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Hematopoietic stem and progenitor cell-restricted Cdx2 expression induces transformation to myelodysplasia and acute leukemia.
Vu, Therese; Straube, Jasmin; Porter, Amy H; Bywater, Megan; Song, Axia; Ling, Victoria; Cooper, Leanne; Pali, Gabor; Bruedigam, Claudia; Jacquelin, Sebastien; Green, Joanne; Magor, Graham; Perkins, Andrew; Chalk, Alistair M; Walkley, Carl R; Heidel, Florian H; Mukhopadhyay, Pamela; Cloonan, Nicole; Gröschel, Stefan; Mallm, Jan-Philipp; Fröhling, Stefan; Scholl, Claudia; Lane, Steven W.
Afiliación
  • Vu T; Cancer Program, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
  • Straube J; School of Medicine, University of Queensland, Brisbane, Australia.
  • Porter AH; University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA.
  • Bywater M; Cancer Program, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
  • Song A; Cancer Program, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
  • Ling V; Cancer Program, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
  • Cooper L; School of Medicine, University of Queensland, Brisbane, Australia.
  • Pali G; Cancer Program, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
  • Bruedigam C; Cancer Program, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
  • Jacquelin S; School of Medicine, University of Queensland, Brisbane, Australia.
  • Green J; Cancer Care Services, Royal Brisbane and Women's Hospital, Brisbane, Australia.
  • Magor G; Cancer Program, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
  • Perkins A; Cancer Program, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
  • Chalk AM; Cancer Program, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
  • Walkley CR; Cancer Program, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
  • Heidel FH; Cancer Program, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
  • Mukhopadhyay P; Australian Centre for Blood Diseases, Monash University, Melbourne, Australia.
  • Cloonan N; Australian Centre for Blood Diseases, Monash University, Melbourne, Australia.
  • Gröschel S; St. Vincent's Institute, Melbourne, Australia.
  • Mallm JP; Department of Medicine, St. Vincent's Hospital, University of Melbourne, Fitzroy, Australia.
  • Fröhling S; St. Vincent's Institute, Melbourne, Australia.
  • Scholl C; Department of Medicine, St. Vincent's Hospital, University of Melbourne, Fitzroy, Australia.
  • Lane SW; Mary MacKillop Institute for Health Research, Australian Catholic University, Melbourne, Australia.
Nat Commun ; 11(1): 3021, 2020 06 15.
Article en En | MEDLINE | ID: mdl-32541670
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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Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Síndromes Mielodisplásicos / Células Madre Hematopoyéticas / Leucemia Mieloide Aguda / Factor de Transcripción CDX2 Tipo de estudio: Prognostic_studies Límite: Animals / Female / Humans Idioma: En Revista: Nat Commun Asunto de la revista: BIOLOGIA / CIENCIA Año: 2020 Tipo del documento: Article País de afiliación: Australia
Texto completo
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Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Síndromes Mielodisplásicos / Células Madre Hematopoyéticas / Leucemia Mieloide Aguda / Factor de Transcripción CDX2 Tipo de estudio: Prognostic_studies Límite: Animals / Female / Humans Idioma: En Revista: Nat Commun Asunto de la revista: BIOLOGIA / CIENCIA Año: 2020 Tipo del documento: Article País de afiliación: Australia