Targeting chromatin regulators inhibits leukemogenic gene expression in NPM1 mutant leukemia

M.W.M. Kühn, E. Song, Z. Feng, A. Sinha, C.W. Chen, A.J. Deshpande, M. Cusan, N. Farnoud, A. Mupo, Carolyn Grove, R. Koche, J.E. Bradner, E. De Stanchina, G.S. Vassiliou, T. Hoshii, S.A. Armstrong

    Research output: Contribution to journalArticle

    38 Citations (Scopus)

    Abstract

    © 2016 American Association for Cancer Research.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.
    Original languageEnglish
    Pages (from-to)1166-1181
    JournalCancer Discovery
    Volume6
    Issue number10
    DOIs
    Publication statusPublished - 2016

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    Acute Myeloid Leukemia
    Chromatin
    Leukemia
    Homeobox Genes
    Gene Expression
    Clustered Regularly Interspaced Short Palindromic Repeats
    Homeodomain Proteins
    Human Activities
    Histones
    Protein-Tyrosine Kinases
    Binding Sites
    Mutation
    Therapeutics
    Genes
    Proteins

    Cite this

    Kühn, M. W. M., Song, E., Feng, Z., Sinha, A., Chen, C. W., Deshpande, A. J., ... Armstrong, S. A. (2016). Targeting chromatin regulators inhibits leukemogenic gene expression in NPM1 mutant leukemia. Cancer Discovery, 6(10), 1166-1181. https://doi.org/10.1158/2159-8290.CD-16-0237
    Kühn, M.W.M. ; Song, E. ; Feng, Z. ; Sinha, A. ; Chen, C.W. ; Deshpande, A.J. ; Cusan, M. ; Farnoud, N. ; Mupo, A. ; Grove, Carolyn ; Koche, R. ; Bradner, J.E. ; De Stanchina, E. ; Vassiliou, G.S. ; Hoshii, T. ; Armstrong, S.A. / Targeting chromatin regulators inhibits leukemogenic gene expression in NPM1 mutant leukemia. In: Cancer Discovery. 2016 ; Vol. 6, No. 10. pp. 1166-1181.
    @article{4a6415d592cd49449fb61edc9189e2be,
    title = "Targeting chromatin regulators inhibits leukemogenic gene expression in NPM1 mutant leukemia",
    abstract = "{\circledC} 2016 American Association for Cancer Research.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.",
    author = "M.W.M. K{\"u}hn and E. Song and Z. Feng and A. Sinha and C.W. Chen and A.J. Deshpande and M. Cusan and N. Farnoud and A. Mupo and Carolyn Grove and R. Koche and J.E. Bradner and {De Stanchina}, E. and G.S. Vassiliou and T. Hoshii and S.A. Armstrong",
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    Kühn, MWM, Song, E, Feng, Z, Sinha, A, Chen, CW, Deshpande, AJ, Cusan, M, Farnoud, N, Mupo, A, Grove, C, Koche, R, Bradner, JE, De Stanchina, E, Vassiliou, GS, Hoshii, T & Armstrong, SA 2016, 'Targeting chromatin regulators inhibits leukemogenic gene expression in NPM1 mutant leukemia' Cancer Discovery, vol. 6, no. 10, pp. 1166-1181. https://doi.org/10.1158/2159-8290.CD-16-0237

    Targeting chromatin regulators inhibits leukemogenic gene expression in NPM1 mutant leukemia. / Kühn, M.W.M.; Song, E.; Feng, Z.; Sinha, A.; Chen, C.W.; Deshpande, A.J.; Cusan, M.; Farnoud, N.; Mupo, A.; Grove, Carolyn; Koche, R.; Bradner, J.E.; De Stanchina, E.; Vassiliou, G.S.; Hoshii, T.; Armstrong, S.A.

    In: Cancer Discovery, Vol. 6, No. 10, 2016, p. 1166-1181.

    Research output: Contribution to journalArticle

    TY - JOUR

    T1 - Targeting chromatin regulators inhibits leukemogenic gene expression in NPM1 mutant leukemia

    AU - Kühn, M.W.M.

    AU - Song, E.

    AU - Feng, Z.

    AU - Sinha, A.

    AU - Chen, C.W.

    AU - Deshpande, A.J.

    AU - Cusan, M.

    AU - Farnoud, N.

    AU - Mupo, A.

    AU - Grove, Carolyn

    AU - Koche, R.

    AU - Bradner, J.E.

    AU - De Stanchina, E.

    AU - Vassiliou, G.S.

    AU - Hoshii, T.

    AU - Armstrong, S.A.

    PY - 2016

    Y1 - 2016

    N2 - © 2016 American Association for Cancer Research.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.

    AB - © 2016 American Association for Cancer Research.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.

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