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Research Watch

HBO1 Is a Targetable Driver of Leukemia Stem Cell Maintenance

DOI: 10.1158/2159-8290.CD-RW2019-190 Published February 2020
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  • Major Finding: HBO1 is required for maintenance of leukemia stem cells (LSC) in acute myeloid leukemia (AML).

  • Concept: A small-molecule HBO1 inhibitor was effective in AML cell lines and primary human AML cells.

  • Impact: Further efforts to target HBO1 in AML may lead to therapies that eliminate disease-driving LSCs.

The efficacy of treatments for acute myeloid leukemia (AML) is limited by their inability to completely eliminate leukemia stem cells (LSC). MacPherson and colleagues identified the MYST-family acetyltransferase HBO1 as a key dependency in LSCs and showed that acetylation of histone H3 at lysine residue 14 is the predominant nonredundant chromatin modification made by HBO1. Ex vivo experiments revealed that loss of HBO1 was associated with increased apoptosis, cell-cycle arrest at the G0–G1 transition, and differentiation of LSCs. Corresponding results were obtained in human AML cell lines in which HBO1 was deleted. Data confirming the critical role of HBO1 in LSC maintenance were obtained using mouse models: Hbo1-knockdown LSCs were unable to perpetuate leukemia in mice, and experiments in which Hbo1 was conditionally deleted provided complementary supporting evidence. Many genes were downregulated by loss of HBO1; notably, some were homeobox genes, which have established roles in LSC maintenance and are associated with poor prognosis when upregulated in AML. These results combined with additional supporting experimental data clearly identified HBO1 as a potential therapeutic target in AML; however, the development of small-molecule inhibitors of histone acetyltransferases has historically been limited by a lack of selectivity. Using a recently developed chemical scaffold that serves as a platform to create inhibitors of MYST-family acetyltransferases, the group generated WM-3835, a cell-permeable small molecule that inhibits HBO1 more strongly than it does other MYST-family proteins. WM-3835 treatment reduced cell viability and phenocopied loss of HBO1 in numerous AML cell lines and decreased clonogenic potential in primary human AML cells harboring disparate driver mutations. Although the rapid metabolism of WM-3835 precluded in vivo experiments, these results highlight the potential of HBO1 inhibition to eradicate LSCs and support the continued investigation of HBO1 as a target in AML treatment.

MacPherson L, Anokye J, Yeung MM, Lam EYN, Chan YC, Weng CF, et al. HBO1 is required for the maintenance of leukaemia stem cells. Nature 2020;577:266–70.

Notes

Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/CDNews.

  • ©2020 American Association for Cancer Research.
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Cancer Discovery: 10 (2)
February 2020
Volume 10, Issue 2
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HBO1 Is a Targetable Driver of Leukemia Stem Cell Maintenance
Cancer Discov February 1 2020 (10) (2) 172; DOI: 10.1158/2159-8290.CD-RW2019-190

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HBO1 Is a Targetable Driver of Leukemia Stem Cell Maintenance
Cancer Discov February 1 2020 (10) (2) 172; DOI: 10.1158/2159-8290.CD-RW2019-190
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