Ring1A and Ring1B inhibit expression of Glis2 to maintain murine MOZ-TIF2 AML stem cells

Haruko Shima; Emi Takamatsu-Ichihara; Mika Shino; Kazutsune Yamagata; Takuo Katsumoto; Yukiko Aikawa; Shuhei Fujita; Haruhiko Koseki; Issay Kitabayashi

doi:10.1182/blood-2017-05-787226

Ring1A and Ring1B inhibit expression of Glis2 to maintain murine MOZ-TIF2 AML stem cells

Blood. 2018 Apr 19;131(16):1833-1845. doi: 10.1182/blood-2017-05-787226. Epub 2018 Jan 25.

Authors

Haruko Shima^{1

2}, Emi Takamatsu-Ichihara¹, Mika Shino¹, Kazutsune Yamagata¹, Takuo Katsumoto¹, Yukiko Aikawa¹, Shuhei Fujita¹, Haruhiko Koseki³, Issay Kitabayashi¹

Affiliations

¹ Division of Hematological Malignancy, National Cancer Center Research Institute, Tokyo, Japan.
² Department of Pediatrics, Keio University, Tokyo, Japan; and.
³ RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan.

PMID: 29371181
DOI: 10.1182/blood-2017-05-787226

Abstract

Eradication of chemotherapy-resistant leukemia stem cells is expected to improve treatment outcomes in patients with acute myelogenous leukemia (AML). In a mouse model of AML expressing the MOZ-TIF2 fusion, we found that Ring1A and Ring1B, components of Polycomb repressive complex 1, play crucial roles in maintaining AML stem cells. Deletion of Ring1A and Ring1B (Ring1A/B) from MOZ-TIF2 AML cells diminished self-renewal capacity and induced the expression of numerous genes, including Glis2 Overexpression of Glis2 caused MOZ-TIF2 AML cells to differentiate into mature cells, whereas Glis2 knockdown in Ring1A/B-deficient MOZ-TIF2 cells inhibited differentiation. Thus, Ring1A/B regulate and maintain AML stem cells in part by repressing Glis2 expression, which promotes their differentiation. These findings provide new insights into the mechanism of AML stem cell homeostasis and reveal novel targets for cancer stem cell therapy.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Differentiation
Gene Expression Regulation, Leukemic*
Histone Acetyltransferases / biosynthesis*
Histone Acetyltransferases / genetics
Kruppel-Like Transcription Factors / biosynthesis*
Kruppel-Like Transcription Factors / genetics
Leukemia, Myeloid, Acute / genetics
Leukemia, Myeloid, Acute / metabolism*
Leukemia, Myeloid, Acute / pathology
Mice
Mice, Knockout
Nerve Tissue Proteins / biosynthesis*
Nerve Tissue Proteins / genetics
Nuclear Receptor Coactivator 2 / biosynthesis*
Nuclear Receptor Coactivator 2 / genetics
Oncogene Proteins, Fusion / biosynthesis*
Oncogene Proteins, Fusion / genetics
Polycomb Repressive Complex 1 / genetics
Polycomb Repressive Complex 1 / metabolism*
Ubiquitin-Protein Ligases / genetics
Ubiquitin-Protein Ligases / metabolism*

Substances

Gli5 protein, mouse
Kruppel-Like Transcription Factors
Ncoa2 protein, mouse
Nerve Tissue Proteins
Nuclear Receptor Coactivator 2
Oncogene Proteins, Fusion
Histone Acetyltransferases
MOZ protein, mouse
Polycomb Repressive Complex 1
Ring1 protein, mouse
Rnf2 protein, mouse
Ubiquitin-Protein Ligases