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

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 and Steven W. Lane ()
Additional contact information
Therese Vu: QIMR Berghofer Medical Research Institute
Jasmin Straube: QIMR Berghofer Medical Research Institute
Amy H. Porter: QIMR Berghofer Medical Research Institute
Megan Bywater: QIMR Berghofer Medical Research Institute
Axia Song: QIMR Berghofer Medical Research Institute
Victoria Ling: QIMR Berghofer Medical Research Institute
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
Carl R. Walkley: St. Vincent’s Institute
Florian H. Heidel: Universitätsklinikum Jena
Pamela Mukhopadhyay: QIMR Berghofer Medical Research Institute
Nicole Cloonan: QIMR Berghofer Medical Research Institute
Stefan Gröschel: German Cancer Research Center
Jan-Philipp Mallm: German Cancer Research Center
Stefan Fröhling: German Cancer Research Center
Claudia Scholl: German Cancer Research Center
Steven W. Lane: QIMR Berghofer Medical Research Institute

Nature Communications, 2020, vol. 11, issue 1, 1-15

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-16840-2

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