Twist-1, A Novel Regulator of Hematopoietic Stem Cell Self-Renewal and Myeloid Lineage Development

Abstract

Transcription factor Twist-1 plays essential roles in specification and differentiation of mesoderm-derived tissues. Growing evidences now link Twist-1 to the acquisition of stem-celllike properties. However, the role of Twist-1 in hematopoietic stem cell (HSC) remains largely uncharacterized. We report that Twist-1 is more highly expressed in murine HSC and its expression declines with differentiation. To investigate Twist-1 gene function, retroviral-mediated overexpression or removal experiments are performed. Competitive repopulation studies demonstrate that enforced expression of Twist-1 in HSC-enriched Lin 2 c-Kit 1 Sca-1 1 (LKS) cells results in an increase in the size of the G 0 population, and in their reconstitution ability after the first and a second transplantation. Conversely, removal of Twist-1 in LKS cells impairs their ability to repopulate. In addition, increased Twist-1 expression causes a shift toward production of myeloid cells. Twist-1 transduction in LKS cells activates myeloid lineage-determining factors PU.1 and GATA-1 and downregulates lymphoid factor GATA-3 in vitro, suggesting that Twist-1-mediated myeloid skewing occurs in hematopoietic stem and progenitor cells (HSPCs). These findings indicate that Twist-1 is not only involved in the maintenance of HSC dormancy and self-renewal capacity but also implicated in the myeloid lineage fate choice of HSPCs. Exploration of the underlying mechanisms reveals that Runx1/c-Mpl/Tie2 regulatory pathway could possibly account for the observed effects caused by Twist-1 overexpression. Our study provides the first evidence supporting a role for Twist-1 in hematopoiesis. STEM CELLS

Twist1 regulates embryonic hematopoietic differentiation through binding to Myb and Gata2 promoter regions

“…33 In agreement, we found that Twist1 loss suppressed Gata1 expression in AGM-derived HSPCs, impairing myeloid differentiation ( Figure 2E,G). However, we observed no change in expression of the myeloid transcription factor Spi1 (Pu.1) in Twist1 2/2 embryos.…”

Twist as a new prognostic marker in hematological malignancies

“…Studies show that increased expression of Twist-1 increases the expression of PU.1 and GATA-1 and reduces GATA-3. Therefore, it seems that Twist-1 causes differentiation induction of HSCs to myeloid lineage through the induction of myeloid specification genes and decreased expression of lymphoid specification genes [42].…”

“…Both c-Mpl and Tie2 are markers of LT-HSCs and play an important role in the regulation of LT-HSC quiescence [45,46]. Dong et al was shown that Twist-1 overexpression causes changes in gene expression of Runx1, c-Mpl and Tie2 transcription factors [42]. Thus, given the importance of Twist-1 expression in LT-HSCs and its relationship with c-Mpl and Tie2 expression, it may play an important role in survival, differentiation and selfrenewal of LT-HSC, which requires further studies to be proved.…”

“…Studies have shown that increased expression of Twist-1 in CD34 ?/-HSCs is observed during CML progression, which is decreased after complete remission and increased in case of relapse [42,85]. Overexpression of Twist proteins in CML patients is a mechanism of resistance to tyrosine kinase inhibitors (TKI) drugs.…”

Nucleophosmin-anaplastic lymphoma kinase: the ultimate oncogene and therapeutic target

“…59 TWIST1 is highly expressed in hematopoietic stem cells and promotes their self-renewal and stemness. 60 It also contributes to epithelial-mesenchymal transition 61 and tumor cell tissue invasion and metastasis formation in gastric, 62 breast, 63 and hepatocellular 64 carcinomas. TWIST1 promotes invasiveness of ALK1 ALCL cells, its expression is NPM-ALK-and STAT3-dependent, and its knockdown sensitizes the cells to ALK inhibition.…”