TY  - JOUR
AU  - Vu, Therese
AU  - Straube, Jasmin
AU  - Porter, Amy H
AU  - Bywater, Megan
AU  - Song, Axia
AU  - Ling, Victoria
AU  - Cooper, Leanne
AU  - Pali, Gabor
AU  - Bruedigam, Claudia
AU  - Jacquelin, Sebastien
AU  - Green, Joanne
AU  - Magor, Graham
AU  - Perkins, Andrew
AU  - Chalk, Alistair M
AU  - Walkley, Carl R
AU  - Heidel, Florian H
AU  - Mukhopadhyay, Pamela
AU  - Cloonan, Nicole
AU  - Gröschel, Stefan
AU  - Mallm, Jan-Philipp
AU  - Fröhling, Stefan
AU  - Scholl, Claudia
AU  - Lane, Steven W
TI  - Hematopoietic stem and progenitor cell-restricted Cdx2 expression induces transformation to myelodysplasia and acute leukemia.
JO  - Nature Communications
VL  - 11
IS  - 1
SN  - 2041-1723
CY  - [London]
PB  - Nature Publishing Group UK
M1  - DKFZ-2020-01190
SP  - 3021
PY  - 2020
AB  - 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.
LB  - PUB:(DE-HGF)16
C6  - pmid:32541670
C2  - pmc:PMC7296000
DO  - DOI:10.1038/s41467-020-16840-2
UR  - https://inrepo02.dkfz.de/record/156883
ER  -