The methyltransferase G9a regulates HoxA9-dependent transcription in AML

Bernhard Lehnertz; Caroline Pabst; Le Su; Michelle Miller; Feng Liu; Lin Yi; Regan Zhang; Jana Krosl; Eric Yung; Jeanette Kirschner; Patty Rosten; T. Michael Underhill; Jian Jin; Joseé Hébert; Guy Sauvageau; R. Keith Humphries; Fabio M. Rossi

doi:10.1101/gad.236794.113

The methyltransferase G9a regulates HoxA9-dependent transcription in AML

Bernhard Lehnertz, Caroline Pabst, Le Su, Michelle Miller, Feng Liu, Lin Yi, Regan Zhang, Jana Krosl, Eric Yung, Jeanette Kirschner, Patty Rosten, T. Michael Underhill, Jian Jin, Joseé Hébert, Guy Sauvageau, R. Keith Humphries, Fabio M. Rossi

Research output: Contribution to journal › Article › peer-review

129 Scopus citations

Abstract

Chromatin modulators are emerging as attractive drug targets, given their widespread implication in human cancers and susceptibility to pharmacological inhibition. Here we establish the histone methyltransferase G9a/ EHMT2 as a selective regulator of fast proliferating myeloid progenitors with no discernible function in hematopoietic stem cells (HSCs). In mouse models of acute myeloid leukemia (AML), loss of G9a significantly delays disease progression and reduces leukemia stem cell (LSC) frequency. We connect this function of G9a to its methyltransferase activity and its interaction with the leukemogenic transcription factor HoxA9 and provide evidence that primary human AML cells are sensitive to G9A inhibition. Our results highlight a clinical potential of G9A inhibition as a means to counteract the proliferation and self-renewal of AML cells by attenuating HoxA9- dependent transcription.

Original language	English
Pages (from-to)	317-327
Number of pages	11
Journal	Genes and Development
Volume	28
Issue number	4
DOIs	https://doi.org/10.1101/gad.236794.113
State	Published - 15 Feb 2014
Externally published	Yes

Keywords

Hematopoiesis
Histone methylation
Hox genes
Leukemia

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Lehnertz, B., Pabst, C., Su, L., Miller, M., Liu, F., Yi, L., Zhang, R., Krosl, J., Yung, E., Kirschner, J., Rosten, P., Michael Underhill, T., Jin, J., Hébert, J., Sauvageau, G., Keith Humphries, R., & Rossi, F. M. (2014). The methyltransferase G9a regulates HoxA9-dependent transcription in AML. Genes and Development, 28(4), 317-327. https://doi.org/10.1101/gad.236794.113

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abstract = "Chromatin modulators are emerging as attractive drug targets, given their widespread implication in human cancers and susceptibility to pharmacological inhibition. Here we establish the histone methyltransferase G9a/ EHMT2 as a selective regulator of fast proliferating myeloid progenitors with no discernible function in hematopoietic stem cells (HSCs). In mouse models of acute myeloid leukemia (AML), loss of G9a significantly delays disease progression and reduces leukemia stem cell (LSC) frequency. We connect this function of G9a to its methyltransferase activity and its interaction with the leukemogenic transcription factor HoxA9 and provide evidence that primary human AML cells are sensitive to G9A inhibition. Our results highlight a clinical potential of G9A inhibition as a means to counteract the proliferation and self-renewal of AML cells by attenuating HoxA9- dependent transcription.",

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AU - Lehnertz, Bernhard

AU - Pabst, Caroline

AU - Su, Le

AU - Miller, Michelle

AU - Liu, Feng

AU - Yi, Lin

AU - Zhang, Regan

AU - Krosl, Jana

AU - Yung, Eric

AU - Kirschner, Jeanette

AU - Rosten, Patty

AU - Michael Underhill, T.

AU - Jin, Jian

AU - Hébert, Joseé

AU - Sauvageau, Guy

AU - Keith Humphries, R.

AU - Rossi, Fabio M.

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AB - Chromatin modulators are emerging as attractive drug targets, given their widespread implication in human cancers and susceptibility to pharmacological inhibition. Here we establish the histone methyltransferase G9a/ EHMT2 as a selective regulator of fast proliferating myeloid progenitors with no discernible function in hematopoietic stem cells (HSCs). In mouse models of acute myeloid leukemia (AML), loss of G9a significantly delays disease progression and reduces leukemia stem cell (LSC) frequency. We connect this function of G9a to its methyltransferase activity and its interaction with the leukemogenic transcription factor HoxA9 and provide evidence that primary human AML cells are sensitive to G9A inhibition. Our results highlight a clinical potential of G9A inhibition as a means to counteract the proliferation and self-renewal of AML cells by attenuating HoxA9- dependent transcription.

KW - Hematopoiesis

KW - Histone methylation

KW - Hox genes

KW - Leukemia

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JO - Genes and Development

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The methyltransferase G9a regulates HoxA9-dependent transcription in AML

Abstract

Keywords

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