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

Jasmin Straube, Megan Bywater, Leanne Cooper, Claudia Bruedigam, Graham Magor, Andrew Perkins, Alistair M. Chalk, Carl R. Walkley, Pamela Mukhopadhyay, Nicole Cloonan, Steven W. Lane

Research output: Contribution to journalArticleResearchpeer-review

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.

Original languageEnglish
Article number3021
Number of pages15
JournalNature Communications
Volume11
Issue number1
DOIs
Publication statusPublished - 15 Jun 2020

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