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.
Highlights
The caudal-related homeobox transcription factor CDX2 is expressed in leukemic cells but not during normal blood formation
To examine the effects of Cdx[2] expression in adult hematopoiesis, we generated a transgenic mouse by insertion of Cdx[2]
The Cdx[2] and mCherry cDNAs were separated by a T2A self-cleaving peptide, which allowed for co-expression of the two proteins after Cre excision of the stop cassette between the loxP sites
Summary
The caudal-related homeobox transcription factor CDX2 is expressed in leukemic cells but not during normal blood formation. Retroviral overexpression models of oncogenesis provide a powerful tool to study the functional consequences of genetic mutations These models have limitations including the ex vivo manipulation of cells and preferential transduction of proliferative progenitor cells, rather than long-term HSCs. these models have limitations including the ex vivo manipulation of cells and preferential transduction of proliferative progenitor cells, rather than long-term HSCs To overcome these barriers and to understand the mechanism of in vivo transformation of HSCs, we generated a transgenic model of Cdx[2] overexpression in hematopoietic stem and progenitor cells (HSPCs) to depict the cellular dynamics of transcriptional deregulation. Ectopic Cdx[2] expression in HSPCs results in lethal MDS, characterized by abnormal blood cell counts, dysgranulopoiesis, and thrombocytopenia, followed by secondary transformation to acute leukemia (AL) in a percentage of surviving mice. This work provides a model of MDS with stepwise transformation to AML that can be used to provide clinically relevant information for patients with MDS and AML with multilineage dysplasia
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
