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Acute Leukemias

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

Leukemia volume 26, pages 1527–1536 (2012)Cite this article

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Abstract

Biallelic CEBPA mutations and FMS-like tyrosine kinase receptor 3 (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 because of a lack of disease models. We have generated an AML mouse model using knockin mouse strains to study cooperation of an internal tandem duplication (ITD) mutation in the Flt3 gene with commonly observed CCAAT/enhancer binding protein alpha (C/EBPα) mutations. This study provides evidence that FLT3 ITD cooperates in leukemogenesis by enhancing the generation of leukemia-initiating granulocyte-monocyte progenitors (GMPs) 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 and GMP cells contain the potential to induce AML similar to corresponding cells in human AML samples showing that this model resembles human disease.

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Abbreviations

3:

GMP

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Acknowledgements

We gratefully thank Pekka Jaako and Zhi Ma for assistance with FACS and Garry Gilliland for making the Flt3ITD/+ mice available. This work was supported by grants from the Swedish Research Council (#K2007-64X-20412-01-3) through Hemato-Linne, Linneaus center of excellence grant, avtal om läkarutbildning och forskning (ALF) from Skåne University Hospital, Crafoordska Stiftelse, John Persson Stiftelse, Gunnar Nilssons Cancerstiftelse, Georg Danielssons Forskningsfond, Åke-Wiberg Stiftelse, Siv-Inger och Per-Erik Anderssons Minnesfond, Barncancerfonden and Forsknings- och utvecklingsenheten (FoU) to Jörg Cammenga and an MRC Program Grant to Claus Nerlov (Grant number 93339).

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Author notes

  1. C Nerlov and J Cammenga: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Molecular Medicine and Gene Therapy, Lund University, Lund, Sweden

    K Reckzeh, M Rehn & J Cammenga

  2. Lund Stem Cell Center, Lund University, Lund, Sweden

    K Reckzeh, M Rehn, S Kharazi, S-E Jacobsen & J Cammenga

  3. EMBL Mouse Biology Unit, Monterotondo, Italy

    O Bereshchenko

  4. Haematopoietic Stem Cell Laboratory, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Headington, UK

    A Mead & S-E Jacobsen

  5. Hematopoietic Stem Cell Laboratory, Lund University, Lund, Sweden

    S Kharazi & S-E Jacobsen

  6. Tissue Stem Cell Genetics, MRC Centre for Regenerative Medicine, Institute for Stem Cell Research, University of Edinburgh, Edinburgh, UK

    C Nerlov

  7. Department of Hematology, Sk,

    J Cammenga

  8. å,

    J Cammenga

  9. nes University Hospital, Lund, Sweden

    J Cammenga

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  1. K Reckzeh
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Correspondence to J Cammenga.

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Reckzeh, K., Bereshchenko, O., Mead, A. et al. Molecular and cellular effects of oncogene cooperation in a genetically accurate AML mouse model. Leukemia 26, 1527–1536 (2012). https://doi.org/10.1038/leu.2012.37

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