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

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/EBPa) 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/EBPa 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.

The European Hematology Association Roadmap for European Hematology Research: a consensus document

“…Specifically, these groups applied genetic models to uncover the important role of CEBPA for granulocytic lineage commitment and differentiation, as well as the causative role for mutant CEBPA in AML, thereby dissecting the complexity of how biallelic CEBPA mutations contribute to leukemogenesis. 23,24 …”

Potent co-operation between the NUP98-NSD1 fusion and the FLT3-ITD mutation in acute myeloid leukemia induction

“…[4][5][6] Clinical observations and experimental studies have shown that FLT3-ITD can co-operate strongly in leukemia induction with a variety of leukemia-initiating gene fusions such as MLL-AF9, MLL-GAS7, AML1-ETO, PML-RARα or NUP98-HOXD13. [7][8][9][10][11][12][13] Several studies have shown that FLT3-ITD alone can cause a myeloproliferative disorder in mice, but is not sufficient to induce AML. [14][15][16] NUP98-NSD1 is the product of a cytogenetically silent chromosomal translocation t(5;11) (q35;p15.5) that generates a fusion between the N-terminus of nucleoporin 98 (NUP98) and the C-terminal part of the nuclear receptor-binding SETdomain-containing protein NSD1.…”

Identification of a germline F692L drug resistance variant in cis with Flt3-internal tandem duplication in knock-in mice

“…Knock-in mouse models have been instrumental in deciphering the hematopoietic and leukemogenic effects of FLT3-ITD alone [4][5][6] and in combination with mutations co-occurring with FLT3-ITD in human AML [7][8][9][10][11][12] ; as well as in studying the effectiveness of different therapeutic approaches in FLT3-ITD-positive leukemias. F692L), was present at allele frequencies of 0.55-0.94.…”