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Hematopoietic stem and progenitor cell-restricted Cdx2 expression induces transformation to myelodysplasia and acute leukemia
Vu, Therese Straube, Jasmin Porter, Amy H. Bywater, Megan Song, Axia Ling, Victoria Cooper, Leanne Pali, Gabor Bruedigam, Claudia Jacquelin, Sebastien
Vu, Therese
Straube, Jasmin
Porter, Amy H.
Bywater, Megan
Song, Axia
Ling, Victoria
Cooper, Leanne
Pali, Gabor
Bruedigam, Claudia
Jacquelin, Sebastien
Author
Vu, Therese
Straube, Jasmin
Porter, Amy H.
Bywater, Megan
Song, Axia
Ling, Victoria
Cooper, Leanne
Pali, Gabor
Bruedigam, Claudia
Jacquelin, Sebastien
Green, Joanne
Magor, Graham
Perkins, Andrew
Chalk, Alistair M.
Walkley, Carl R.
Heidel, Florian H.
Mukhopadhyay, Pamela
Cloonan, Nicole
Gröschel, Stefan
Mallm, Jan-Philipp
Fröhling, Stefan
Scholl, Claudia
Lane, Steven W.
Straube, Jasmin
Porter, Amy H.
Bywater, Megan
Song, Axia
Ling, Victoria
Cooper, Leanne
Pali, Gabor
Bruedigam, Claudia
Jacquelin, Sebastien
Green, Joanne
Magor, Graham
Perkins, Andrew
Chalk, Alistair M.
Walkley, Carl R.
Heidel, Florian H.
Mukhopadhyay, Pamela
Cloonan, Nicole
Gröschel, Stefan
Mallm, Jan-Philipp
Fröhling, Stefan
Scholl, Claudia
Lane, Steven W.
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.
Keywords
Date
2020
Type
Journal article
Journal
Nature Communications
Book
Volume
11
Issue
Page Range
1-15
Article Number
ACU Department
Mary MacKillop Institute for Health Research
Faculty of Health Sciences
Faculty of Health Sciences
Collections
Relation URI
Source URL
Event URL
Open Access Status
Published as ‘gold’ (paid) open access
License
CC BY 4.0
File Access
Open