PU.1-mediated upregulation of CSF1R is crucial for leukemia stem cell potential induced by MOZ-TIF2

Yukiko Aikawa, Takuo Katsumoto, Pu Zhang, Haruko Shima, Mika Shino, Kiminori Terui, Etsuro Ito, Hiroaki Ohno, E. Richard Stanley, Harinder Singh, Daniel G. Tenen, Issay Kitabayashi

Research output: Contribution to journalArticle

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Abstract

Leukemias and other cancers possess self-renewing stem cells that help to maintain the cancer. Cancer stem cell eradication is thought to be crucial for successful anticancer therapy. Using an acute myeloid leukemia (AML) model induced by the leukemia-associated monocytic leukemia zinc finger (MOZ)-TIF2 fusion protein, we show here that AML can be cured by the ablation of leukemia stem cells. The MOZ fusion proteins MOZ-TIF2 and MOZ-CBP interacted with the transcription factor PU.1 to stimulate the expression of macrophage colony-stimulating factor receptor (CSF1R, also known as M-CSFR, c-FMS or CD115). Studies using PU.1-deficient mice showed that PU.1 is essential for the ability of MOZ-TIF2 to establish and maintain AML stem cells. Cells expressing high amounts of CSF1R (CSF1R high cells), but not those expressing low amounts of CSF1R (CSF1R low cells), showed potent leukemia-initiating activity. Using transgenic mice expressing a drug-inducible suicide gene controlled by the CSF1R promoter, we cured AML by ablation of CSF1R high cells. Moreover, induction of AML was suppressed in CSF1R-deficient mice and CSF1R inhibitors slowed the progression of MOZ-TIF2-induced leukemia. Thus, in this subtype of AML, leukemia stem cells are contained within the CSF1R high cell population, and we suggest that targeting of PU.1-mediated upregulation of CSF1R expression might be a useful therapeutic approach.

Original languageEnglish
Pages (from-to)580-585
Number of pages6
JournalNature Medicine
Volume16
Issue number5
DOIs
Publication statusPublished - 2010 May
Externally publishedYes

Fingerprint

Stem cells
Leukemia
Up-Regulation
Stem Cells
Acute Myeloid Leukemia
Ablation
Core Binding Factor alpha Subunits
Fusion reactions
Macrophage Colony-Stimulating Factor Receptors
Cells
Myeloid Progenitor Cells
Zinc
Aptitude
Neoplastic Stem Cells
Zinc Fingers
Genes
Suicide
Transgenic Mice
Neoplasms
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Aikawa, Y., Katsumoto, T., Zhang, P., Shima, H., Shino, M., Terui, K., ... Kitabayashi, I. (2010). PU.1-mediated upregulation of CSF1R is crucial for leukemia stem cell potential induced by MOZ-TIF2. Nature Medicine, 16(5), 580-585. https://doi.org/10.1038/nm.2122

PU.1-mediated upregulation of CSF1R is crucial for leukemia stem cell potential induced by MOZ-TIF2. / Aikawa, Yukiko; Katsumoto, Takuo; Zhang, Pu; Shima, Haruko; Shino, Mika; Terui, Kiminori; Ito, Etsuro; Ohno, Hiroaki; Stanley, E. Richard; Singh, Harinder; Tenen, Daniel G.; Kitabayashi, Issay.

In: Nature Medicine, Vol. 16, No. 5, 05.2010, p. 580-585.

Research output: Contribution to journalArticle

Aikawa, Y, Katsumoto, T, Zhang, P, Shima, H, Shino, M, Terui, K, Ito, E, Ohno, H, Stanley, ER, Singh, H, Tenen, DG & Kitabayashi, I 2010, 'PU.1-mediated upregulation of CSF1R is crucial for leukemia stem cell potential induced by MOZ-TIF2', Nature Medicine, vol. 16, no. 5, pp. 580-585. https://doi.org/10.1038/nm.2122
Aikawa, Yukiko ; Katsumoto, Takuo ; Zhang, Pu ; Shima, Haruko ; Shino, Mika ; Terui, Kiminori ; Ito, Etsuro ; Ohno, Hiroaki ; Stanley, E. Richard ; Singh, Harinder ; Tenen, Daniel G. ; Kitabayashi, Issay. / PU.1-mediated upregulation of CSF1R is crucial for leukemia stem cell potential induced by MOZ-TIF2. In: Nature Medicine. 2010 ; Vol. 16, No. 5. pp. 580-585.
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