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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]
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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]
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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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BackgroundInfluentialSelf-citationmethylKit: a comprehensive R package for the analysis of genome-wide DNA methylation profiles
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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
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“while the presence of cooperating Flt3-ITD mutations does lead to increased incidence of leukemia.(26) Leukemogenesis may be dependent on the downregulation of Gata2 by hypermethylation, an effect that can be overcome by reintroduction of Gata2.”
BackgroundInfluentialInflammation-Induced Tumorigenesis and Metastasis
Hibino, S., Kawazoe, T., Kasahara, H., Itoh, S., Ishimoto, T., Sakata‐Yanagimoto, M., & Taniguchi, K. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22115421 · Cited by 319
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“The additional mutations that cause AML include AML1-ETO fusion gene,(17) CBFb-SMMHC gene fusion,(18) NUP98 translocations,(19)NPM1,(20) and loss of Tet2.(21) Recently, many studies have reported exome sequencing of AML, but these studies have a limited number of FLT3-ITD subtypes and almost none have matched diagnosi…”
BackgroundGenetic and epigenetic heterogeneity in acute myeloid leukemia
Li, S., Mason, C. E., & Melnick, A. M. (2016) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2016.03.011 · Cited by 195
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“org function can also lead to gain of cytosine methylation (18), although this effect is less pronounced than loss of 5hmC (26, 55, 56).”
BackgroundSelf-citationCytarabine and daunorubicin for the treatment of acute myeloid leukemia
Murphy, T., & Yee, K. W. L. (2017) · Expert Opinion on Pharmacotherapy · doi:10.1080/14656566.2017.1391216 · Cited by 180
“Furthermore, as the development and progression of leukemia stems from combinatorial effects of mutations rather than individual gene mutations [55,100], targeting mutant proteins that are not present in the entire leukemia cell population is unlikely to cure the disease, although it may control the disease for a peri…”
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Hu, D., & Shilatifard, A. (2016) · Genes & Development · doi:10.1101/gad.284109.116 · Cited by 175
“However, the molecular mechanisms by which MLL chimeras could contribute to the pathogenesis of leukemia were unknown until the biochemical identification of the translocation partner ELL as a transcription elongation factor for RNA polymerase II (Pol II) (Shilatifard et al. 1996; Shilatifard 1998).”
BackgroundA Highly Sensitive and Robust Method for Genome-wide 5hmC Profiling of Rare Cell Populations
Han, D., Lu, X., Shih, A. H., Nie, J., You, Q., Xu, M. M., Melnick, A. M., Levine, R. L., & He, C. (2016) · Molecular Cell · doi:10.1016/j.molcel.2016.06.028 · Cited by 167
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InfluentialSelf-citationDose-dependent role of the cohesin complex in normal and malignant hematopoiesis
Viny, A. D., Ott, C. J., Spitzer, B. G., Rivas, M. A., Meydan, C., Papalexi, E., Yelin, D., SHANK, K. R., Reyes, J. M., Chiu, A., et al. (2015) · The Journal of Experimental Medicine · doi:10.1084/jem.20151317 · Cited by 159
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Clinical resistance to crenolanib in acute myeloid leukemia due to diverse molecular mechanisms
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“Other Normal SilencedDouble mutation Single mutation IDH1 mutation TKD ITD IDH2 mutation”
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Shih, A. H., Meydan, C., SHANK, K. R., Garrett-Bakelman, F. E., Ward, P. S., Intlekofer, A. M., Nazir, A., Stein, E. M., Knapp, K. M., Glass, J. L., et al. (2017) · Cancer Discovery · doi:10.1158/2159-8290.cd-16-1049 · Cited by 113
“A feature of Flt3;Tet2-mutant leukemia is resistance to traditional AML chemotherapy and to FLT3 kinase inhibitors, thus antiproliferative therapy is insufficient to effectively target leukemias marked by mutations that disrupt DNA demethylation (18, 21).”
InfluentialSelf-citationTissue-specific DNA demethylation is required for proper B-cell differentiation and function
Orlanski, S., Labi, V., Reizel, Y., Spiro, A., Lichtenstein, M., Levin-Klein, R., Koralov, S. B., Skversky‐Blocq, Y., Rajewsky, K., Cedar, H., et al. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1604365113 · Cited by 103
“There is evidence that normal hematopoiesis is very sensitive to changes in DNA methylation metabolism, with knockouts of either Dnmt3a, Tet1, or Tet2 causing defects in differentiation while predisposing mice to hematopoietic malignancies (16, 19, 22, 56, 59, 60).”
BackgroundCombined Loss of Tet1 and Tet2 Promotes B Cell, but Not Myeloid Malignancies, in Mice
Zhao, Z., Chen, L., Dawlaty, M. M., Pan, F., Weeks, O. I., Zhou, Y., Cao, Z., Shi, H., Wang, J., Lin, L., et al. (2015) · Cell Reports · doi:10.1016/j.celrep.2015.10.037 · Cited by 104
“Another recent study has shown that combined Tet2 loss and Flt3 mutation alter DNA methylation and gene expression in LSK cells, but not with either mutation alone, and similar results are seen in human AML patients with combined TET2 and FLT3 mutations (Shih et al., 2015).”
Self-citationMeyer, S. E., Qin, T., Muench, D. E., Masuda, K., Venkatasubramanian, M., Orr, E., Suarez, L., Gore, S. D., Delwel, R., Paietta, E. M., et al. (2016) · Cancer Discovery · doi:10.1158/2159-8290.cd-16-0008 · Cited by 101
Self-citationAberrant DNA Methylation in Acute Myeloid Leukemia and Its Clinical Implications
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“This is further supported by the findings that depletion of Tet2 together with Flt3-ITD mutation can synergistically dysregulate DNA methylation and interfere with normal hematopoietic differentiation, resulting in an accumulation of HSPC and GMP populations [72].”
BackgroundMutations in 5-methylcytosine oxidase TET2 and RhoA cooperatively disrupt T cell homeostasis
Zang, S., Li, J., Yang, H., Zeng, H., Han, W., Zhang, J., Lee, M., Moczygemba, M. M., Isgandarova, S., Yang, Y., et al. (2017) · Journal of Clinical Investigation · doi:10.1172/jci92026 · Cited by 100
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“16,17 Of note, there were detectable decreases in the size of the common lymphoid progenitor (CLP) population in Flt3 ITD/+ and Npm1 cA/+ ; Flt3 ITD/+ mice (Figure 1C) (in part due to the reduction in Il-7Rα-positive cells) (Figure S2B).”
Emerging concepts of epigenetic dysregulation in hematological malignancies
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Self-citationTET2 in Normal and Malignant HematopoiesisPreprint
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“Interestingly, when TET2 loss was combined with a FLT3-ITD mutation there was a distinct set of genomic loci that underwent hypermethylation compared with either mutation alone (Shih et al. 2015).”
Self-citationLi, Y., Kong, W., Yang, W., Patel, R. M., Casey, E. B., Okeyo-Owuor, T., White, J. M., Porter, S. N., Morris, S. A., & Magee, J. A. (2020) · Cell stem cell · doi:10.1016/j.stem.2020.08.001 · Cited by 95
“Prior studies have shown that HPC-1s are the cells of origin for FLT3-driven acute myeloid leukemia (AML) (Mead et al., 2013; Shih et al., 2015), and we therefore tested whether Ifnar deletion altered FLT3 target gene expression in these cells.”
BackgroundTargeting apoptosis in acute myeloid leukaemia
Cassier, P. A., Castets, M., Belhabri, A., & Vey, N. (2017) · British Journal of Cancer · doi:10.1038/bjc.2017.281 · Cited by 86
“This classification has recently been challenged by data suggesting that alterations do not happen independently of each other but rather cooperate in disease progression (Shih et al, 2015).”
BackgroundEpigenetic Modifications in Acute Myeloid Leukemia: Prognosis, Treatment, and Heterogeneity
Goldman, S. L., Hassan, C., Khunte, M., Soldatenko, A., Jong, Y., Afshinnekoo, E., & Mason, C. E. (2019) · Frontiers in Genetics · doi:10.3389/fgene.2019.00133 · Cited by 90
Self-citationLeukemic Stem Cells: From Leukemic Niche Biology to Treatment Opportunities
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JAK2/IDH-mutant–driven myeloproliferative neoplasm is sensitive to combined targeted inhibition
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“Furthermore, we and others have shown that the Flt3ITD allele can cooperate with IDH2 gain of function or with loss of Tet2 function to induce AML and that the resultant AML is initiated and maintained by the multipotent progenitor (MPP) cell population (15, 16).”
BackgroundResultInfluentialSelf-citationNormal Hematopoiesis Is a Balancing Act of Self-Renewal and RegenerationPreprint
Olson, O. C., Kang, Y.-A., & Passegue, E. A. (2020) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a035519 · Cited by 89
Portraits of TET-mediated DNA hydroxymethylation in cancer
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DNA methylation and hydroxymethylation in hematologic differentiation and transformation
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Bcor loss perturbs myeloid differentiation and promotes leukaemogenesis
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“Sequences from this group were considered only when a difference in methylation of at least 25% was found (Reizel et al., 2015; Shih et al., 2015).”
BackgroundTET-Mediated Epigenetic Regulation in Immune Cell Development and Disease
Tsiouplis, N. J., Bailey, D. W., Chiou, L. F., Wissink, F. J., & Tsagaratou, A. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2020.623948 · Cited by 63
“In myeloid neoplasms, TET2 and IDH1/2 mutations are usually mutually exclusive (Figueroa et al., 2010; Shih et al., 2015; Inoue et al., 2016), but they are often paired together in Angioimmunoblastic T-cell Lymphoma (AITL) (Wang et al.”
BackgroundFrequent somatic TET2 mutations in chronic NK-LGL leukemia with distinct patterns of cytopenias
Olson, T. L., Cheon, H., Xing, J. C., Olson, K. C., Paila, U., Hamele, C. E., Neelamraju, Y., Shemo, B. C., Schmachtenberg, M. W., Sundararaman, S. K., et al. (2021) · Blood · doi:10.1182/blood.2020005831 · Cited by 63
Recent advances in the understanding and treatment of acute myeloid leukemia
Watts, J. M., & Nimer, S. D. (2018) · F1000Research · doi:10.12688/f1000research.14116.1 · Cited by 61
Self-citationDysregulation of TET2 in hematologic malignancies
Chiba, S. (2016) · International Journal of Hematology · doi:10.1007/s12185-016-2122-z · Cited by 62
“The offspring of such crosses have been shown to develop blood cancers 1 3 recapitulating MDS [36, 37], AML [38], and MPN [39, 40].”
BackgroundInfluentialMutated Chromatin Regulatory Factors as Tumor Drivers in Cancer
Koschmann, C. J., Núñez, F. J., Mendez, F., Brosnan‐Cashman, J. A., Meeker, A. K., Lowenstein, P. R., & Castro, M. G. (2017) · Cancer Research · doi:10.1158/0008-5472.can-16-2301 · Cited by 60
“However, similar to DNM3TA, studies in TET2-deficient mice demonstrate that the TET2 mutation alone is not enough to produce AML (41).”
Synergistic effect of BCL2 and FLT3 co-inhibition in acute myeloid leukemia
Brinton, L. T., Zhang, P., Williams, K., Canfield, D., Orwick, S. J., Sher, S., Wasmuth, R., Beaver, L. P., Cempre, C. B., Skinner, J. N., et al. (2020) · Journal of Hematology & Oncology · doi:10.1186/s13045-020-00973-4 · Cited by 59
TET2: A cornerstone in normal and malignant hematopoiesis
Kunimoto, H., & Nakajima, H. (2020) · Cancer Science · doi:10.1111/cas.14688 · Cited by 56
Single-nucleotide human disease mutation inactivates a blood-regenerative GATA2 enhancer
Soukup, A. A., Zheng, Y., Mehta, C., Wu, J., Liu, P., Cao, M., Hofmann, I., Zhou, Y., Zhang, J., Johnson, K. D., et al. (2019) · Journal of Clinical Investigation · doi:10.1172/jci122694 · Cited by 57
DNMT3A and TET2 in the Pre-Leukemic Phase of Hematopoietic Disorders
Sato, H., Wheat, J. C., Steidl, U. G., & Ito, K. (2016) · Frontiers in Oncology · doi:10.3389/fonc.2016.00187 · Cited by 59
“Notably, as many of these mutations can be found in flow cytometry defined HSC or early progenitor cells from patients with AML or MDS, TET2 mutations are hypothesized to be possible pre-leukemic mutations (67, 68, 124).”
BackgroundSelf-citationTumor propagating cells: drivers of tumor plasticity, heterogeneity, and recurrence
Vessoni, A. T., Filippi‐Chiela, E. C., Lenz, G., & Batista, L. F. Z. (2019) · Oncogene · doi:10.1038/s41388-019-1128-4 · Cited by 59
Epigenetic regulation of cancer stemness
Galassi, C., Manic, G., Esteller, M., Galluzzi, L., & Vitale, I. (2025) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-025-02340-6 · Cited by 62
“40 Con fi rming its ability to suppress AML, restoring TET2 expression prevents leukemogenesis.”
Mediator Kinase Phosphorylation of STAT1 S727 Promotes Growth of Neoplasms With JAK-STAT Activation
Niţulescu, I., Meyer, S. C., Wen, Q. J., Crispino, J. D., Lemieux, M. E., Levine, R. L., Pelish, H. E., & Shair, M. D. (2017) · EBioMedicine · doi:10.1016/j.ebiom.2017.11.013 · Cited by 55
Self-citationHematopoietic Stem Cells and the Immune System in Development and Aging
Shevyrev, D., Tereshchenko, V., Berezina, T. N., & Александрович, Р. С. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24065862 · Cited by 58
Integrating Enhancer Mechanisms to Establish a Hierarchical Blood Development Program
Mehta, C., Johnson, K. D., Gao, X., Ong, I. M., Katsumura, K. R., McIver, S. C., Ranheim, E. A., & Bresnick, E. H. (2017) · Cell Reports · doi:10.1016/j.celrep.2017.08.090 · Cited by 50
“, 2016), and it mediates leukemogenic activity in a mouse model involving Tet2 deficiency and mutant Flt3(ITD) expression (Shih et al., 2015).”
Roles of IDH1/2 and TET2 mutations in myeloid disorders
Inoue, S., Lemonnier, F., & Mak, T. W. (2016) · International Journal of Hematology · doi:10.1007/s12185-016-1973-7 · Cited by 52
Human leukemia mutations corrupt but do not abrogate GATA-2 function
Katsumura, K. R., Mehta, C., Hewitt, K. J., Soukup, A. A., de Andrade, I. F., Ranheim, E. A., Johnson, K. D., & Bresnick, E. H. (2018) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1813015115 · Cited by 48
USP15 suppresses tumor immunity via deubiquitylation and inactivation of TET2
Chen, L., Smith, M. D., Lv, L., Nakagawa, T., Li, Z., Sun, S., Brown, N. G., Xiong, Y., & Xu, Y. (2020) · Science Advances · doi:10.1126/sciadv.abc9730 · Cited by 50
Diagnosis and Therapy of Acute Myeloid Leukemia in the Era of Molecular Risk Stratification
Komanduri, K. V., & Levine, R. L. (2015) · Annual Review of Medicine · doi:10.1146/annurev-med-051914-021329 · Cited by 49
Self-citationAberrant GATA2 epigenetic dysregulation induces a GATA2/GATA6 switch in human gastric cancer
Song, S., Jeon, M.-S., Nam, J., Kang, J. K., Lee, Y. J., Kang, J. Y., Kim, H. P., Han, S., Kang, G. H., & Kim, T. Y. (2017) · Oncogene · doi:10.1038/onc.2017.397 · Cited by 46
Duy, C., Teater, M. R., Garrett-Bakelman, F. E., Lee, T. C., Meydan, C., Glass, J. L., Li, M., Hellmuth, J. C., Mohammad, H. P., Smitheman, K. N., et al. (2019) · Cancer Discovery · doi:10.1158/2159-8290.cd-19-0106 · Cited by 45
Self-citationOverexpression of CD200 is a stem cell-specific mechanism of immune evasion in AML
Herbrich, S. M., Baran, N., Cai, T., Weng, C. C. Y., Aitken, M. J. L., Post, S. M., Henderson, J. M., Shi, C., Havránek, O., Richard-Carpentier, G., et al. (2021) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2021-002968 · Cited by 47
Shearstone, J. R., Golonzhka, O., Chonkar, A., Tamang, D., van Duzer, J. H., Jones, S. S., & Jarpe, M. B. (2016) · PLoS ONE · doi:10.1371/journal.pone.0153767 · Cited by 43
“A causal link between epigenetic silencing of GATA2 and AML was recently shown, where re-expression of GATA2 resulted in the differentiation of leukemic stem cells and prevention of lethal AML in vivo [72].”
BackgroundBuscarlet, M., Tessier, A., Provost, S., Mollica, L. R., & Busque, L. (2016) · Experimental Hematology · doi:10.1016/j.exphem.2016.07.009 · Cited by 45
Döhner, H., Wei, A. H., Roboz, G. J., Montesinos, P., Thol, F. R., Ravandi, F., Dombret, H., Porkka, K., Sandhu, I., Skikne, B., et al. (2022) · Blood · doi:10.1182/blood.2022016293 · Cited by 44
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
“More recently, we and others have shown that AMLs are also characterized by significant epigenetic heterogeneity, even in the context of similar genetic alterations (Shih et al., 2015; Li et al., 2016).”
Tanaka, T. N., Morita, K., Loghavi, S., Wang, F., Furudate, K., Sasaki, Y., Little, L., Gumbs, C. E., Matthews, J. A., Daver, N. G., et al. (2021) · Blood · doi:10.1182/blood.2020010483 · Cited by 43
The many layers of epigenetic dysfunction in B-cell lymphomas
Jiang, Y., Domínguez, P. M., & Melnick, A. M. (2016) · Current Opinion in Hematology · doi:10.1097/moh.0000000000000249 · Cited by 42
Self-citationCai, Z., Lu, X., Zhang, C., Nelanuthala, S., Aguilera, F., Hadley, A., Ramdas, B., Fang, F., Nephew, K. P., Kotzin, J. J., et al. (2020) · Journal of Clinical Investigation · doi:10.1172/jci140707 · Cited by 42
“Importantly, the Gata-2 locus has recently been shown to be affected in Tet2–/– Flt3ITD mice, which develop AML associated with an increased presence of cKit+Mac-1+ blasts (10).”
BackgroundXu, Q., Wang, C., Zhou, J., Xu, Z.-M., Gao, J., Sui, P., Walsh, C. P., Ji, H., & Xu, G. (2022) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2107599119 · Cited by 41
Li, J., Chin, C. R., Ying, H., Meydan, C., Teater, M. R., Xia, M., Farinha, P., Takata, K., Chu, C.-S., Jiang, Y., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-47012-1 · Cited by 47
Self-citationClinical implications of genome-wide DNA methylation studies in acute myeloid leukemia
Li, Y., Xu, Q., Lv, N., Wang, L., Zhao, H., Wang, X., Guo, J., Chen, C., Li, Y., & Yu, L. (2017) · Journal of Hematology & Oncology · doi:10.1186/s13045-017-0409-z · Cited by 42
“The data also suggested that leukemic transformation by these epigenetic changes is reversible and therapies that reactivate silenced genes might improve outcomes for AML patients [88].”
BackgroundMercher, T., & Schwaller, J. (2019) · Frontiers in Pediatrics · doi:10.3389/fped.2019.00401 · Cited by 42
Goswami, S., Mani, R., Nunes, J. J., Chiang, C., Zapolnik, K., Hu, E. Y., Frissora, F. W., Mo, X., Walker, L. A., Yan, P. S., et al. (2021) · Blood · doi:10.1182/blood.2020010344 · Cited by 41
Zeng, H., He, H., Guo, L., Li, J., Lee, M., Han, W., Guzman, A. G., Zang, S., Zhou, Y., Zhang, X., et al. (2019) · Cancer Letters · doi:10.1016/j.canlet.2019.09.013 · Cited by 38
Targeting Bim via a lncRNA Morrbid Regulates the Survival of Preleukemic and Leukemic Cells
Cai, Z., Aguilera, F., Ramdas, B., Daulatabad, S. V., Srivastava, R., Kotzin, J. J., Carroll, M. P., Wertheim, G. B. W., Williams, A., Janga, S. C., et al. (2020) · Cell Reports · doi:10.1016/j.celrep.2020.107816 · Cited by 37
“Furthermore, the Tet2−/−; Flt3ITD/ITD model of AML, the preleukemic model bearing Tet2 loss, and a murine model expressing a knockin allele of Flt3ITD manifest several cardinal features of human AML, chronic myelomonocytic leukemia (CMML), and myeloproliferative neoplasm (MPN), respectively (Chu et al., 2012; Moran-Cr…”
BackgroundResultXie, J., Sheng, M., Rong, S., Zhou, D., Wang, C., Wu, W., Huang, J., Sun, Y., Wang, Y., Chen, P., et al. (2023) · Leukemia · doi:10.1038/s41375-023-02055-z · Cited by 39
Self-citationSomatic Mutations Drive Specific, but Reversible, Epigenetic Heterogeneity States in AML
Li, S., Chen, X., Wang, J., Meydan, C., Glass, J. L., Shih, A. H., Delwel, R., Levine, R. L., Mason, C. E., & Melnick, A. M. (2020) · Cancer Discovery · doi:10.1158/2159-8290.cd-19-0897 · Cited by 35
“December 2020 CANCER DISCOVERY | 1947 methylation status of the Lineage−Sca+cKit+ (LSK) cell populations from wild-type (3 samples), Idh2R140Q (3 samples), Flt3ITD (3 samples), Tet2−/− (3 samples), Idh2R140Q;Flt3ITD (4 samples), and Tet2−/−;Flt3ITD mice (3 samples) were profiled (11).”
BackgroundMethodInfluentialSelf-citationEvolving Treatment Strategies for Elderly Leukemia Patients with IDH Mutations
Buege, M. J., DiPippo, A. J., & Dinardo, C. D. (2018) · Cancers · doi:10.3390/cancers10060187 · Cited by 35
“, FLT3ITD) to produce epigenetic modifications leading to overt leukemic transformation [11,81,82].”
BackgroundPathogenic Mechanisms in Acute Myeloid Leukemia
Chakraborty, S., & Park, C. Y. (2022) · Current Treatment Options in Oncology · doi:10.1007/s11864-022-01021-8 · Cited by 36
Romine, K. A., MacPherson, K., Cho, H.-J., Kosaka, Y., Flynn, P., Byrd, K., Coy, J. L., Newman, M., Pandita, R., Loo, C. P., et al. (2023) · Leukemia · doi:10.1038/s41375-023-01808-0 · Cited by 35
“Accordingly, we showed that a LysM- Cre Flt3-ITD/Tet2 AML mouse model, similar to the previously described Vav-Cre Flt3-ITD/Tet2 model [34] but retaining wild-type T cells, phenocopies the immune exhaustion and PD1 refractoriness found in many patients with AML.”
MethodSHP2 inhibition reduces leukemogenesis in models of combined genetic and epigenetic mutations
Pandey, R., Ramdas, B., Wan, C., Sandusky, G. E., Mohseni, M., Zhang, C., & Kapur, R. (2019) · Journal of Clinical Investigation · doi:10.1172/jci130520 · Cited by 35
“These results are in striking contrast to treatment of leukemic mice carrying mutant Tet2–/– Flt3ITD cells with a FLT3ITD-specific inhibitor, AC220 (3).”
BackgroundResultInfluentialTranscriptional networks in acute myeloid leukemia
Thoms, J. A. I., Beck, D., & Pimanda, J. E. (2019) · Genes Chromosomes and Cancer · doi:10.1002/gcc.22794 · Cited by 33
Anderson, N., Sheth, V., Li, H., Harris, M. W., Qiu, S., Crossman, D., Kumar, H., Agarwal, P., Nagasawa, T., Paterson, A., et al. (2022) · Leukemia · doi:10.1038/s41375-022-01798-5 · Cited by 29
“Phenotypic LT-HSC (CD48-CD150+ LSK) were almost absent in Flt3-ITD TET2-KO mice, consistent with previous reports, and were not transplanted [14, 22].”
BackgroundMethodResultPorter, S. N., Cluster, A. S., Yang, W., Busken, K. A., Patel, R. M., Ryoo, J., & Magee, J. A. (2016) · eLife · doi:10.7554/elife.18882 · Cited by 34
Morinishi, L. S., Kochanowski, K., Levine, R. L., Wu, L. F., & Altschuler, S. J. (2020) · Cell Systems · doi:10.1016/j.cels.2020.06.003 · Cited by 32
Self-citationRole of TET dioxygenases in the regulation of both normal and pathological hematopoiesis
Joshi, K., Zhang, L., Breslin, P., Kini, A. R., & Zhang, J. (2022) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-022-02496-x · Cited by 31
Clonal evolution of preleukemic hematopoietic stem cells in acute myeloid leukemia
Sykes, S. M., Kokkaliaris, K. D., Milsom, M. D., Levine, R. L., & Majeti, R. (2015) · Experimental Hematology · doi:10.1016/j.exphem.2015.08.012 · Cited by 32
“As previously described by Dr. Levine's group, these mice develop a fully penetrant AML disease phenotype that is resistant to treatment with the front line combination therapy of Doxorubicin and Cytarabine [11].”
BackgroundSelf-citationEpigenetic dysregulation of hematopoietic stem cells and preleukemic state
Kunimoto, H., & Nakajima, H. (2017) · International Journal of Hematology · doi:10.1007/s12185-017-2257-6 · Cited by 30
Chromatin regulator Asxl1 loss and Nf1 haploinsufficiency cooperate to accelerate myeloid malignancy
Zhang, P., He, F., Bai, J., Yamamoto, S., Shi, C., Zhang, L., Sheng, M., Zhang, L., Guo, Y., Man, N., et al. (2018) · Journal of Clinical Investigation · doi:10.1172/jci121366 · Cited by 29
“For example, loss of Tet2 or Dnmt3a cooperates with Flt3ITD to induce myeloid leukemia (37-39).”
Self-citationAging and leukemic evolution of hematopoietic stem cells under various stress conditions
Kurosawa, S., & Iwama, A. (2020) · Inflammation and Regeneration · doi:10.1186/s41232-020-00138-3 · Cited by 29
ABCA1 Exerts Tumor-Suppressor Function in Myeloproliferative Neoplasms
Viaud, M., Abdel-Wahab, O. I., Gall, J., Ivanov, S., Guinamard, R., Sore, S., Merlin, J., Ayrault, M., Guilbaud, E., Jacquel, A., et al. (2020) · Cell Reports · doi:10.1016/j.celrep.2020.02.056 · Cited by 28
“In myeloid malignancies, hematopoietic stem and progenitor cells (HSPCs) acquire specific combinations of leukemia disease alleles required to promote hematopoietic transformation (Shih et al., 2015; Kunimoto et al., 2018).”
BackgroundSelf-citationTan, P. T., Tiong, I. S., Fleming, S. A., Pomilio, G., Cummings, N., Droogleever, M., McManus, J. F., Schwarer, A. P., Catalano, J. V., Patil, S. S., et al. (2016) · Oncotarget · doi:10.18632/oncotarget.13699 · Cited by 27
“4EBP1: Eukaryotic translation initiation factor 4E-binding protein 1; AKT: Protein kinase B; AML: Acute myeloid leukemia; Cmax: Maximum concentration; CR: Complete remission; CRi: Complete remission with incomplete blood count recovery; CTCAE: Common terminology criteria for adverse events; CYP3A4: Cytochrome P450 3A4…”
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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