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

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 m...

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Main Authors: Vu, Therese (Author) , Straube, Jasmin (Author) , Porter, Amy H. (Author) , Bywater, Megan (Author) , Song, Axia (Author) , Ling, Victoria (Author) , Cooper, Leanne (Author) , Pali, Gabor (Author) , Bruedigam, Claudia (Author) , Jacquelin, Sebastien (Author) , Green, Joanne (Author) , Magor, Graham (Author) , Perkins, Andrew (Author) , Chalk, Alistair M. (Author) , Walkley, Carl R. (Author) , Heidel, Florian H. (Author) , Mukhopadhyay, Pamela (Author) , Cloonan, Nicole (Author) , Gröschel, Stefan (Author) , Mallm, Jan-Philipp (Author) , Fröhling, Stefan (Author) , Scholl, Claudia (Author) , Lane, Steven W. (Author)
Format: Article (Journal)
Language:English
Published: June 15, 2020
In: Nature Communications
Year: 2020, Volume: 11
ISSN:2041-1723
DOI:10.1038/s41467-020-16840-2
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1038/s41467-020-16840-2
Verlag, lizenzpflichtig, Volltext: https://www.nature.com/articles/s41467-020-16840-2
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Author Notes: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 Perkins, Alistair M. Chalk, Carl R. Walkley, Florian H. Heidel, Pamela Mukhopadhyay, Nicole Cloonan, Stefan Gröschel, Jan-Philipp Mallm, Stefan Fröhling, Claudia Scholl & Steven W. Lane

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520 |a 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. 
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