Tgif1 Regulates Quiescence and Self-Renewal of Hematopoietic Stem Cells

Abstract

b TG-interacting factor 1 (TGIF1) is a transcriptional repressor that can modulate retinoic acid and transforming growth factor ␤ signaling pathways. It is required for myeloid progenitor cell differentiation and survival, and mutations in the TGIF1 gene cause holoprosencephaly. Furthermore, we have previously observed that acute myelogenous leukemia (AML) patients with low TGIF1 levels had worse prognoses. Here, we explored the role of Tgif1 in murine hematopoietic stem cell (HSC) function. CFU assays showed that Tgif1 ؊/؊ bone marrow cells produced more total colonies and had higher serial CFU potential. These effects were also observed in vivo, where Tgif1 ؊/؊ bone marrow cells had higher repopulation potential in short-and long-term competitive repopulation assays than wild-type cells. Serial transplantation and replating studies showed that Tgif1 ؊/؊ HSCs exhibited greater self-renewal and were less proliferative and more quiescent than wild-type cells, suggesting that Tgif1 is required for stem cells to enter the cell cycle. Furthermore, HSCs from Tgif1 ؉/؊ mice had a phenotype similar to that of HSCs from Tgif1 ؊/؊ mice, while bone marrow cells with overexpressing Tgif1 showed increased proliferation and lower survival in long-term transplant studies. Taken together, our data suggest that Tgif1 suppresses stem cell self-renewal and provide clues as to how reduced expression of TGIF1 may contribute to poor long-term survival in patients with AML.

Trap1a is an X-linked and cell-intrinsic regulator of thymocyte development

“…We carried out in silico analyses for Trap1a expression. As shown in Figure 5c, RNAseq data 15 showed that Trap1a was not expressed in thymocytes, whereas databases generated by others 18,19 revealed low levels of expression in BM LSK stem/progenitor cells and CLP cells (Figure 5d). Because thymocyte progenitors were identified as part of the LSK population, 21 we used PCR to validate Trap1a expression in LSK cells.…”

“…17 The expression values of hematopoietic stem cells, LSK and common lymphoid progenitors (CLP) were extracted from the expression result file through GEO Series accession numbers GSE50896 18 and GSE50739. 19 …”

TGIF1 is a negative regulator of MLL-rearranged acute myeloid leukemia

“…28 This is contrasted by recent in vivo experiments where BM reconstitution was inhibited by forced expression of TGIF1 and conversely promoted by its loss, perhaps suggesting a role for TGIF1 in regulating hematopoietic stem cell (HSC) biology. 29 Finally, unpublished observations cited in various reports suggest that TGIF1 expression is a favorable prognostic factor in AML patients, raising the possibility that TGIF1 may have a role in leukemogenesis. [28][29][30][31] Here we have focused on the function of TGIF1 in MLLrearranged AML and demonstrate that it interferes with an MEIS1-dependent transcriptional network required for AML maintenance by directly competing with MEIS1 for binding to common regions within the chromatin.…”

TGIF1 promoted the growth and migration of cancer cells in nonsmall cell lung cancer

“…TGIF family includes two members, TGIF1 and TGIF2 [16]. Previous studies showed the pivotal functions of TGIF in holoprosencephaly, adipocyte differentiation, hematopoietic stem cell, and vascularization [17][18][19][20]. Also, the functions of TGIF in cancer, including leukemia [21], gastric cancer [22], and ovarian cancer [23], were reported.…”