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Growth factor independence 1 (Gfi1) as a new target for leukemia therapy

ABSTRACT: Using (conditional) Gfi1 knock-out mice we show that ablation of the transcriptional repressor Gfi1 cures mice from lymphoid leukemia and reduces the expansion of primary human T-ALL xenografts in mice. We find that Gfi1 alters the p53 dependent transcriptional activation of a substantial subset of known p53 target genes and thus sets a threshold for cell death. We used Affymetrix mouse Gene-1.0-ST arrays to define the changes in the gene expression pattern of wt or Gfi1-KO thymocytes (Gfi1-fl/fl X MX-CRE, induced by pIpC) that were either untreated (WT, GfiKO thymocytes), irradiated (WT_irr, Gfi1KO_irr), ENU transformed (WT_Tum, Gfi1KO_Tum), or transformed by Notch1-CT and ENU-induced to enhance tumorigenesis (WT_Notch_Tum, Gfi1KO_Notch_Tum).

ORGANISM(S): Mus musculus

PROVIDER: GSE32910 | GEO | 2012/10/03

SECONDARY ACCESSION(S): PRJNA146535

REPOSITORIES: GEO

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Project description:Growth factor independent 1 (Gfi1) is a transcriptional repressor originally identified as a common integration site in Moloney-murine-leukemia-virus-induced T-cell leukemia. Gfi1-/- mice display increased apoptosis of developing thymocytes and T lymphopenia; however, there are contradictory reports of the absolute number of Gfi1-/- early T lineage progenitors. We used floxed alleles of Gfi1 crossed to various T-cell-specific Cre transgenes to map the requirements for Gfi1 during lymphoid priming and development. We show that Gfi1 is necessary for the proper formation and function of both lymphoid-primed multipotent progenitors and early T lineage progenitors. These defects correlate with a global inability of Gfi1-/- progenitors to enforce the activation of lymphoid genes including IL7R, Rag1, Flt3 and Notch1. Forced expression of intracellular Notch1 fails to rescue the Gfi1-/- defective lymphoid gene signature or Gfi1-/- T cell development. Instead, activation of Notch1 in Gfi1-/- cells results in a potent synthetic lethal phenotype that is most dramatic in immature thymocytes, but absent in mature peripheral T cells where developmental transcriptional programs are silent. Moreover, we find that the requirement for Gfi1-transcriptional integration of Notch-driven lymphoid transcriptional programs is cell autonomous. Our data indicate that Gfi1 is required at multiple independent stages of lymphoid development. In hematopoietic progenitors Gfi1 is necessary to integrate Notch1 signaling, mediate lymphoid priming, the formation of early T lineage progenitors and subsequent T lineage commitment. Lineage negative cells were purified by magnetic beads from RosaCreERT2 Gfi1 ex4-5 floxed mice and an activated Notch1 signal was introduced using a GFP+ retroviral vector. GFP+ progenitors were FACS-sorted and cultured in semi-solid media for one week to allow sufficient time to to instruct lymphoid differentiation, then replated in 1uM 4-OHT or EtOH control. After an additional 7 days, CFU were disrupted and RNA was isolated for global gene expression using microarrays.

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Growth factor independence 1 (Gfi1) as a new target for leukemia therapy

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