Dose-dependent role of Gfi1 in murine hematopoietic stem cell self-renewal and differentiation

Abstract

Gfi1 (Growth factor independence 1) is a transcription factor that influences the stem cell capacity of hematopoietic stem cells (HSCs) as well as their differentiation into the myeloid and lymphoid lineage. Loss of Gfi1 impedes the repopulation capacity of HSCs and leads to a block in granulocyte generation causing severe neutropenia and monocytosis. Competitive transplantation assays showed that Gfi1-deficient cells were not able to reconstitute myeloid and lymphoid hematopoiesis in competition with Gfi1-wildtype (GFI1-36S) cells. Low Gfi1 levels (GFI1-knockdown = GFI1-KD) in blasts of myelodysplastic neoplasms, acute and chronic myeloid leukemia patients are associated with poor patient survival. To understand how reduced levels or loss of Gfi1 contribute to hematopoiesis, we analyzed the effect of GFI1-KD and Gfi1-KO on HSCs and more mature cell types in mice. GFI1-KD and Gfi1-KO led to strong decrease in HSC numbers, while the numbers of early progenitors (Lin- Sca1+cKit+ cells) were slightly increased. Competitive transplantation assays showed that GFI1-KD and Gfi1-KO HSCs can still engraft and expand, but they cannot contribute to myeloid and lymphoid differentiation.