncogene, MLL-AF9 (MA9; Krivtsov et al., 2006; Somervaille and Cleary, 2006). c-Kit + BM HSPCs from WT or CD97 − / − mice were infected with a murine stem cell virus (MSCV)…”
InfluentialEriksson, M., Peña-Martínez, P., Ramakrishnan, R., Chapellier, M., Högberg, C., Glowacki, G., Orsmark-Pietras, C., Velasco-Hernandez, T., Lazarevic, V., Juliusson, G., et al. (2017) · Blood Advances · doi:10.1182/bloodadvances.2017006148 · Cited by 45
“We found TLR1 to be expressed on leukemic granulocyte and macrophage progenitor cells, enriched for LSCs in this model (supplemental Figure 5A).(39) Moreover, TLR2 was expressed on c-Kit(1) leukemia cells (supplemental Figure 5B).”
Liu, J., Guo, B., Chen, Z., Wang, N., Iacovino, M., Cheng, J., Roden, C., Pan, W. Q., Khan, S. A., Chen, S., et al. (2017) · Blood · doi:10.1182/blood-2016-06-721027 · Cited by 50
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“Some evidence suggests that they arise from adult stem cells because they possess biomarkers that are similar to such cells (11); other evidence shows that CSCs are subpopulations of progenitor cells (12).”
BackgroundChronic Exposure of Renal Stem Cells to Inorganic Arsenic Induces a Cancer Phenotype
Tokar, E. J., Person, R. J., Sun, Y., Perantoni, A., & Waalkes, M. (2012) · Chemical Research in Toxicology · doi:10.1021/tx3004054 · Cited by 45
Molecular and Epigenetic Mechanisms of MLL in Human Leukemogenesis
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“Several recent papers have identified additional target genes that contribute to MLL-FP leukemogenesis including a central role for MEIS1 [176], Eya1, Six1 [177], MEF2C [178,179], RUNX2, ITF-2 [178], IGSF4 [180], MYB [181,182], the Wnt pathway [131,139], CD133 [183], as well as MYC target genes in general [184–186].”
BackgroundCell Fusion, Drug Resistance and Recurrence CSCs
Nagler, C., Zänker, K. S., & Dittmar, T. (2011) · Advances in experimental medicine and biology · doi:10.1007/978-94-007-0782-5_9 · Cited by 45
Myelodysplastic syndromes: lost between two states?
Acquaviva, C., Gelsi‐Boyer, V., & Birnbaum, D. (2010) · Leukemia · doi:10.1038/leu.2009.157 · Cited by 42
Regulation of Immune Responses and Hematopoiesis by the Rap1 Signal
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Integrative genomic analysis by interoperation of bioinformatics tools in GenomeSpace
Qu, K., Garamszegi, S., Wu, F., Thorvaldsdóttir, H., Liefeld, T., Ocana, M., Borges-Rivera, D., Pochet, N. L. M. M., Robinson, J. T., Demchak, B., et al. (2016) · Nature Methods · doi:10.1038/nmeth.3732 · Cited by 50
Murine Models of Acute Leukemia: Important Tools in Current Pediatric Leukemia Research
Jacoby, E., Chien, C. D., & Fry, T. (2014) · Frontiers in Oncology · doi:10.3389/fonc.2014.00095 · Cited by 44
“In trying to study ALL, expression of ALL associated genes/mutations/translocations has led to AML in a significant number of instances.”
BackgroundInfluentialThiel, A. T., Feng, Z., Pant, D., Chodosh, L., & Hua, X. (2013) · Haematologica · doi:10.3324/haematol.2012.074195 · Cited by 44
“Plasmids The following plasmids were described elsewhere: pMIGMLL-AF9-ires-GFP, pMSCVpgk-Hoxa9-GFP, pMSCVpacMeis1A, and pcDNA3-CEBPA-HA.(1-3) Dr.”
MethodSelf-citationKhandanpour, C., Krongold, J., Schütte, J., Bouwman, F. C. M., Vaßen, L., Gaudreau, M., Chen, R., Calero‐Nieto, F. J., Diamanti, E., Hannah, R., et al. (2012) · Blood · doi:10.1182/blood-2011-02-334722 · Cited by 45
In vitro biology of human myeloid leukemia.
Mayani, H., Flores-Figueroa, E., & Chávez-González, A. (2009) · Leukemia research : a Forum for Studies on Leukemia and Normal Hemopoiesis · doi:10.1016/j.leukres.2008.11.011 · Cited by 44
Gao, Y., Zimmer, J. T., Vasic, R., Liu, C., Gbyli, R., Zheng, S.-J., Patel, A. J., Liu, W., Qi, Z., Li, Y., et al. (2023) · Cell Reports · doi:10.1016/j.celrep.2023.113163 · Cited by 46
Tumor Heterogeneity and Consequences for Bladder Cancer Treatment
Lavallée, É., Sfakianos, J. P., & Mulholland, D. J. (2021) · Cancers · doi:10.3390/cancers13215297 · Cited by 60
Anstee, N., Bilardi, R., Ng, A. P., Xu, Z., Robati, M., Vandenberg, C., & Cory, S. (2018) · Cell Death and Differentiation · doi:10.1038/s41418-018-0209-1 · Cited by 43
Lam, J., van den Bosch, M. T. J., Węgrzyn, J., Parker, J., Ibrahim, R., Slowski, K., Chang, L., Martínez-Høyer, S., Condorelli, G., Boldin, M., et al. (2018) · Nature Communications · doi:10.1038/s41467-018-04831-3 · Cited by 44
Increased DNA methylation of Dnmt3b targets impairs leukemogenesis
Schulze, I., Rohde, C., Scheller, M., Bäumer, N., Krause, A., Herbst, F., Riemke, P., Hebestreit, K., Tschanter, P., Lin, Q., et al. (2016) · Blood · doi:10.1182/blood-2015-07-655928 · Cited by 42
“InMLL-AF9 leukemia, the populationof c-Kit(1)cells is highly enriched forLICs.(39,47)ForcedDnmt3b expression in thepresent study increasednumbersofc-Kit(1) leukemiccells but reduced colony formation potential.”
BackgroundInfluentialGFI1 as a novel prognostic and therapeutic factor for AML/MDS
Hönes, J. M., Botezatu, L., Helness, A., Vadnais, C., Vaßen, L., Robert, F., Hergenhan, S. M., Thivakaran, A., Schütte, J., Al-Matary, Y. S., et al. (2016) · Leukemia · doi:10.1038/leu.2016.11 · Cited by 47
Rho GTPases in hematopoietic stem cell functions
Cancelas, J. A., & Williams, D. A. (2009) · Current Opinion in Hematology · doi:10.1097/moh.0b013e32832c4b80 · Cited by 40
Cancer stem cells in leukemia, recent advances
Zou, G.-M. (2007) · Journal of Cellular Physiology · doi:10.1002/jcp.21140 · Cited by 41
“Both normal HSCs and leukemia stem cells depend on SDF-1 mediated CXCR4 signaling for homing and mobilization (Lapidot and Kollet, 2002).”
BackgroundSera, Y., Nakata, Y., Ueda, T., Yamasaki, N., Koide, S., Kobayashi, H., Ikeda, K.-I., Kobatake, K., Iwasaki, M., Oda, H., et al. (2021) · Blood · doi:10.1182/blood.2019001044 · Cited by 42
Chambers, C., Čermáková, K., Chan, Y. S., Kurtz, K. J., Wohlan, K., Lewis, A. H., Wang, C., Pham, A., Dejmek, M., Šála, M., et al. (2023) · Cancer Research · doi:10.1158/0008-5472.can-22-2129 · Cited by 52
Ramakrishnan, R., Peña‐Martínez, P., Agarwal, P., Rodriguez‐Zabala, M., Chapellier, M., Högberg, C., Eriksson, M. D., Yudovich, D., Shah, M., Ehinger, M., et al. (2020) · Cell Reports · doi:10.1016/j.celrep.2020.107684 · Cited by 46
“This AML model is suitable for screens because of its short disease latency and high penetrance (Chapellier et al., 2019; Krivtsov et al., 2006; Puram et al., 2016).”
InfluentialJMJD1C-mediated metabolic dysregulation contributes to HOXA9-dependent leukemogenesis
Lynch, J., Salik, B., Connerty, P., Vick, B., Leung, H., Pijning, A. E., Jeremias, I., Spiekermann, K., Trahair, T., Liu, T., et al. (2019) · Leukemia · doi:10.1038/s41375-018-0354-z · Cited by 42
Self-citationFrequent loss of RAF kinase inhibitor protein expression in acute myeloid leukemia
Zebisch, A., Wölfler, A., Fried, I., Wolf, O., LIND, K., Bodner, C., Haller, M., Drasche, A., Pirkebner, D., Matallanas, D., et al. (2012) · Leukemia · doi:10.1038/leu.2012.61 · Cited by 43
Physiological cellular reprogramming and cancer
Abollo‐Jiménez, F., Jiménez, R., & Cobaleda, C. (2010) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2010.02.002 · Cited by 42
“[78] Somervaille TC, Cleary ML. Identification and characterization of leukemia stem cells in murine MLL-AF9 acute myeloid leukemia.”
InfluentialA Case of Identity: HOX Genes in Normal and Cancer Stem Cells
Smith, J., Zyoud, A., & Allegrucci, C. (2019) · Cancers · doi:10.3390/cancers11040512 · Cited by 41
“They can originate from transformation of normal tissue-resident stem/progenitor cells or reprogramming of differentiated cells [63,64].”
BackgroundCAMKs support development of acute myeloid leukemia
Kang, X., Cui, C., Wang, C., Wu, G., Chen, H., Lu, Z., Chen, X., Wang, L., Huang, J., Geng, H., et al. (2018) · Journal of Hematology & Oncology · doi:10.1186/s13045-018-0574-8 · Cited by 50
“Because LILRBs are highly expressed by monocytic AML (M5) cells [1], we used a retroviral MLL-AF9 transplantation mouse M5 AML model [19, 20] to investigate the relationship between PirB signaling and CAMKs in AML development.”
MethodMLL is essential for NUP98-HOXA9-induced leukemia
Shima, Y., Yumoto, M., Katsumoto, T., & Kitabayashi, I. (2015) · Leukemia · doi:10.1038/leu.2017.62 · Cited by 41
“In AML, leukemia-initiating cells are generated from hematopoietic stem cells or myeloid progenitor cells (31-33), in which MLL mainteins HOXA gene expression (12, 13).”
BackgroundInhibitory leukocyte immunoglobulin-like receptors in cancer development
Zhang, F., Zheng, J., Kang, X., Deng, M., Lu, Z., Kim, J., & Zhang, C. C. (2015) · Science China Life Sciences · doi:10.1007/s11427-015-4925-1 · Cited by 45
Proteolytically cleaved MLL subunits are susceptible to distinct degradation pathways
Yokoyama, A., Ficara, F., Murphy, M., Meisel, C., Naresh, A., Kitabayashi, I., & Cleary, M. L. (2011) · Journal of Cell Science · doi:10.1242/jcs.080523 · Cited by 37
“During hematopoietic development, MLL maintains expression of Hoxa9 (Jude et al., 2007; Yagi et al., 1998), which is highly expressed in HSCs and MPPs and progressively downregulated in more differentiated progenitors (Forsberg et al., 2005; Krivtsov et al., 2006; Somervaille and Cleary, 2006).”
BackgroundCancer stem cells: never Wnt away from the niche
Malanchi, I., & Huelsken, J. (2008) · Current Opinion in Oncology · doi:10.1097/cco.0b013e32831d1faf · Cited by 47
Zhao, R. C., Zhu, Y., & Shi, Y. (2008) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2008.04.008 · Cited by 38
“More recently, the MLL-AF9 fusion protein has been shown to transform committed granulocyte-macrophage progenitors into leukemia stem cells (Krivtsov et al., 2006).”
BackgroundOld disease, new culprit: Tumor stem cells in cancer
Lee, J. T., & Herlyn, M. (2007) · Journal of Cellular Physiology · doi:10.1002/jcp.21252 · Cited by 38
“…within a given tissue acquire genetic alterations that induce dedifferentiation of those cells to amore progenitor-like state (Bachoo et al., 2002; Krivtsov et al., 2006; Sharif et al., 2007); such an event would help to explain the cellular heterogeneity found in tumors, aswell as clarify why…”
BackgroundZhang, Z., Zhou, K., Li, H., Small, A., Xue, J., Huang, H., Weng, H., Su, R. J., Tan, B., Shen, C., et al. (2023) · Genes & Diseases · doi:10.1016/j.gendis.2023.01.016 · Cited by 40
Wilkinson, A., Chang, K., Kuns, R. D., Henden, A. S., Minnie, S. A., Ensbey, K. S., Clouston, A. D., Zhang, P., Koyama, M., Hidalgo, J., et al. (2019) · Blood · doi:10.1182/blood.2019000396 · Cited by 49
Xu, B., Cai, L., Butler, J. M., Chen, D., Lu, X., Allison, D. F., Lu, R., Rafii, S., Parker, J. S., Zheng, D., et al. (2018) · Stem Cell Reports · doi:10.1016/j.stemcr.2018.01.020 · Cited by 37
“Consistently, when we related our RNA-seq data to the previously reported HSC gene sets by gene set enrichment analysis (GSEA), we found that, relative to Bptf, Bptf LSK cells are enriched with LSK signature genes (Chambers et al., 2007; Krivtsov et al., 2006) and those sustained by a crucial HSC regulator, KMT2A (Art…”
ResultLoss of Dnmt3b accelerates MLL-AF9 leukemia progression
Zheng, Y., Zhang, H., Wang, Y., Li, X., Lu, P., Dong, F., Pang, Y., Ma, S., Cheng, H., Hao, S., et al. (2016) · Leukemia · doi:10.1038/leu.2016.112 · Cited by 41
Self-citationTreatment of acute myeloid leukemia models by targeting a cell surface RNA-binding protein
George, B. M., Eleftheriou, M., Yankova, E., Perr, J., Chai, P., Nestola, G., Almahayni, K., Evans, S., Damaskou, A., Hemberger, H., et al. (2025) · Nature Biotechnology · doi:10.1038/s41587-025-02648-2 · Cited by 37
“LSCs are better charac terized in mouse leukemia models 43,44 , and, as we illustrated in this study, csNPM1 is upregulated in well-defined and clinically relevant murine LSCs.”
Feng, S., Yuan, Y., Lin, Z., Li, M., Ye, D., Shi, L., Li, D., Zhao, M., Chen, M., He, X., et al. (2024) · Experimental Hematology and Oncology · doi:10.1186/s40164-024-00489-4 · Cited by 40
“To further investigate the antileukemia activity of DAC + RSL3, we used an MLL-AF9-transformed murine model for this test in vivo [42].”
MethodColligan, S. H., Amitrano, A. M., Zollo, R. A., Peresie, J., Kramer, E. D., Morreale, B. G., Barbi, J. J., Singh, P. K., Yu, H., Wang, J., et al. (2022) · Journal of Clinical Investigation · doi:10.1172/jci158661 · Cited by 51
Self-citationVCAM1 confers innate immune tolerance on haematopoietic and leukaemic stem cells
Pinho, S., Wei, Q.-Z., Maryanovich, M., Zhang, D.-C., Balandrán, J., Pierce, H., Nakahara, F., Staulo, A. D., Bartholdy, B. A., Xu, J., et al. (2022) · Nature Cell Biology · doi:10.1038/s41556-022-00849-4 · Cited by 39
Ciciarello, M., Corradi, G., Forte, D., Cavo, M., & Curti, A. (2021) · Cancers · doi:10.3390/cancers13215319 · Cited by 45
Schwarzer, A., Talbot, S. R., Selich, A., Morgan, M. A., Schott, J. W., Dittrich‐Breiholz, O., Bastone, A. L., Weigel, B., Ha, T. C., Dziadek, V., et al. (2021) · Molecular Therapy · doi:10.1016/j.ymthe.2021.06.017 · Cited by 50
Leukemia cell of origin influences apoptotic priming and sensitivity to LSD1 inhibition
Cai, S. F., Chu, H.-H. S., Goldberg, A., Parvin, S., Koche, R., Glass, J., Stein, E., Tallman, M., Şen, F., Famulare, C., et al. (2020) · bioRxiv · doi:10.1101/2020.05.11.089060 · Cited by 39
“Previous studies have demonstrated leukemogenic fusion genes, such as MLL-AF9, have the capacity to induce transformation of murine hematopoietic stem cells and of myeloid progenitors, and that these leukemias have many similarities in their biology and in the immunophenotype of the cells capable of propagating the di…”
BackgroundSelf-citationYang, L., Liu, L., Gao, H., Pinnamaneni, J. P., Sanagasetti, D., Singh, V., Wang, K., Mathison, M. N., Zhang, Q., Chen, F., et al. (2017) · Journal of Hematology & Oncology · doi:10.1186/s13045-017-0531-y · Cited by 44
Cell Fusion Hypothesis of the Cancer Stem Cell
Lü, X., & Kang, Y. (2011) · Advances in experimental medicine and biology · doi:10.1007/978-94-007-0782-5_6 · Cited by 41
“Limited reactivation of hematopoietic stem cell self-renewal genes is sufficient to drive the unlimited proliferating potential [ 75 ].”
BackgroundTargeted therapy in haematological malignancies
Hamilton, A., Gallipoli, P., Nicholson, E., & Holyoake, T. L. (2009) · The Journal of Pathology · doi:10.1002/path.2669 · Cited by 35
“Furthermore, expression of the MLL-AF9 oncoprotein has also since been shown to initiate AML in isolated granulocyte-macrophage progenitor cells [84].”
BackgroundThe Emerging Picture of Human Breast Cancer as a Stem Cell-based Disease
Cobaleda, C., Cruz, J. J., González‐Sarmiento, R., Sánchez-Garcı́a, I., & Pérez‐Losada, J. (2008) · Stem Cell Reviews and Reports · doi:10.1007/s12015-008-9012-6 · Cited by 45
“In fact, in other systems, like some types of leukemia, it has been proposed that progenitor cells might become a de novo CSCs by the acquisition of stem cell properties [63–66].”
BackgroundXu, X., Yu, Y., Zhang, W., Ma, W., He, C., Qiu, G., Wang, X., Liu, Q., Zhao, M.-Y., Xie, J.-Y., et al. (2024) · Nature Cell Biology · doi:10.1038/s41556-024-01349-3 · Cited by 38
AMKL chimeric transcription factors are potent inducers of leukemia
Dang, J., Nance, S. R., Ma, J., Cheng, J., Walsh, M. P., Vogel, P., Easton, J. B., Song, G., Rusch, M. A., Gedman, A. L., et al. (2017) · Leukemia · doi:10.1038/leu.2017.51 · Cited by 41
MLL1 and DOT1L cooperate with meningioma-1 to induce acute myeloid leukemia
Riedel, S. S., Haladyna, J. N., Bezzant, M., Stevens, B. M., Pollyea, D. A., Sinha, A. U., Armstrong, S. A., Wei, Q., Pollock, R. M., Daigle, S. R., et al. (2016) · Journal of Clinical Investigation · doi:10.1172/jci80825 · Cited by 39
“It is in clear contrast to cell-of-origin requirements in the MLL-AF9– driven mouse leukemia model; forced expression of MLL-AF9 induces high-level Hoxa9 expression and in vivo leukemogenic potential in cell-of-origin populations spanning the developmental stages of LT-HSC through GMPs, where the HOXA cluster is silen…”
ResultSelf-citationTesta, U. (2010) · Annals of Hematology · doi:10.1007/s00277-010-1118-7 · Cited by 60
Nakahara, F., Sakata-Yanagimoto, M., Komeno, Y., Kato, N., Uchida, T., Haraguchi, K., Kumano, K., Harada, Y., Harada, H., Kitaura, J., et al. (2010) · Blood · doi:10.1182/blood-2009-05-222836 · Cited by 38
Barry, E., Corry, G. N., & Rasmussen, T. P. (2010) · Expert Opinion on Therapeutic Targets · doi:10.1517/14728221003623241 · Cited by 50
“As a result, MLL-AF4 targeting of DOT1L appears to directly produce a hematopoietic stem cell-like transcriptional profile similar to that found in leukemia stem cells [87,89,92].”
Background
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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