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Hematopoietic stem and progenitor cell-restricted Cdx2 expression induces transformation to myelodysplasia and acute leukemia

Author

Listed:
  • Therese Vu

    (QIMR Berghofer Medical Research Institute
    University of Queensland
    University of Colorado Anschutz Medical Campus)

  • Jasmin Straube

    (QIMR Berghofer Medical Research Institute)

  • Amy H. Porter

    (QIMR Berghofer Medical Research Institute)

  • Megan Bywater

    (QIMR Berghofer Medical Research Institute
    University of Queensland)

  • Axia Song

    (QIMR Berghofer Medical Research Institute)

  • Victoria Ling

    (QIMR Berghofer Medical Research Institute
    University of Queensland
    Royal Brisbane and Women’s Hospital)

  • Leanne Cooper

    (QIMR Berghofer Medical Research Institute)

  • Gabor Pali

    (QIMR Berghofer Medical Research Institute)

  • Claudia Bruedigam

    (QIMR Berghofer Medical Research Institute)

  • Sebastien Jacquelin

    (QIMR Berghofer Medical Research Institute)

  • Joanne Green

    (QIMR Berghofer Medical Research Institute)

  • Graham Magor

    (Monash University)

  • Andrew Perkins

    (Monash University)

  • Alistair M. Chalk

    (St. Vincent’s Institute
    University of Melbourne)

  • Carl R. Walkley

    (St. Vincent’s Institute
    University of Melbourne
    Australian Catholic University)

  • Florian H. Heidel

    (Universitätsklinikum Jena)

  • Pamela Mukhopadhyay

    (QIMR Berghofer Medical Research Institute)

  • Nicole Cloonan

    (QIMR Berghofer Medical Research Institute
    University of Auckland)

  • Stefan Gröschel

    (German Cancer Research Center
    Heidelberg University Hospital)

  • Jan-Philipp Mallm

    (German Cancer Research Center)

  • Stefan Fröhling

    (German Cancer Research Center
    National Center for Tumor Diseases Heidelberg)

  • Claudia Scholl

    (German Cancer Research Center
    National Center for Tumor Diseases Heidelberg)

  • Steven W. Lane

    (QIMR Berghofer Medical Research Institute
    University of Queensland
    Royal Brisbane and Women’s Hospital)

Abstract

The caudal-related homeobox transcription factor CDX2 is expressed in leukemic cells but not during normal blood formation. Retroviral overexpression of Cdx2 induces AML in mice, however the developmental stage at which CDX2 exerts its effect is unknown. We developed a conditionally inducible Cdx2 mouse model to determine the effects of in vivo, inducible Cdx2 expression in hematopoietic stem and progenitor cells (HSPCs). Cdx2-transgenic mice develop myelodysplastic syndrome with progression to acute leukemia associated with acquisition of additional driver mutations. Cdx2-expressing HSPCs demonstrate enrichment of hematopoietic-specific enhancers associated with pro-differentiation transcription factors. Furthermore, treatment of Cdx2 AML with azacitidine decreases leukemic burden. Extended scheduling of low-dose azacitidine shows greater efficacy in comparison to intermittent higher-dose azacitidine, linked to more specific epigenetic modulation. Conditional Cdx2 expression in HSPCs is an inducible model of de novo leukemic transformation and can be used to optimize treatment in high-risk AML.

Suggested Citation

  • Therese Vu & Jasmin Straube & Amy H. Porter & Megan Bywater & Axia Song & Victoria Ling & Leanne Cooper & Gabor Pali & Claudia Bruedigam & Sebastien Jacquelin & Joanne Green & Graham Magor & Andrew Pe, 2020. "Hematopoietic stem and progenitor cell-restricted Cdx2 expression induces transformation to myelodysplasia and acute leukemia," Nature Communications, Nature, vol. 11(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-16840-2
    DOI: 10.1038/s41467-020-16840-2
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