Essential role of PU.1 in maintenance of mixed lineage leukemia-associated leukemic stem cells

Yukiko Aikawa; Kazutsune Yamagata; Takuo Katsumoto; Yutaka Shima; Mika Shino; E. Richard Stanley; Michael L. Cleary; Koichi Akashi; Daniel G. Tenen; Issay Kitabayashi

doi:10.1111/cas.12593

Essential role of PU.1 in maintenance of mixed lineage leukemia-associated leukemic stem cells

Yukiko Aikawa, Kazutsune Yamagata, Takuo Katsumoto, Yutaka Shima, Mika Shino, E. Richard Stanley, Michael L. Cleary, Koichi Akashi, Daniel G. Tenen, Issay Kitabayashi

Developmental & Molecular Biology

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

16 Scopus citations

Abstract

Acute myeloid leukemia is a clonal malignant disorder derived from a small number of leukemic stem cells (LSCs). Rearrangements of the mixed lineage leukemia (MLL) gene are found in acute myeloid leukemia associated with poor prognosis. The upregulation of Hox genes is critical for LSC induction and maintenance, but is unlikely to support malignancy and the high LSC frequency observed in MLL leukemias. The present study shows that MLL fusion proteins interact with the transcription factor PU.1 to activate the transcription of CSF-1R, which is critical for LSC activity. Acute myeloid leukemia is cured by either deletion of PU.1 or ablation of cells expressing CSF-1R. Kinase inhibitors specific for CSF-1R prolong survival time. These findings indicate that PU.1-mediated upregulation of CSF-1R is a critical effector of MLL leukemogenesis.

Original language	English (US)
Pages (from-to)	227-236
Number of pages	10
Journal	Cancer Science
Volume	106
Issue number	3
DOIs	https://doi.org/10.1111/cas.12593
State	Published - Mar 1 2015

Keywords

Acute myeloid leukemia
CSF-1R
Mixed lineage leukemia
Spi-1
Stem cells

ASJC Scopus subject areas

Oncology
Cancer Research

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1111/cas.12593

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title = "Essential role of PU.1 in maintenance of mixed lineage leukemia-associated leukemic stem cells",

abstract = "Acute myeloid leukemia is a clonal malignant disorder derived from a small number of leukemic stem cells (LSCs). Rearrangements of the mixed lineage leukemia (MLL) gene are found in acute myeloid leukemia associated with poor prognosis. The upregulation of Hox genes is critical for LSC induction and maintenance, but is unlikely to support malignancy and the high LSC frequency observed in MLL leukemias. The present study shows that MLL fusion proteins interact with the transcription factor PU.1 to activate the transcription of CSF-1R, which is critical for LSC activity. Acute myeloid leukemia is cured by either deletion of PU.1 or ablation of cells expressing CSF-1R. Kinase inhibitors specific for CSF-1R prolong survival time. These findings indicate that PU.1-mediated upregulation of CSF-1R is a critical effector of MLL leukemogenesis.",

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author = "Yukiko Aikawa and Kazutsune Yamagata and Takuo Katsumoto and Yutaka Shima and Mika Shino and Stanley, {E. Richard} and Cleary, {Michael L.} and Koichi Akashi and Tenen, {Daniel G.} and Issay Kitabayashi",

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doi = "10.1111/cas.12593",

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AU - Aikawa, Yukiko

AU - Yamagata, Kazutsune

AU - Katsumoto, Takuo

AU - Shima, Yutaka

AU - Shino, Mika

AU - Stanley, E. Richard

AU - Cleary, Michael L.

AU - Akashi, Koichi

AU - Tenen, Daniel G.

AU - Kitabayashi, Issay

PY - 2015/3/1

Y1 - 2015/3/1

N2 - Acute myeloid leukemia is a clonal malignant disorder derived from a small number of leukemic stem cells (LSCs). Rearrangements of the mixed lineage leukemia (MLL) gene are found in acute myeloid leukemia associated with poor prognosis. The upregulation of Hox genes is critical for LSC induction and maintenance, but is unlikely to support malignancy and the high LSC frequency observed in MLL leukemias. The present study shows that MLL fusion proteins interact with the transcription factor PU.1 to activate the transcription of CSF-1R, which is critical for LSC activity. Acute myeloid leukemia is cured by either deletion of PU.1 or ablation of cells expressing CSF-1R. Kinase inhibitors specific for CSF-1R prolong survival time. These findings indicate that PU.1-mediated upregulation of CSF-1R is a critical effector of MLL leukemogenesis.

AB - Acute myeloid leukemia is a clonal malignant disorder derived from a small number of leukemic stem cells (LSCs). Rearrangements of the mixed lineage leukemia (MLL) gene are found in acute myeloid leukemia associated with poor prognosis. The upregulation of Hox genes is critical for LSC induction and maintenance, but is unlikely to support malignancy and the high LSC frequency observed in MLL leukemias. The present study shows that MLL fusion proteins interact with the transcription factor PU.1 to activate the transcription of CSF-1R, which is critical for LSC activity. Acute myeloid leukemia is cured by either deletion of PU.1 or ablation of cells expressing CSF-1R. Kinase inhibitors specific for CSF-1R prolong survival time. These findings indicate that PU.1-mediated upregulation of CSF-1R is a critical effector of MLL leukemogenesis.

KW - Acute myeloid leukemia

KW - CSF-1R

KW - Mixed lineage leukemia

KW - Spi-1

KW - Stem cells

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Essential role of PU.1 in maintenance of mixed lineage leukemia-associated leukemic stem cells

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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