Article

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

Molecular Oncology Division, National Cancer Center Research Institute, Tsukiji, Tokyo, Japan.
Nature medicine (Impact Factor: 28.05). 04/2010; 16(5):580-5, 1p following 585. DOI: 10.1038/nm.2122
Source: PubMed

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.

0 Followers
 · 
205 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: The differentiation from multipotent hematopoietic stem cells (HSC) to mature and functional blood cells requires the finely tuned regulation of gene expression at each stage of development. Specific transcription factors play a key role in this process as they modulate the expression of their target genes in an exquisitely lineage-specific manner. A large number of important transcriptional regulators have been identified which establish and maintain specific gene expression patterns during hematopoietic development. Hematopoiesis is therefore a paradigm for investigating how transcription factors function in mammalian cells, thanks also to the evolution of genome-wide and the next-generation sequencing technologies. In this review, we focus on the current knowledge of the biological and functional properties of the hematopoietic master regulator RUNX1 (also known as AML1, CBFA2, PEBP2aB) transcription factor and its main downstream target PU.1. We will outline their relationship in determining the fate of the myeloid lineage during normal stem cell development and under conditions when hematopoietic development is subverted by leukemic transformation.
    International Journal of Hematology 03/2015; DOI:10.1007/s12185-015-1762-8 · 1.68 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Cancer is a leading cause of human death, but it is still not fully understood. Recent cell biology advances in dedifferentiation have improved the understanding of cancer initiation and development. Dedifferentiation, or cell conversion to a less differentiated state, plays an essential role in the regeneration of multicellular organisms. Stem cells derived from dedifferentiated cells may be a new resource for regenerative medicine. However, the genetic changes responsible for dedifferentiation are found to be involved in tumorigenesis, which indicates safety concerns for the application of dedifferentiation-derived stem cells, such as induced pluripotent stem cells. Understanding the relationship between dedifferentiation and tumorigenesis is not only helpful to the development of more efficacious cancer prevention and treatment but also pivotal to the safe application of dedifferentiation-derived cells in clinical settings. In this article, we discuss the involvement of dedifferentiation in the initiation of cancer and the role of p53 in cell dedifferentiation.
    BioScience 10/2014; 64(10). DOI:10.1093/biosci/biu133 · 5.44 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: IDH1 and IDH2 mutations occur frequently in acute myeloid leukemia (AML) and other cancers. The mutant IDH enzymes convert α-ketoglutarate (α-KG) to the oncometabolite 2-hydroxyglutarate (2-HG), which dysregulates a set of α-KG-dependent dioxygenases. To determine whether mutant IDH enzymes are valid targets for cancer therapy, we created a mouse model of AML in which mice were transplanted with nucleophosmin1 (NPM1)+/- hematopoietic stem/progenitor cells co-transduced with four mutant genes (NPMc, IDH2/R140Q, DNMT3A/R882H, and FLT3/ITD) which often occur simultaneously in human AML patients. Conditional deletion of IDH2/R140Q blocked 2-HG production and maintenance of leukemia stem cells, resulting in survival of the AML mice. IDH2/R140Q was necessary for the engraftment or survival of NPMc+ cells in vivo. Gene expression analysis indicated that NPMc increased expression of Hoxa9. IDH2/R140Q also increased the level of Meis1 and activated the hypoxia pathway in AML cells. IDH2/R140Q decreased the 5hmC modification and expression of some differentiation-inducing genes (Ebf1 and Spib). Taken together, our results indicated that IDH2 mutation is critical for the development and maintenance of AML stem-like cells, and they provided a preclinical justification for targeting mutant IDH enzymes as a strategy for anticancer therapy. Copyright © 2015, American Association for Cancer Research.
    Cancer Research 03/2015; 75(10). DOI:10.1158/0008-5472.CAN-14-2200 · 9.28 Impact Factor

Full-text (2 Sources)

Download
104 Downloads
Available from
May 23, 2014