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Acute myeloid leukemia

FoxO1-dependent induction of acute myeloid leukemia by osteoblasts in mice

Leukemia volume 30, pages 1–13 (2016)Cite this article

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Abstract

Osteoblasts, the bone forming cells, affect self-renewal and expansion of hematopoietic stem cells (HSCs), as well as homing of healthy hematopoietic cells and tumor cells into the bone marrow. Constitutive activation of β-catenin in osteoblasts is sufficient to alter the differentiation potential of myeloid and lymphoid progenitors and to initiate the development of acute myeloid leukemia (AML) in mice. We show here that Notch1 is the receptor mediating the leukemogenic properties of osteoblast-activated β-catenin in HSCs. Moreover, using cell-specific gene inactivation mouse models, we show that FoxO1 expression in osteoblasts is required for and mediates the leukemogenic properties of β-catenin. At the molecular level, FoxO1 interacts with β-catenin in osteoblasts to induce expression of the Notch ligand, Jagged-1. Subsequent activation of Notch signaling in long-term repopulating HSC progenitors induces the leukemogenic transformation of HSCs and ultimately leads to the development of AML. These findings identify FoxO1 expressed in osteoblasts as a factor affecting hematopoiesis and provide a molecular mechanism whereby the FoxO1/activated β-catenin interaction results in AML. These observations support the notion that the bone marrow niche is an instigator of leukemia and raise the prospect that FoxO1 oncogenic properties may occur in other tissues.

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Acknowledgements

The authors are grateful to Dr Makoto Taketo for providing the Catnb+/lox(ex3) mice and to Dr Ronald A DePinho for providing the FoxO1fl mice. We are also thankful to Steven Shikhel for critical reading of the manuscript, to Alexandra Tarasenko for technical assistance, and to the histology and metabolic unit facility of the Diabetes and Endocrinology Research Center (DERC, supported by NIDDK DK063608-07) and the Molecular Pathology facility of the Herbert Irving Cancer Center of Columbia University Medical Center for help with histological analysis. This work was supported by the National Institutes of Health (R01 AR054447, R01 AR055931 and P01 AG032959 to SK).

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Authors and Affiliations

  1. Department of Physiology and Cellular Biophysics, College of Physicians and Surgeons, Columbia University, New York, NY, USA

    A Kode, I Mosialou & S Kousteni

  2. Division of Endocrinology, Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY, USA

    S J Manavalan

  3. Department of Genetics and Development, College of Physicians and Surgeons, Columbia University, New York, NY, USA

    C V Rathinam

  4. Department of Biomedical Informatics, Biomedical Informatics Shared Resource, Herbert Irving Comprehensive Cancer Center, College of Physicians and Surgeons, Columbia University, New York, NY, USA

    R A Friedman

  5. Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

    J Teruya-Feldstein

  6. Department of Pathology and Cell Biology, College of Physicians and Surgeons, Columbia University, New York, NY, USA

    G Bhagat

  7. Department of Pathology, Institute for Cancer Genetics Irving Cancer Research Center, Columbia University, New York, NY, USA

    G Bhagat

  8. Department of Medicine, Leukemia Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    E Berman

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  1. A Kode
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Kode, A., Mosialou, I., Manavalan, S. et al. FoxO1-dependent induction of acute myeloid leukemia by osteoblasts in mice. Leukemia 30, 1–13 (2016). https://doi.org/10.1038/leu.2015.161

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