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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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Sall4 overexpression blocks murine hematopoiesis in a dose-dependent manner
Milanovich, S. J., Peterson, J., Allred, J. R., Stelloh, C. T., Rajasekaran, K., Fisher, J. B., Duncan, S. A., Malarkannan, S., & Rao, S. (2014) · Experimental Hematology · doi:10.1016/j.exphem.2014.09.004 · Cited by 20
“with overexpression of either Sall4 isoform, we chose to focus on Sall4b overexpression for in vivo experiments using a syngeneic mouse hematopoietic cell transplant model [20].”
BackgroundMethodImplication of IRF4 Aberrant Gene Expression in the Acute Leukemias of Childhood
Adamaki, M., Lambrou, G. Ι., Athanasiadou, A., Tzanoudaki, M., Vlahopoulos, S., & Moschovi, M. A. (2013) · PLoS ONE · doi:10.1371/journal.pone.0072326 · Cited by 28
“For example, it has already been demonstrated that a subset of genes expressed in normal HSCs are highly reactivated in leukemic stem cells (LSCs), thus indicating that the LSCs express the self-renewal-associated programme normally characterising the HSCs [3].”
BackgroundInfluentialKustikova, O. S., Geiger, H., Li, Z., Brugman, M. H., Chambers, S. M., Shaw, C. A., Pike‐Overzet, K., de Ridder, D., Staal, F. J. T., von Keudell, G., et al. (2006) · Blood · doi:10.1182/blood-2006-08-044156 · Cited by 92
Wu, W., Jiang, Y., Xing, D., Zhai, Y., Sun, H., He, X. M., Luo, K., Xu, P., Pan, F., Dong, G., et al. (2024) · Cell Death Discovery · doi:10.1038/s41420-024-01940-5 · Cited by 22
“The aberrant transcriptional program is mediated through chromatin modi fi cations that promote malignant transformation, but imparting targetable therapeutic dependencies [6 – 8].”
Comprehensive Review on the Effect of Stem Cells in Cancer Progression
Das, S., Khan, T. H., & Sarkar, D. (2024) · Current Tissue Microenvironment Reports · doi:10.1007/s43152-024-00053-6 · Cited by 23
“Multiple lines of data suggest that mutated progenitor cells can give rise to the development of cancer stem cells [18–21].”
Pirillo, C., Birch, F., Tissot, F. S., Antón, S. G., Haltalli, M. L. R., Tini, V., Kong, I. Y., Piot, C., Partridge, B., Pospori, C., et al. (2022) · Blood Advances · doi:10.1182/bloodadvances.2021004321 · Cited by 28
An oncogenic enhancer encodes selective selenium dependency in AML
Eagle, K., Jiang, Y., Shi, X. E., Li, M., Obholzer, N. D., Hu, T., Perez, M. W., Koren, J. V., Kitano, A., Yi, J. S., et al. (2022) · Cell stem cell · doi:10.1016/j.stem.2022.01.003 · Cited by 40
HBO1-MLL interaction promotes AF4/ENL/P-TEFb-mediated leukemogenesisPreprint
Takahashi, S., Kanai, A., Okuda, H., Miyamoto, R., Komata, Y., Kawamura, T., Matsui, H., Inaba, T., Takaori-Kondo, A., & Yokoyama, A. (2021) · bioRxiv · doi:10.1101/2021.01.08.425834 · Cited by 21
The invasion of de-differentiating cancer cells into hierarchical tissues
Zhou, D., Luo, Y., Dingli, D., & Traulsen, A. (2019) · bioRxiv · doi:10.1371/journal.pcbi.1007167 · Cited by 21
Smyd2 is a Myc-regulated gene critical for MLL-AF9 induced leukemogenesis
Bağişlar, S., Sabò, A., Kress, T. R., Doni, M., Nicoli, P., Campaner, S., & Amati, B. (2016) · OncoTarget · doi:10.18632/oncotarget.12012 · Cited by 21
“Interestingly, while MLL-AF9-induced leukemias depend on a subset of self-renewing stem cells [46], this does not appear to be the case in Eμ-myc lymphomas [47].”
BackgroundThys, R. G., Lehman, C. E., Pierce, L., & Wang, Y.-H. (2015) · Mutation research · doi:10.1016/j.mrfmmm.2015.06.011 · Cited by 21
Self-citationEssential role of PR-domain protein MDS1-EVI1 in MLL-AF9 leukemia.
Zhang, Y., Owens, K. S., Hatem, L., Glass, C., Karuppaiah, K., Camargo, F., & Perkins, A. (2013) · Blood · doi:10.1182/blood-2012-08-453662 · Cited by 21
MLL Becomes Functional through Intra-Molecular Interaction Not by Proteolytic Processing
Yokoyama, A., Ficara, F., Murphy, M., Meisel, C., Hatanaka, C., Kitabayashi, I., & Cleary, M. L. (2013) · PLoS ONE · doi:10.1371/journal.pone.0073649 · Cited by 24
“proliferation [11], [12] and suppress senescence to cause acute leukemia [8], [10].”
BackgroundInfluentialProgress in materials for thermal ablation of cancer cells
Xu, Y., Heberlein, W., Mahmood, M., Orza, A., Karmakar, A., Mustafa, T. A., Biris, A., Casciano, D., & Biris, A. (2012) · Journal of Materials Chemistry · doi:10.1039/c2jm32792a · Cited by 21
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Self-citationWang, P.-Y., Fay, Y., Chen, C.-Y., Stevens, B. M., Neering, S., Rossi, R. M., Bushnell, T., Kuzin, I., Heinrich, D., Bottaro, A., et al. (2008) · Blood · doi:10.1182/blood-2008-02-142190 · Cited by 21
Tremblay, C. S., Hoàng, T., & Hoang, T. (2010) · Progress in molecular biology and translational science · doi:10.1016/s1877-1173(10)92006-1 · Cited by 20
Role of "cancer stem cells" and cell survival in tumor development and maintenance.Preprint
Adams, J., Kelly, P., Dakic, A., Carotta, S., Nutt, S., & Strasser, A. (2008) · Cold Spring Harbor Symposia on Quantitative Biology · doi:10.1101/sqb.2008.73.004 · Cited by 21
Song, Z., Cui, Y., Xin, L., Xiao, R., Feng, J., Li, C., Yin, Z., Wang, H., Li, Q., Wang, M., et al. (2025) · Cell stem cell · doi:10.1016/j.stem.2025.01.013 · Cited by 22
Mercier, F., Shi, J., Sykes, D. B., Oki, T., Jankovic, M., Man, C. H., Kfoury, Y. S., Miller, E., He, S., Zhu, A., et al. (2022) · Blood Advances · doi:10.1182/bloodadvances.2022007250 · Cited by 22
“The MLL/AF9 Cas9-GFP (“MA”) line was established by sorting multipotent progenitors (Lineagec-KitSca-1) from a male Cas9-GFP donor with a MSCV-MLL/AF9-IRES-GFP construct.(30) The HOXA9/MEIS1 Cas9-GFP (“HM”) line was established by sorting Lineage progenitors from a male Cas9-GFP donor and transducing with a MSCV-HoxA9…”
BackgroundMethodInfluentialMEF2C opposes Notch in lymphoid lineage decision and drives leukemia in the thymus
Canté-Barrett, K., Meijer, M. T., Cordo’, V., Hagelaar, R., Yang, W., Yu, J., Smits, W. K., Nulle, M. E., Jansen, J. P., Pieters, R., et al. (2022) · JCI Insight · doi:10.1172/jci.insight.150363 · Cited by 28
The cellular origins of cancer with particular reference to the gastrointestinal tract
Alison, M. R. (2020) · International Journal of Experimental Pathology · doi:10.1111/iep.12364 · Cited by 29
Basu, S., Nandy, A., & Biswas, D. (2020) · Biochimica et Biophysica Acta. Gene Regulatory Mechanisms · doi:10.1016/j.bbagrm.2020.194563 · Cited by 20
The transcriptional regulator FUBP1 influences disease outcome in murine and human myeloid leukemia
Hoang, V. T., Verma, D., Godavarthy, P. S., Llavona, P., Steiner, M., Gerlach, K., Michels, B. E., Bohnenberger, H., Wachter, A., Oellerich, T., et al. (2019) · Leukemia · doi:10.1038/s41375-018-0358-8 · Cited by 27
Liang, B., Li, N., Zhang, S., Qi, A.-H., Feng, J., Jing, W., Shi, C.-C., Ma, Z., & Gao, S.-M. (2019) · International Journal of Nanomedicine · doi:10.2147/ijn.s190027 · Cited by 20
“antileukemia activity of IDa/mPegPlga NPs in Mll-aF9-induced murine leukemia As reported, MLL-rearranged leukemia has been used as a classical model to assess the antileukemia activity of chemotherapy drugs, because MLL fusion proteins can efficiently transform HSPC into leukemia stem cell.(22) Therefore, MLL-AF9-indu…”
Luteinizing hormone signaling restricts hematopoietic stem cell expansion during puberty
Peng, Y. J., Yu, H. T., Hao, X., Dong, W., Yin, X., Lin, M., Zheng, J., & Zhou, B. O. (2018) · The EMBO Journal · doi:10.15252/embj.201898984 · Cited by 21
“Lhcgr deletion accelerated leukemogenesis To investigate whether the abnormally elevated hematopoiesis in Lhcgr-deficient mice relates to leukemia development, we used a transplantable murine AML model driven by the MLL-AF9 oncogene (Krivtsov et al, 2006).”
MethodPKC epsilon is a Key Regulator of Mitochondrial Redox Homeostasis in Acute Myeloid Leukemia
Marcantonio, D. D., Martinez, E., Sidoli, S., Vadaketh, J., Nieborowska-Skorska, M., Gupta, A., Meadows, J., Ferraro, F., Masselli, E., Challen, G. A., et al. (2017) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-17-2684 · Cited by 20
“To assess the impact of PKCe inhibition in vivo, we utilized a GEMM of AML that is driven by the human leukemogenic fusion protein MLL-AF9 (24).”
MethodDetermining Physical Mechanisms of Gene Expression Regulation from Single Cell Gene Expression Data
Ezer, D., Moignard, V., Göttgens, B., & Adryan, B. (2016) · PLoS Comput. Biol. · doi:10.1371/journal.pcbi.1005072 · Cited by 20
“[15]: two cell types from a healthy mouse (GMP, Lin+) and two from a leukemic mouse (LGMP, LLin+), whose leukemic cells came from a MLL-AF9 fusion protein [25].”
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Hirao, A., & Hoshii, T. (2013) · Cancer Science · doi:10.1111/cas.12189 · Cited by 24
Regalo, G., & Leutz, A. (2013) · EMBO Molecular Medicine · doi:10.1002/emmm.201302834 · Cited by 22
“Although not yet fully uncovered, the mechanistic explanation for the phenotypic ambiguity of MLL leukaemia might be assigned to the disturbance of a transcriptional progenitor signature (Krivtsov et al, 2006).”
New targets for the immunotherapy of colon cancer—does reactive disease hold the answer?
Boncheva, V., Bonney, S., Brooks, S., Tangney, M., O'Sullivan, G., Mirnezami, A., & Guinn, B.-A. (2013) · Cancer Gene Therapy · doi:10.1038/cgt.2013.5 · Cited by 20
Jenkins, C. R., Shevchuk, O. O., Giambra, V., Lam, S. H. L., Carboni, J., Gottardis, M., Holzenberger, M., Pollak, M., Humphries, R., & Weng, A. P. (2012) · Experimental Hematology · doi:10.1016/j.exphem.2012.05.003 · Cited by 20
“The MLL-AF9 fusion oncoprotein enacts a self-renewal program in committed myeloid progenitors in a fashion that is dependent on Wnt/b-catenin signaling, and leukemic granulocytemonocyte progenitors (GMPs) are thought to represent leukemia stem cells in this disease model [2,5].”
BackgroundMethodInfluentialIdentification of leukemia stem cells in acute myeloid leukemia and their clinical relevance
Hoang, V. T., Zepeda-Moreno, A., & Ho, A. D. (2012) · Biotechnology Journal · doi:10.1002/biot.201100350 · Cited by 20
Hsp90 Directly Modulates the Spatial Distribution of AF9/MLLT3 and Affects Target Gene Expression*
Lin, J. J., & Hemenway, C. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.101642 · Cited by 20
Zebrafish as a Model for Cancer Self-Renewal
Ignatius, M. S., & Langenau, D. M. (2009) · Zebrafish · doi:10.1089/zeb.2009.0610 · Cited by 21
“In a complementary study of MLL-AF9-induced AML, LICs comprised up to 50% of granulocyte-macrophage progenitors and similarly expressed more differentiated markers of granulocyte-macrophage progenitors, in contrast to the more primitive HSC markers that one would expect.(33) These results starkly contrast the human xe…”
Regulation of Stem Cell Self-Renewal and Oncogenesis by RNA-Binding Proteins
Hattori, A., Buac, K., & Ito, T. (2016) · Advances in experimental medicine and biology · doi:10.1007/978-3-319-29073-7_7 · Cited by 21
Lee, G., Shim, J., Cho, B., Jung, J., Lee, D.-S., & Oh, I. (2010) · International Journal of Hematology · doi:10.1007/s12185-010-0734-2 · Cited by 20
“Instead, a murine model of APML was produced by the oncogenic targeting of the normal counterpart of committed myeloid progenitor cells [ 14 , 15], suggesting that stem cell characteristics can be reacquired by normal committed cells during the development of LSCs.”
BackgroundEpigenetic dysregulation in acute myeloid leukemia
Schrezenmeier, J., & Huntly, B. J. P. (2025) · Seminars in Hematology · doi:10.1053/j.seminhematol.2025.06.003 · Cited by 21
“The HOXA9/MEIS1-driven programme enforced by MLL–Menin–DOT1L complexes confers stem cell-like properties [45].”
Zeisig, B., Fung, T.-K., Zarowiecki, M., Tsai, C.-T., Luo, H.-C., Stanojević, B., Lynn, C., Leung, A. Y., Zuna, J., Zaliova, M., et al. (2021) · Science Translational Medicine · doi:10.1126/scitranslmed.abc4822 · Cited by 19
The molecular signature of AML with increased ALDH activity suggests a stem cell origin
Blume, R., Rempel, E., Manta, L., Saeed, B. R., Wang, W., Raffel, S., Ermakova, O. V., Eckstein, V., Beneš, V., Trumpp, A., et al. (2018) · Leukemia & lymphoma/Leukemia and lymphoma · doi:10.1080/10428194.2017.1422862 · Cited by 20
“In addition, it has been shown that even more differentiated cells can reacquire stem cell properties if certain mutations occur [44].”
BackgroundUpdate on acute myeloid leukemia stem cells: New discoveries and therapeutic opportunities
Stahl, M. F., Kim, T. K., & Zeidan, A. M. (2016) · World Journal of Stem Cells · doi:10.4252/wjsc.v8.i10.316 · Cited by 20
Small molecule regulation of normal and leukemic stem cells
Fares, I., Rivest-Khan, L., Cohen, S., & Sauvageau, G. (2015) · Current opinion in hematology · doi:10.1097/moh.0000000000000151 · Cited by 19
“However, groups have shown that LSCs could also arise from committed progenitors that reacquire a self-renewal program from various genetic alterations [36].”
BackgroundEssential role of PU .1 in maintenance of mixed lineage leukemia‐associated leukemic stem cells
Aikawa, Y., Yamagata, K., Katsumoto, T., Shima, Y., Shino, M., Stanley, E. R., Cleary, M. L., Akashi, K., Tenen, D. G., & Kitabayashi, I. (2014) · Cancer Science · doi:10.1111/cas.12593 · Cited by 19
C/EBPalpha in leukemogenesis: a matter of being in the right place with the right signals.
Castilla, L. (2008) · Cancer Cell · doi:10.1016/j.ccr.2008.03.009 · Cited by 19
“The expression profile of CebpaL/L-LICs and its clustering with the expression profile of MLL-AF9-transformed leukemia-GMPs (Krivtsov et al., 2006) revealed that LICs may share common and initiator-mutation-specific expression signatures that drive leukemia development.”
BackgroundZeng, A. G. X., Iacobucci, I., Shah, S., Mitchell, A., Wong, G., Bansal, S., Chen, D., Gao, Q.-S., Kim, H., Kennedy, J., et al. (2023) · bioRxiv · doi:10.1101/2023.12.26.573390 · Cited by 18
“To investigate LSC heterogeneity in AML, we first turned to bulk transcriptomes from KMT2A - rearranged ( KMT2A -r) AML patients, where committed LSCs have been most commonly observed 84–86 and where both cellular and transcriptional heterogeneity has been reported 70,90 .”
Interleukin 4 promotes phagocytosis of murine leukemia cells counteracted by CD47 upregulation
Peña-Martínez, P., Ramakrishnan, R., Högberg, C., Jansson, C., Nord, D. G., & Järås, M. (2021) · Haematologica · doi:10.3324/haematol.2020.270421 · Cited by 18
“erated in a dsRed C57BL/6 transgenic background (6051; Jackson Laboratory, Bar Harbour, NY, USA), as previously described.(14) The”
MethodNguyen, C. H., Bauer, K., Hackl, H., Schlerka, A., Koller, E., Hladik, A., Stoiber, D., Zuber, J., Staber, P., Hoelbl-Kovacic, A., et al. (2019) · Cell Death and Disease · doi:10.1038/s41419-019-2172-2 · Cited by 18
Shi, X. E., Kitano, A., Jiang, Y., Luu, V., Hoegenauer, K. A., & Nakada, D. (2018) · Experimental Hematology · doi:10.1016/j.exphem.2018.04.009 · Cited by 21
“LICs have been identified in the immunotypically-defined GMP fraction, termed leukemic-GMPs (LGMPs), in multiple murine AML models (Cozzio et al., 2003; Krivtsov et al., 2006).”
BackgroundEnforced GFI1 expression impedes human and murine leukemic cell growth
Hönes, J. M., Thivakaran, A., Botezatu, L., Patnana, P. K., Castro, S. V. D. C., Al-Matary, Y. S., Schütte, J., Fischer, K. B. I., Vaßen, L., Görgens, A., et al. (2017) · Scientific Reports · doi:10.1038/s41598-017-15866-9 · Cited by 19
Guirguis, A. A., Slape, C. I., Failla, L. M., Saw, J., Tremblay, C. S., Powell, D., Rossello, F. J., Wei, A. H., Strasser, A., & Curtis, D. J. (2016) · Cell Death and Differentiation · doi:10.1038/cdd.2015.159 · Cited by 17
Christopeit, M., Tischer, J., Bornhäuser, M., Uharek, L., Pfrepper, C., Behre, G., Niederwieser, D. W., Kroger, N., Rösler, W., Klein, S., et al. (2015) · Annals of Hematology · doi:10.1007/s00277-014-2297-4
Olme, C.-H., Brown, N., Finnon, R., Bouffler, S. D., & Badie, C. (2013) · Mutation Research/Genetic Toxicology and Environmental Mutagenesis · doi:10.1016/j.mrgentox.2013.04.018 · Cited by 16
Pathprinting: An integrative approach to understand the functional basis of disease
Altschuler, G. M., Hofmann, O., Kalatskaya, I., Payne, R., Sui, S. J. H., Saxena, U., Krivtsov, A. V., Armstrong, S. A., Cai, T., Stein, L. D., et al. (2013) · Genome Medicine · doi:10.1186/gm472 · Cited by 16
“Well-characterized mouse models of AML (AML) have been used to explore the molecular basis for the stem cell-like behavior of sub-populations of leukemia cells [48].”
BackgroundSelf-citationEvolutionary Dynamics of Chronic Myeloid Leukemia
Dingli, D., Traulsen, A., Lenaerts, T., & Pacheco, J. M. (2010) · Genes & Cancer · doi:10.1177/1947601910371122 · Cited by 18
Singh, I., Fernández-Pérez, D., Sanchez, P. S., & Rodriguez-Fraticelli, A. (2025) · Cell stem cell · doi:10.1016/j.stem.2025.01.012 · Cited by 30
Role of HOX genes in cancer progression and their therapeutical aspects.
Yadav, C., Yadav, R., Nanda, S., Ranga, S., Ahuja, P., & Tanwar, M. (2024) · Gene · doi:10.1016/j.gene.2024.148501 · Cited by 17
Therapeutic targeting of leukemia stem cells in acute myeloid leukemia
Barbosa, K., & Deshpande, A. J. (2023) · Frontiers in Oncology · doi:10.3389/fonc.2023.1204895 · Cited by 20
“Therefore, immunophenotypically, AML-LSCs may not entirely resemble normal human HSCs, but more of a multipotent progenitor (MPP) (9) or a granulocyte-macrophage progenitor (GMP)-like stage (10) (Figures 1B, C).”
BackgroundThakral, D., Gupta, R., & Khan, A. (2022) · Stem Cell Reviews and Reports · doi:10.1007/s12015-022-10349-5 · Cited by 19
Circular RNAs in stem cells: from basic research to clinical implications
Lu, H., Li, J., Yang, G., Yi, C., Zhang, D., Yu, F., & Ma, Z. (2021) · Bioscience Reports · doi:10.1042/bsr20212510 · Cited by 29
“Several theories have been proposed to ex311 plain the potential origins of CSCs, including the embryonal-rest hypothesis, CSC hypothesis, and origin of CSCs 312 [134-138].”
BackgroundAhmed, H., Nimmagadda, S. C., Al-Matary, Y., Fiori, M., May, T., Frank, D., Patnana, P., Récher, C., Schliemann, C., Mikesch, J., et al. (2021) · British Journal of Haematology · doi:10.1111/bjh.17940 · Cited by 17
“Importantly, our investigation validated Notch signalling as one of the important pathways mediating the interaction of AML and MSCs using different murine and human AML cell lines and murine models of human AML.”
MethodInfluentialMEIS1 in Hematopoiesis and Cancer. How MEIS1-PBX Interaction Can Be Used in Therapy
Blasi, F., & Bruckmann, C. (2021) · Journal of Developmental Biology · doi:10.3390/jdb9040044 · Cited by 20
MYC-induced human acute myeloid leukemia requires a continuing IL-3/GM-CSF costimulus
Bulaeva, E., Pellacani, D., Nakamichi, N., Hammond, C. A., Beer, P. A., Lorzadeh, A., Moksa, M., Carles, A., Bilenky, M., Lefort, S., et al. (2020) · Blood · doi:10.1182/blood.2020006374 · Cited by 31
Uckelmann, H. J., & Armstrong, S. A. (2020) · Stem Cell Reports · doi:10.1016/j.stemcr.2020.05.013 · Cited by 20
“The concept that a committed progenitor cell with higher proliferation potential could gain self-renewal capacity and act as a cell of origin for AML was first demonstrated in the early 2000s using overexpression of fusion oncogenes, such asMLL-AF9,MLL-ENL, andMOZ-TIF2 inmyeloid progenitors (Cozzio et al., 2003; Huntl…”
BackgroundSelf-citationInhibition of Slug effectively targets leukemia stem cells via the Slc13a3/ROS signaling pathway
Zhang, Z.-H., Li, L., Wu, C., Yin, G.-S., Zhu, P., Zhou, Y.-L., Hong, Y., Ni, H., Qian, Z., & Wu, W.-S. (2019) · Leukemia · doi:10.1038/s41375-019-0566-x · Cited by 17
Dong, F., Bai, H.-T., Wang, X.-F., Zhang, S.-S., Wang, Z., Xie, M., Zhang, S., Wang, J., Sha, H., Cheng, T., et al. (2019) · Blood Advances · doi:10.1182/bloodadvances.2018022400 · Cited by 17
“For example, Lin(2)Sca-1(2)c-Kit(1)CD34 FcgRII/III(1)GFP(1) cells (L-GMP) were shown to be enriched in LSCs in the mouse model and CD123(1)CD34(1)CD38(2) cells were shown to be enriched in LSCs in AML patients.(23,42) Although the surface markers may change after transformation, LSCs seemed phenotypically similar to n…”
BackgroundMethodInfluentialSelf-citationHistone methylation regulator PTIP is required to maintain normal and leukemic bone marrow niches
Das, P., Veazey, K. J., Van, H. T., Kaushik, S., Lin, K., Lu, Y., Ishii, M., Kikuta, J., Ge, K., Nussenzweig, A., et al. (2018) · Proceedings of the National Academy of Sciences of the United States of America · doi:10.1073/pnas.1806019115 · Cited by 17
“For this, we used a murine AML model driven by the MLL-AF9 oncogene (47, 48).”
MethodA Novel Inducible Mouse Model of MLL-ENL-driven Mixed-lineage Acute Leukemia
Stavropoulou, V., Almosailleakh, M., Royo, H., Spetz, J., Juge, S., Brault, L., Kopp, P., Iacovino, M., Kyba, M., Tzankov, A., et al. (2018) · HemaSphere · doi:10.1097/hs9.0000000000000051 · Cited by 17
Miltiades, P., Lamprianidou, E., Vassilakopoulos, T., Papageorgiou, S., Galanopoulos, A., Kontos, C., Adamopoulos, P., Nakou, E., Vakalopoulou, S., Garypidou, V., et al. (2015) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-15-1288 · Cited by 17
“multipotent progenitor (LMPP)-like and granulocyte-macrophage progenitor (GMP)-like compartments (25, 28).”
BackgroundPreventing clonal evolutionary processes in cancer: Insights from mathematical models
Rodriguez-Brenes, I. A., & Wodarz, D. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1501730112 · Cited by 18
“, 38, 39), progenitor cell populations have been identified as targets for tumor initiation in several types of acute myeloid leukemias (40, 41).”
BackgroundRegulating the leukemia stem cell
Cleary, M. (2009) · Baillière's Best Practice & Research: Clinical Haematology · doi:10.1016/j.beha.2009.08.005 · Cited by 17
Zhou, G., Li, G., Chen, S., & Zhu, C. H. (2007) · Acta Pharmacologica Sinica · doi:10.1111/j.1745-7254.2007.00684.x · Cited by 11
Breast cancer, a stem cell disease.
González-Sarmiento, R., & Pérez-Losada, J. (2008) · Current Stem Cell Research & Therapy · doi:10.2174/157488808783489453 · Cited by 17
Targeting protein-protein interaction between MLL1 and reciprocal proteins for leukemia therapy
Wang, Z.-H., Li, D.-D., Chen, W.-L., You, Q.-D., & Guo, X.-K. (2018) · Bioorganic & Medicinal Chemistry · doi:10.1016/j.bmc.2017.11.045 · Cited by 16
Therapeutic targeting of chromatin alterations in leukemia and solid tumors
Perner, F., Berg, T., Sasca, D., Mersiowsky, S., Gadrey, J. Y., Thomas, J. M., Kühn, M. W. M., & Lübbert, M. (2025) · International Journal of Cancer · doi:10.1002/ijc.35389 · Cited by 16
HIPK3 maintains sensitivity to platinum drugs and prevents disease progression in gastric cancer.
Wu, Q.-N., Qi, J., Liu, Z.-K., Luo, X.-J., Yu, K., Lu, Y.-X., Wang, Y., Jin, Y., Liu, J., Huang, L.-Y., et al. (2024) · Cancer Letters · doi:10.1016/j.canlet.2024.216643 · Cited by 16
Self-citationRajagopalan, A., Feng, Y., Gayatri, M. B., Ranheim, E. A., Klungness, T., Matson, D. R., Lee, M. H., Jung, M. M., Zhou, Y., Gao, X., et al. (2023) · Journal of Clinical Investigation · doi:10.1172/jci173116 · Cited by 17
“Using published data sets (31, 32), we previously showed that NP –/– HSPCs gain partial HSC signature and largely retain the MEP signature (14).”
MethodPan, F., Iwasaki, M., Wu, W., Jiang, Y.-N., Yang, X., Zhu, L., Zhao, Z., & Cleary, M. L. (2023) · Blood Advances · doi:10.1182/bloodadvances.2022008787 · Cited by 16
Acute myeloid leukemia: therapeutic targeting of stem cells
Pabon, C. M., Abbas, H., & Konopleva, M. (2022) · Expert opinion on therapeutic targets · doi:10.1080/14728222.2022.2083957 · Cited by 16
Non-canonical H3K79me2-dependent pathways promote the survival of MLL-rearranged leukemia
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Learning from mouse models of MLL fusion gene-driven acute leukemia.
Schwaller, J. (2020) · Biochimica et Biophysica Acta. Gene Regulatory Mechanisms · doi:10.1016/j.bbagrm.2020.194550 · Cited by 16
Transcription factor Oct1 protects against hematopoietic stress and promotes acute myeloid leukemia
Jafek, J. L., Shakya, A., Tai, P.-Y., Ibarra, A., Kim, H., Maddox, J., Chumley, J., Spangrude, G. J., Miles, R. R., Kelley, T. W., et al. (2019) · Experimental Hematology · doi:10.1016/j.exphem.2019.07.002 · Cited by 18
“To determine the role of Oct1 in a mouse model of high-risk AML, we utilized retroviral MLL-AF9 transduction of primary murine hematopoietic progenitors [58,59] and the transplantation of these cells into lethally irradiated recipient mice.”
MethodEffective cancer subtyping by employing density peaks clustering by using gene expression microarray
Mehmood, R., El-Ashram, S. A., Bie, R., & Sun, Y. (2018) · Personal and Ubiquitous Computing · doi:10.1007/s00779-018-1112-y · Cited by 16
“However, accuracy of HC reported in [14] was 95.”
Epigenetic therapy as a novel approach for GFI136N-associated murine/human AML
Botezatu, L., Michel, L., Helness, A., Vadnais, C., Makishima, H., Hönes, J. M., Robert, F., Vaßen, L., Thivakaran, A., Al-Matary, Y. S., et al. (2016) · Experimental Hematology · doi:10.1016/j.exphem.2016.05.004 · Cited by 18
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Voutsadakis, I. (2015) · Biomarkers in Medicine · doi:10.2217/bmm.15.4 · Cited by 16
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“2010a) and transformation of hematopoietic SCs into leukemic SCs (Krivtsov et al. 2006).”
BackgroundSchnerch, A., Lee, J., Graham, M., Guezguez, B., & Bhatia, M. (2013) · Stem Cells and Development · doi:10.1089/scd.2012.0204 · Cited by 16
“In addition, full-length MLL (the mammalian homolog of Drosophila trithorax) was up-regulated in eHPCs and has an important role in hematopoietic establishment [64] and hematologic malignancies [65–67], while an alternative isoform of MLL is more highly expressed in SRCs.”
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The Tissue-Specific Stem Cell as a Target for Chemoprevention
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“This has also been demonstrated in the hematopoietic system: overexpression of the MLL fusion gene in a progenitor cell confers stem-like self-renewal capabilities and results in leukemia [28].”
Melanoma‐initiating cells: a compass needed
Refaeli, Y., Bhoumik, A., Roop, D. R., & Ronai, Z. (2009) · EMBO Reports · doi:10.1038/embor.2009.184 · Cited by 16
Knocking the Wnt out of the Sails of Leukemia Stem Cell Development
Deshpande, A. J., & Buske, C. (2007) · Cell stem cell · doi:10.1016/j.stem.2007.11.006 · Cited by 14
“These data confirm the observations that normal and tumor stem cells share overlapping programs (Krivtsov et al., 2006) driven by common genetic determinants.”
ResultDutta, S., Krause, A., Vosberg, S., Herold, T., Ksienzyk, B., Quintanilla-Martinez, L., Tizazu, B., Chopra, M., Graf, A., Krebs, S., et al. (2016) · Leukemia · doi:10.1038/leu.2015.349 · Cited by 16
Arumugam, P. I., Higashimoto, T., Urbinati, F., Modlich, U., Nestheide, S. V., Xia, P., Fox, C. F., Corsinotti, A., Baum, C., & Malik, P. (2009) · Molecular Therapy · doi:10.1038/mt.2009.183 · Cited by 80
Sex-dependent differences in hematopoietic stem cell aging and leukemogenic potential
Zhang, C., Hao, T., Bortoluzzi, A., Chen, M.-H., Wu, X., Wang, J., Ermel, R. W., Kim, Y., Chen, S., & Chen, W. (2024) · Oncogene · doi:10.1038/s41388-024-03197-9 · Cited by 17
Self-citationLiu, Y., Li, Q., Song, L., Gong, C., Tang, S., Budinich, K. A., Vanderbeck, A., Mathias, K. M., Wertheim, G. B. W., Nguyen, S. C., et al. (2024) · Cancer Discovery · doi:10.1158/2159-8290.cd-23-0876 · Cited by 23
“Thus, ENL mutants join a list of oncogenes, such as NUP98-fusions (20, 22, 23, 79–83), MLL/KMT2A fusions (84, 85), MN1 fusion (86, 87), and mutant NPM1 (24, 88, 89), that drive leukemogenesis in part by elevating Hoxa expression.”
BackgroundImmunoproteasome function maintains oncogenic gene expression in KMT2A-complex driven leukemia
Tubío-Santamaría, N., Jayavelu, A., Schnoeder, T., Eifert, T., Hsu, C.-J., Perner, F., Zhang, Q.-R., Wenge, D. V., Hansen, F. M., Kirkpatrick, J. M., et al. (2023) · Molecular Cancer · doi:10.1186/s12943-023-01907-7 · Cited by 15
“Next, we assessed the frequency of L-GMPs (Lin − Sca1 − c-Kit + CD34 + FcgR + ) by flow cytometry, which have been described as the functionally relevant LSC population in MA9 driven leukemia [29].”
MethodSelf-citationmiR-30e-5p regulates leukemia stem cell self-renewal through the Cyb561/ROS signaling pathway
Ge, Y., Hong, M., Zhang, Y., Wang, J., Li, L., Zhu, H.-K., Sheng, Y., Wu, W.-S., & Zhang, Z.-H. (2023) · Haematologica · doi:10.3324/haematol.2023.282837 · Cited by 15
“caused by genetic mutations in hematopoietic stem cells (HSCs) or committed progenitor compartments.(1,2) Despite ongoing efforts, the standard therapy for most types of AML has not shown significant improvements, with a 5-year overall survival rate of approximately 24% in the United States.”
BackgroundSelf-citationU2af1 is a haplo-essential gene required for hematopoietic cancer cell survival in mice
Wadugu, B. A., Srivatsan, S. N., Heard, A. D., Alberti, M. O., Ndonwi, M., Liu, J., Grieb, S., Bradley, J. L., Shao, J., Ahmed, T., et al. (2021) · Journal of Clinical Investigation · doi:10.1172/jci141401 · Cited by 21
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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