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.
journal_name
Nat Communjournal_title
Nature communicationsauthors
Vu T,Straube J,Porter AH,Bywater M,Song A,Ling V,Cooper L,Pali G,Bruedigam C,Jacquelin S,Green J,Magor G,Perkins A,Chalk AM,Walkley CR,Heidel FH,Mukhopadhyay P,Cloonan N,Gröschel S,Mallm JP,Fröhling S,Scholl C,doi
10.1038/s41467-020-16840-2subject
Has Abstractpub_date
2020-06-15 00:00:00pages
3021issue
1issn
2041-1723pii
10.1038/s41467-020-16840-2journal_volume
11pub_type
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