Hematopoietic Stem and Progenitor Cell-restricted Cdx2 Expression Induces Transformation to Myelodysplasia and Acute Leukemia

Overview

Journal Nat Commun

Specialty Biology

Date 2020 Jun 17

PMID 32541670

Citations 10

Authors

Therese Vu

Jasmin Straube

Amy H Porter

Megan Bywater

Axia Song

Victoria Ling

Leanne Cooper

Gabor Pali

Claudia Bruedigam

Sebastien Jacquelin

Joanne Green

Graham Magor

Andrew Perkins

Alistair M Chalk

Carl R Walkley

Florian H Heidel

Pamela Mukhopadhyay

Nicole Cloonan

Stefan Groschel

Jan-Philipp Mallm

Stefan Frohling

Claudia Scholl

Steven W Lane

Affiliations

Soon will be listed here.

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.

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