Growth factor independent-1 Maintains Notch1-Dependent Transcriptional Programming of Lymphoid Precursors

Abstract

Growth factor independent 1 (Gfi1) is a transcriptional repressor originally identified as a gene activated in T-cell leukemias induced by Moloney-murine-leukemia virus infection. Notch1 is a transmembrane receptor that is frequently mutated in human T-cell acute lymphoblastic leukemia (T-ALL). Gfi1 is an important factor in the initiation and maintenance of lymphoid leukemias and its deficiency significantly impedes Notch dependent initiation of T-ALL in animal models. Here, we show that immature hematopoietic cells require Gfi1 to competently integrate Notch-activated signaling. Notch1 activation coupled with Gfi1 deficiency early in T-lineage specification leads to a dramatic loss of T-cells, whereas activation in later stages leaves development unaffected. In Gfi1 deficient multipotent precursors, Notch activation induces lethality and is cell autonomous. Further, without Gfi1, multipotent progenitors do not maintain Notch1-activated global expression profiles typical for T-lineage precursors. In agreement with this, we find that both lymphoid-primed multipotent progenitors (LMPP) and early T lineage progenitors (ETP) do not properly form or function in Gfi1−/− mice. These defects correlate with an inability of Gfi1−/− progenitors to activate lymphoid genes, including IL7R, Rag1, Flt3 and Notch1. Our data indicate that Gfi1 is required for hematopoietic precursors to withstand Notch1 activation and to maintain Notch1 dependent transcriptional programming to determine early T-lymphoid lineage identity.

From cytopenia to leukemia: the role of Gfi1 and Gfi1b in blood formation

“…[52][53][54] Similar analyses with murine Gfi1b-deficient HSCs, megakaryocytes, or erythroid cells demonstrated that Gfi1b helps to establish gene expression programs necessary for the development of both erythroid and megakaryocytic lineages 29,32,55 and confirms the complementary roles of Gfi1 and Gfi1b in hematopoiesis already suspected by their differential, cell type-specific expression pattern.…”

Developmental gene networks: a triathlon on the course to T cell identity

“…Similarly, although the basic helix–loop–helix (bHLH) factor Lyl1 plays its best-known role in hematopoietic progenitors and B-cells 56, 57 , deletion of Lyl1 severely impairs development of lymphoid precursors in bone marrow and specifically reduces ETP expansion, progression to DN2, and early T-cell survival 56, 58, 59 . Lyl1, working in dimers with E2A or HEB, probably helps to maintain expression of the crucial ETP–DN2 growth factor receptor Kit, similar to the function of the related protein SCL ( Tal1 ), and promotes expression of Gfi1 , a regulatory factor required for normal generation of ETPs and for proper responses to Notch signaling 58, 60, 61 . Erg and Hhex are implicated in early T-cell self-renewal in both normal and malignant contexts 62, 63 .…”

Forging T-Lymphocyte Identity

“…Recently, Gfi1 has been shown to be essential in LMPPs and ETPs to enable cells to be stimulated by Notch signals. Without Gfi1, Notch signaling is toxic, and the cells fail to activate a T-cell gene expression program (Phelan et al , 2013). The mechanism is still being dissected.…”