RGD Reference Report - Growth factor independence 1 protects hematopoietic stem cells against apoptosis but also prevents the development of a myeloproliferative-like disease.

General

Growth factor independence 1 protects hematopoietic stem cells against apoptosis but also prevents the development of a myeloproliferative-like disease.
Authors:	Khandanpour, C Kosan, C Gaudreau, MC Duhrsen, U Hebert, J Zeng, H Moroy, T
Citation:	Khandanpour C, etal., Stem Cells. 2011 Feb;29(2):376-85. doi: 10.1002/stem.575.
RGD ID:	11040451
Pubmed:	PMID:21732494 (View Abstract at PubMed)
DOI:	DOI:10.1002/stem.575 (Journal Full-text)
The regulation of gene transcription is elementary for the function of hematopoietic stem cells (HSCs). The transcriptional repressor growth factor independence 1 (Gfi1) restricts HSC proliferation and is essential to maintain their self-renewal capacity and multipotency after transplantation. In addition, Gfi1(-/-) HSCs are severely compromised in their ability to compete with wild-type (wt) HSCs after transplantation. We now report that Gfi1 protects HSCs against stress-induced apoptosis, probably, by repressing the proapoptotic target gene Bax, since irradiated Gfi1(-/-) HSCs display higher expression of Bax and show a higher rate of apoptosis than wt HSCs. This protective function of Gfi1 appears to be functionally relevant since Gfi1(-/-) HSCs that express Bcl-2, which antagonizes the effects of Bax, regain their ability to self renew and to initiate multilineage differentiation after transplantation. Surprisingly, Gfi1(-/-) xBcl-2 transgenic mice also show a strong, systemic expansion of Mac-1(+) Gr-1(-) myeloid cells in bone marrow and peripheral lymphoid organs. These cells express high levels of the proleukemogenic transcription factor Hoxa9 and, in older mice, appear as atypical monocytoid-blastoid cells in the peripheral blood. As a result of this massive expansion of myeloid cells, all Gfi1(-/-) xBcl-2 mice eventually succumb to a myeloproliferative-like disease resembling a preleukemic state. In summary, our data demonstrate that Gfi1's ability to protect against apoptosis is essential for HSC function. In addition, our finding show that Gfi1 prevents the development of myeloproliferative diseases and provides evidence how Gfi1 deficiency could be linked to myeloid leukemia.

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Term	Qualifier	Evidence	With	Reference	Notes	Source	Original Reference(s)
myeloid leukemia		ISO	Gfi1 (Mus musculus)	11040451; 11040451		RGD
myeloid leukemia		IMP		11040451		RGD

Objects Annotated

Genes (Rattus norvegicus)

Gfi1 (growth factor independent 1 transcriptional repressor)

Genes (Mus musculus)

Gfi1 (growth factor independent 1 transcription repressor)

Genes (Homo sapiens)

GFI1 (growth factor independent 1 transcriptional repressor)

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Growth factor independence 1 protects hematopoietic stem cells against apoptosis but also prevents the development of a myeloproliferative-like disease.