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Mutational Cooperativity Linked to Combinatorial Epigenetic Gain of Function in Acute Myeloid Leukemia
Open accessAbstract
Specific combinations of acute myeloid leukemia (AML) disease alleles, including FLT3 and TET2 mutations, confer distinct biologic features and adverse outcome. We generated mice with mutations in Tet2 and Flt3, which resulted in fully penetrant, lethal AML. Multipotent Tet2(-/-);Flt3(ITD) progenitors (LSK CD48(+)CD150(-)) propagate disease in secondary recipients and were refractory to standard AML chemotherapy and FLT3-targeted therapy. Flt3(ITD) mutations and Tet2 loss cooperatively remodeled DNA methylation and gene expression to an extent not seen with either mutant allele alone, including at the Gata2 locus. Re-expression of Gata2 induced differentiation in AML stem cells and attenuated leukemogenesis. TET2 and FLT3 mutations cooperatively induce AML, with a defined leukemia stem cell population characterized by site-specific changes in DNA methylation and gene expression.
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“Only combined loss of Tet2 and Dnmt3A (18) or presence of AML-associated gene lesions impairing myeloid cell maturation triggers malignant transformation of Tet2-deficient mouse HSC (13).”
From PU.1-Dependent Enhancer Inhibition Separates Tet2 -Deficient Hematopoiesis from Malignant Transformation (2022) · cites this paper as [13]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
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“both of the latter develop a late-onset myeloproliferative phenotype (Supplementary Fig. S2B–S2I; refs. 13, 17).”
From PU.1-Dependent Enhancer Inhibition Separates Tet2 -Deficient Hematopoiesis from Malignant Transformation (2022) · cites this paper as [13]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
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“It is noteworthy that MPPGM (also commonly referred to as MPP3) (Challen et al., 2021) appears to be a nexus of myeloid expansion under both inflammatory conditions and in animal models of myeloid malignancy (Schepers et al., 2013; Pietras et al., 2015; Shih et al., 2015; Pietras et al., 2016; Herault et al., 2017; Hernandez et al., 2020; Kang et al., 2020; Rabe et al., 2020).”
From PU.1 is required to restrain myelopoiesis during chronic inflammatory stress (2023) · cites this paper as Shih et al., 2015
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Cites
Bonnet, D. A., & Dick, J. E. (1997) · Nature Medicine · doi:10.1038/nm0797-730 · Cited by 7,197 · cited 2×
“Transplantation studies of human leukemias demonstrated that leukemia initiating capacity is highest in CD34+CD38 stem cells (Bonnet and Dick, 1997).”
BackgroundMolecular signatures database (MSigDB) 3.0
Liberzon, A., Subramanian, A., Pinchback, R., Thorvaldsdóttir, H., Tamayo, P., & Mesirov, J. P. (2011) · Bioinformatics · doi:10.1093/bioinformatics/btr260 · Cited by 7,111 · cited 2×
“Gene set enrichment analysis (GSEA) analysis showed that VTet2 / Flt3ITD LSK cells were characterized by enrichment of an embryonic stem cell signature and reduced expression of a GATA target signature (Figure 4C) (Liberzon et al., 2011; Wong et al., 2008).”
BackgroundConversion of 5-Methylcytosine to 5-Hydroxymethylcytosine in Mammalian DNA by MLL Partner TET1
Tahiliani, M., Koh, K. P., Shen, Y., Pastor, W. A., Bandukwala, H., Brudno, Y., Agarwal, S., Iyer, L. M., Liu, D. R., Aravind, L., et al. (2009) · Science · doi:10.1126/science.1170116 · Cited by 5,836 · cited 1×
“TET2 catalyzes the 5-hydroxylation of methylcytosine to 5-hydroxymethylcytosine (5-hmC) leading to DNA demethylation (Guo et al., 2011; Tahiliani et al., 2009).”
BackgroundGenomic and Epigenomic Landscapes of Adult De Novo Acute Myeloid Leukemia
The Cancer Genome Atlas Research Network (2013) · New England Journal of Medicine · doi:10.1056/nejmoa1301689 · Cited by 5,078 · cited 5×
“Although the combination of Tet2 and Flt3 mutations in our mouse model was sufficient to promote leukemogenesis, additional mutations and chromosomal alterations are sometimes seen in TET2;FLT3ITD mutant human AML (Cancer Genome Atlas Research Network, 2013), suggesting additional events may be required to transform h…”
BackgroundMethodInfluentialAge-related clonal hematopoiesis associated with adverse outcomes
Jaiswal, S., Fontanillas, P., Flannick, J., Manning, A., Grauman, P. V., Mar, B. G., Lindsley, R. C., Mermel, C. H., Burtt, N., Chavez, A., et al. (2014) · New England Journal of Medicine · doi:10.1056/nejmoa1408617 · Cited by 4,841 · cited 2×
“Analysis of AML and normal subjects suggests mutations in TET2 and in epigenetic regulators can represent early acquiredmutations in ‘‘pre-leukemic’’ stem cells, which subsequently acquire further mutations leading to overt transformation (Genovese et al., 2014; Jaiswal et al., 2014; Jan et al., 2012).”
BackgroundClonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence
Genovese, G., Kähler, A. K., Handsaker, R. E., Lindberg, J., Rose, S. A., Bakhoum, S. F., Chambert, K., Mick, E., Neale, B. M., Fromer, M., et al. (2014) · New England Journal of Medicine · doi:10.1056/nejmoa1409405 · Cited by 3,531 · cited 1×
“…of AML and normal subjects suggests mutations in TET2 and in epigenetic regulators can represent early acquiredmutations in ‘‘pre-leukemic’’ stem cells, which subsequently acquire further mutations leading to overt transformation (Genovese et al., 2014; Jaiswal et al., 2014; Jan et al., 2012).”
BackgroundFigueroa, M. E., Abdel-Wahab, O., Lu, C., Ward, P. S., Patel, J., Shih, A., Li, Y., Bhagwat, N., Vasanthakumar, A., Fernandez, H. F., et al. (2010) · Cancer Cell · doi:10.1016/j.ccr.2010.11.015 · Cited by 2,766 · cited 9×
“In addition, mutations in IDH1 and IDH2 inhibit TET2 function through production of 2-hydroxyglutarate (Figueroa et al., 2010), and WT1 mutations lead to reduced TET2 function and reductions in 5hmC (Rampal et al.”
BackgroundInfluentialSelf-citationmethylKit: a comprehensive R package for the analysis of genome-wide DNA methylation profiles
Akalin, A., Kormáksson, M., Li, S., Garrett-Bakelman, F. E., Figueroa, M. E., Melnick, A. M., & Mason, C. E. (2012) · Genome biology · doi:10.1186/gb-2012-13-10-r87 · Cited by 2,269 · cited 8×
“Notably, of the 27 genes with promoter DMRs and differential expression, 19 were differentially methylated in TET2 mutant AML patients (Table S6) (Akalin et al., 2012a).”
BackgroundMethodInfluentialSelf-citationPrognostic Relevance of Integrated Genetic Profiling in Acute Myeloid Leukemia
Patel, J. P., Gönen, M., Figueroa, M. E., Fernandez, H. F., Sun, Z., Racevskis, J., Vlierberghe, P. V., Dolgalev, I., Thomas, S., Aminova, O., et al. (2012) · New England Journal of Medicine · doi:10.1056/nejmoa1112304 · Cited by 1,990 · cited 9×
“In particular, TET2mutations are associated with adverse outcome in the setting of concurrent FLT3ITD mutations (Hou et al., 2014; Patel et al., 2012), suggesting thesemutations cooperate to induce a poor-prognosis subtype.”
BackgroundInfluentialSelf-citationAge-related mutations associated with clonal hematopoietic expansion and malignancies
Xie, M., Lu, C., Wang, J., McLellan, M. D., Johnson, K. J., Wendl, M. C., McMichael, J. F., Schmidt, H. K., Yellapantula, V., Miller, C. A., et al. (2014) · Nature Medicine · doi:10.1038/nm.3733 · Cited by 1,874
Cited by
Sorted by citations
Role of TET enzymes in DNA methylation, development, and cancer
Rasmussen, K. D., & Helin, K. (2016) · Genes & Development · doi:10.1101/gad.276568.115 · Cited by 1,040
“AML1-ETO or FLT3-ITD (two common oncogenic alterations) in Tet2-depleted hematopoietic cells results in complete leukemogenic transformation into AML-like diseases (Rasmussen et al. 2015; Shih et al. 2015; Hatlen et al. 2016).”
BackgroundRestoration of TET2 Function Blocks Aberrant Self-Renewal and Leukemia Progression
Cimmino, L., Dolgalev, I., Wang, Y., Yoshimi, A., Martin, G. H., Wang, J., Ng, V., Xia, B., Witkowski, M. T., Mitchell-Flack, M., et al. (2017) · Cell · doi:10.1016/j.cell.2017.07.032 · Cited by 707
Self-citationAscorbate regulates haematopoietic stem cell function and leukaemogenesis
Agathocleous, M., Meacham, C. E., Burgess, R. J., Piskounova, E., Zhao, Z., Crane, G. M., Cowin, B. L., Bruner, E., Murphy, M. M., Chen, W., et al. (2017) · Nature · doi:10.1038/nature23876 · Cited by 545
“CD48 + CD150 − LSK HPC cells, which can initiate AML from Flt3 ITD ;Tet2 Δ/+ cells 31 , expanded to a significantly greater extent in the bone marrow (Extended Data Fig.”
InfluentialBurchert, A., Bug, G., Fritz, L. V., Finke, J., Stelljes, M., Röllig, C., Wollmer, E., Wäsch, R., Bornhäuser, M., Berg, T., et al. (2020) · Journal of Clinical Oncology · doi:10.1200/jco.19.03345 · Cited by 576
Biology and relevance of human acute myeloid leukemia stem cells
Thomas, D., & Majeti, R. (2017) · Blood · doi:10.1182/blood-2016-10-696054 · Cited by 517
“In a recent published combinatorial model of TET2 knockout and FLT3-ITD mutation, secondary transplantation of FACS-purified LSK CD48(1) CD150(2) MPP-like cells, which are not normally associated with self-renewal, initiated andmaintained leukemia.(69) In contrast, GMPlike blasts were unable to initiate disease, sugge…”
Background
Metadata
- Authors
- Shih, A. H., Jiang, Y., Meydan, C., Shank, K., Pandey, S., Barreyro, L., Antony-Debre, I., Viale, A., Socci, N., Sun, Y., Robertson, A., Cavatore, M., de Stanchina, E., Hricik, T., Rapaport, F., Woods, B., Wei, C., Hatlen, M., Baljevic, M., Nimer, S. D., Tallman, M., Paietta, E., Cimmino, L., Aifantis, I., Steidl, U., Mason, C., Melnick, A., & Levine, R. L.
- Affiliations
- Memorial Sloan Kettering Cancer Center (US)
- Weill Cornell Medicine (US)
- Albert Einstein College of Medicine (US)
- University of Miami (US)
- Montefiore Medical Center (US)
- Howard Hughes Medical Institute (US)
- Cornell University (US)
- Corresponding author
- Melnick, Ari
- Levine, Ross L.
- ORCID
- Venue
- Cancer Cell
- Publisher
- Elsevier BV
- Published
- 2015-04
- Volume
- 27
- Issue
- 4
- Pages
- 502-515
- ISSN
- 1535-6108 (ISSN-L)
- PMC
- PMC4518555
- OpenAlex
- W1977440531
- Cited by
- 236
- References
- 50
- Citations by year
- 2026: 12 · 2025: 15 · 2024: 12 · 2023: 15 · 2022: 18 · 2021: 22 · 2020: 25 · 2019: 23 · 2018: 19 · 2017: 33 · 2016: 31 · 2015: 11
- FWCI
- 22.62
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cancer Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- HAL (submittedVersion, other-oa)
- Funders
- National Human Genome Research Institute (R01HG006798)
- National Cancer Institute (U10CA180820, R01CA166429, CA172636-01, R01CA169784, R01CA173636, U10CA180827, U10CA021115, P30CA008748, P30CA013330, U24CA196172, R01CA166835)
- National Institute of Neurological Disorders and Stroke (R01NS076465)
- Topics
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinoids in leukemia and cellular processes
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Keywords
- acute myeloid leukemia, TET2, FLT3-ITD, DNA methylation, GATA2, leukemia stem cells, leukemogenesis, mouse model, chemoresistance
- MeSH terms
- Antineoplastic Agents, Cell Differentiation, Cytarabine, DNA-Binding Proteins, Doxorubicin, Mutation, Proto-Oncogene Proteins, Leukemia, Myeloid, Acute, Gene Expression Regulation, Neoplastic, DNA Methylation, Gene Silencing, Epigenesis, Genetic, Dioxygenases, GATA2 Transcription Factor, fms-Like Tyrosine Kinase 3, Haploinsufficiency
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