Hematopoietic stem and progenitor cell-restricted Cdx2 expression induces transformation to myelodysplasia and acute leukemia.
Therese VuJasmin StraubeAmy H PorterMegan BywaterAxia SongVictoria Y LingLeanne CooperGabor PaliClaudia BruedigamSebastien JacquelinJoanne GreenGraham MagorAndrew Charles PerkinsAlistair M ChalkCarl R WalkleyFlorian H HeidelPamela MukhopadhyayNicole CloonanStefan GröschelJan Philipp MallmStefan FröhlingClaudia SchollSteven W LanePublished in: Nature communications (2020)
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.
Keyphrases
- acute myeloid leukemia
- transcription factor
- low dose
- poor prognosis
- mouse model
- allogeneic hematopoietic stem cell transplantation
- type diabetes
- binding protein
- gene expression
- induced apoptosis
- dna methylation
- high dose
- metabolic syndrome
- risk factors
- cell death
- cell cycle arrest
- long non coding rna
- combination therapy
- anti inflammatory
- skeletal muscle
- endoplasmic reticulum stress
- insulin resistance
- replacement therapy