The DOI matches its Crossref record; 50 of the 50 references it cites were found in a registry or an index.
Targeting Chromatin Regulators Inhibits Leukemogenic Gene Expression in NPM1 Mutant Leukemia
Open accessAbstract
Homeobox (HOX) proteins and the receptor tyrosine kinase FLT3 are frequently highly expressed and mutated in acute myeloid leukemia (AML). Aberrant HOX expression is found in nearly all AMLs that harbor a mutation in the Nucleophosmin (NPM1) gene, and FLT3 is concomitantly mutated in approximately 60% of these cases. Little is known about how mutant NPM1 (NPM1mut) cells maintain aberrant gene expression. Here, we demonstrate that the histone modifiers MLL1 and DOT1L control HOX and FLT3 expression and differentiation in NPM1mut AML. Using a CRISPR/Cas9 genome editing domain screen, we show NPM1mut AML to be exceptionally dependent on the menin binding site in MLL1. Pharmacologic small-molecule inhibition of the menin–MLL1 protein interaction had profound antileukemic activity in human and murine models of NPM1mut AML. Combined pharmacologic inhibition of menin–MLL1 and DOT1L resulted in dramatic suppression of HOX and FLT3 expression, induction of differentiation, and superior activity against NPM1mut leukemia. Significance: MLL1 and DOT1L are chromatin regulators that control HOX, MEIS1, and FLT3 expression and are therapeutic targets in NPM1mut AML. Combinatorial small-molecule inhibition has synergistic on-target activity and constitutes a novel therapeutic concept for this common AML subtype. Cancer Discov; 6(10); 1166–81. ©2016 AACR. See related commentary by Hourigan and Aplan, p. 1087. This article is highlighted in the In This Issue feature, p. 1069
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Cites
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Cytoplasmic Nucleophosmin in Acute Myelogenous Leukemia with a Normal Karyotype
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Transformation from committed progenitor to leukaemia stem cell initiated by MLL–AF9
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“MLL1-rearranged leukemias exhibit aberrant HOXA-cluster expression as a consequence of chromatin binding of the MLL1fusion complex(18), which in turn requires the association with at least two other proteins, menin and LEDGF.”
BackgroundSelf-citationMLL translocations, histone modifications and leukaemia stem-cell development
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Self-citationSelective Killing of Mixed Lineage Leukemia Cells by a Potent Small-Molecule DOT1L Inhibitor
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Self-citationAltered Hox expression and segmental identity in Mll-mutant mice
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MLL-Rearranged Leukemia Is Dependent on Aberrant H3K79 Methylation by DOT1L
Bernt, K. M., Zhu, N., Sinha, A. U., Vempati, S., Faber, J., Krivtsov, A. V., Feng, Z., Punt, N., Daigle, A., Bullinger, L., et al. (2011) · Cancer Cell · doi:10.1016/j.ccr.2011.06.010 · Cited by 870
Self-citationAssessment of Minimal Residual Disease in Standard-Risk AML
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Cited by
The menin inhibitor revumenib in KMT2A-rearranged or NPM1-mutant leukaemia
Issa, G. C., Aldoss, I., DiPersio, J., Cuglievan, B., Stone, R., Arellano, M., Thirman, M. J., Patel, M. R., Dickens, D. S., Shenoy, S., et al. (2023) · Nature · doi:10.1038/s41586-023-05812-3 · Cited by 507
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Self-citationMutant NPM1 Maintains the Leukemic State through HOX Expression
Brunetti, L., Gundry, M. C., Sorcini, D., Guzman, A. G., Huang, Y.-H., Ramabadran, R., Gionfriddo, I., Mezzasoma, F., Milano, F., Nabet, B., et al. (2018) · Cancer Cell · doi:10.1016/j.ccell.2018.08.005 · Cited by 313
Therapeutic targeting of preleukemia cells in a mouse model of NPM1 mutant acute myeloid leukemia
Uckelmann, H. J., Kim, S. M., Wong, E. M., Hatton, C., Giovinazzo, H., Gadrey, J. Y., Krivtsov, A. V., Rücker, F. G., Döhner, K., McGeehan, G. M., et al. (2020) · Science · doi:10.1126/science.aax5863 · Cited by 257
Self-citationTaylor, S. J., Stauber, J., Bohorquez, O., Tatsumi, G., Kumari, R., Chakraborty, J., Bartholdy, B. A., Schwenger, E., Sundaravel, S., Farahat, A. A., et al. (2024) · Nature Genetics · doi:10.1038/s41588-024-01911-7 · Cited by 22
Metadata
- Authors
- Kühn, M. W. M., Song, E., Feng, Z., Sinha, A., Chen, C.-W., Deshpande, A. J., Cusan, M., Farnoud, N., Mupo, A., Grove, C., Koche, R., Bradner, J. E., de Stanchina, E., Vassiliou, G. S., Hoshii, T., & Armstrong, S. A.
- Venue
- Cancer Discovery
- Published
- 2016-10-01
- Volume
- 6
- Issue
- 10
- Pages
- 1166-1181
- ISSN
- 2159-8274 (ISSN-L)
- 2159-8290
- OpenAlex
- W4241093998
- Cited by
- 264
- References
- 50
- FWCI
- 10.80
- Type
- journal article
- Language
- en
- Open access
- green
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- Kühn, M. W. M., Song, E., Feng, Z., Sinha, A., Chen, C.-W., Deshpande, A. J., Cusan, M., Farnoud, N., Mupo, A., Grove, C., Koche, R., Bradner, J. E., de Stanchina, E., Vassiliou, G. S., Hoshii, T., & Armstrong, S. A. (2016). Targeting Chromatin Regulators Inhibits Leukemogenic Gene Expression in NPM1 Mutant Leukemia. Cancer Discovery. https://doi.org/10.1158/2159-8290.cd-16-0237
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