Oncogenic transcription factor Evi1 regulates hematopoietic stem cell proliferation through GATA-2 expression

Abstract

Because androgen function is regulated by its receptors, androgen-androgen receptor signaling is crucial for regulating spermatogenesis. Androgen is mainly testosterone secreted by testis. Based on the results of early studies in goats, the administration of melatonin over an extended period of time increases steroid production, but the underlying mechanism remains unclear. Here, we report the expression of the melatonin membrane receptors MT1 and MT2 and the retinoic acid receptor-related orphan receptor-alpha (RORα) in the goat testis. An in vitro differentiation system using spermatogonial stem cells (SSCs) cultured in the presence of testicular somatic cells was able to support the formation of sperm-like cells with a single flagellum. The addition of 10-7 M melatonin to the in vitro culture system increased RORα expression and considerably improved the efficiency of haploid cell differentiation, and the addition of the RORα agonist CGP52608 significantly increased the testosterone concentration and expression of GATA binding factor 4 (GATA-4). Furthermore, inhibitors of melatonin membrane receptors and a RORα antagonist (T0901317) also led to a considerable reduction in the efficiency of haploid spermatid formation, which was coupled with the suppression of GATA-4 expression. Based on these results, RORα may play a crucial role in enhancing melatonin-regulated GATA-4 transcription and steroid hormone synthesis in the goat spermatogonial stem cell differentiation culture system.

Significant increase of self-renewal in hematopoietic cells after forced expression of EVI1

“…One of them is HOXB4, which, when transduced in HSCs leads to a 40-fold expansion in vitro in a period of 12 days and acts as a transcriptional regulator of genes that govern self-renewal [15]. EVI1 seems to act in a similar way, perhaps by up-regulating genes controlling HSC maintenance and proliferation such as GATA2 [16]. …”

“…This paper is based on a presentation at the Seventh International Workshop on Molecular Aspects of Myeloid Stem Cell Development and Leukemia in Annapolis, Maryland, May [13][14][15][16] 2007, sponsored by The Leukemia & Lymphoma Society.…”

Mechanisms of self-renewal in hematopoietic stem cells

“…Ecotropic viral integration site 1 (Evi-1) is an oncogenic transcription factor of the SET/PR domain protein family, and it is predominantly expressed in both embryonic and adult HSCs [97]. Mouse embryos lacking Evi-1 die due to the remarkably decreased number and reconstitution capacity of HSCs.…”

Overexpression of GATA2 predicts an adverse prognosis for patients with acute myeloid leukemia and it is associated with distinct molecular abnormalities

“…6 Furthermore, EVI1 has been shown to bind directly to the GATA2 promoter and act as an enhancer, suggesting that GATA2 represents a critical target of EVI1. 7 High levels of GATA2 expression have been associated with myeloid neoplasms involving 3q rearrangements. 8 When we analyzed the 20 patients with 3q rearrangements by fluorescence in situ hybridization, EVI1 was overexpressed in the nine patients with 3q21 and/or 3q26 aberrations (two 3q21 rearrangements, six 3q26 and one 3q21q26).…”