FANCA deficiency promotes leukemic progression by allowing emergence of cells carrying oncogenic driver mutations

ABSTRACT: Leukaemia is caused by the clonal evolution of a cell that accumulates mutations/genomic rearrangements, allowing unrestrained cell growth. However, recent identification of leukaemic mutations in the blood cells of healthy individuals revealed that additional events are required to expand the mutated clones for overt leukaemia. Here, we assessed the functional consequences of deleting the Fanconi anaemia A (Fanca) gene, which encodes a DNA damage response protein, in Spi1 transgenic mice that develop preleukaemic syndrome. Loss of FANCA increases SPI1-associated disease penetrance and favours leukaemic progression without increasing the global mutation load of leukaemic clones. However, leukaemic FANCA-deleted cells display heterozygote activating mutations in known oncogenes, such as Kit or Nras, that are identified at low frequency in WT mice with preleukaemic syndrome, indicating that FANCA loss-of-function supports the emergence of oncogene mutated leukaemic cells. We show that a unique transcriptional deregulation is associated with the leukaemic status of cells devoid of FANCA activity, including MDM4, NOTCH and Wnt/-catenin pathways. Our observations provide evidence that FANCA-deficient preleukaemic cells carrying oncogenic Kit or Ras mutations require a favourable intracellular environment to allow the emergence of leukaemic clones. The loss of FANCA may provide this mandatory cellular setup by allowing the simultaneous activation of several proliferative pathways.

ORGANISM(S): Mus musculus

PROVIDER: GSE164411 | GEO | 2023/08/31

REPOSITORIES: GEO