Molecular and cellular effects of oncogene cooperation in a genetically accurate AML mouse model.

Research output: Contribution to journalArticle

Abstract

Biallelic CEBPA mutations and FLT3 length mutations are frequently identified in human acute myeloid leukemia (AML) with normal cytogenetics. However, the molecular and cellular mechanisms of oncogene cooperation remain unclear due to a lack of disease models. We have generated an AML mouse model using knockin mouse strains to study cooperation of internal tandem duplication (ITD) mutation in the Flt3 gene with commonly observed C/EBPα mutations. This study provides evidence that FLT3 ITD cooperates in leukemogenesis by enhancing the generation of leukemia-initiating granulocyte-monocyte progenitors (GMP) otherwise prevented by a block in differentiation and skewed lineage priming induced by biallelic C/EBPα mutations. These cellular changes are accompanied by an upregulation of hematopoietic stem cell and STAT5 target genes. By gene expression analysis in premalignant populations we further show a role of FLT3 ITD in activating genes involved in survival/transformation and chemoresistance. Both multipotent progenitors (MPP) and GMP cells contain the potential to induce AML similar to corresponding cells in human AML samples showing that this model resembles human disease.Leukemia accepted article preview online, 9 February 2012; doi:10.1038/leu.2012.37.

Details

Authors
  • Kristian Reckzeh
  • O Bereshchenko
  • A Mead
  • Matilda Rehn
  • Shabnam Kharazi
  • Sten Eirik W Jacobsen
  • Claus Nerlov
  • Jörg Cammenga
Organisations
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Cancer and Oncology
Original languageEnglish
Pages (from-to)1527-1536
JournalLeukemia
Volume26
Issue number7
Publication statusPublished - 2012
Publication categoryResearch
Peer-reviewedYes

Related research output

Reckzeh, K., 2012, Division of Molecular Medicine and Gene Therapy, Dept of Laboratory Medicine. 100 p.

Research output: ThesisDoctoral Thesis (compilation)

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