PU.1 determines the self-renewal capacity of erythroid progenitor cells

Abstract

PU.1 is a hematopoietic-specific transcriptional activator that is absolutely required for the differentiation of B lymphocytes and myeloid-lineage cells. Although PU.1 is also expressed by early erythroid progenitor cells, its role in erythropoiesis, if any, is unknown. To investigate the relevance of PU.1 in erythropoiesis, we produced a line of PU.1-deficient mice carrying a green fluorescent protein reporter at this locus. We report here that PU.1 is tightly regulated during differentiation—it is expressed at low levels in erythroid progenitor cells and down-regulated upon terminal differentiation. Strikingly, PU.1-deficient fetal erythroid progenitors lose their self-renewal capacity and undergo proliferation arrest, premature differentiation, and apoptosis. In adult mice lacking one PU.1 allele, similar defects are detected following stress-induced erythropoiesis. These studies identify PU.1 as a novel and critical regulator of erythropoiesis and highlight the versatility of this transcription factor in promoting or preventing differentiation depending on the hematopoietic lineage.

Spi-1/PU.1 participates in erythroleukemogenesis by inhibiting apoptosis in cooperation with Epo signaling and by blocking erythroid differentiation

“…26,27 Previous reports have shown that Spi-1 sustains a pool of immature erythroid progenitors during fetal development in mice by exerting proliferative and antiapoptotic actions. 7 These activities are transient because Spi-1 is rapidly silenced during normal erythroid differentiation. 7,8 Our results indicate that Spi-1 renewal and antiapoptotic activities can be functional in engaged erythroid cells from adult mice when its expression is enforced and that these activities may be implicated in the conversion of a normal into a preleukemic proerythroblast.…”

“…[3][4][5][6] PU.1 is expressed in erythroid progenitors and is silenced at an early stage of both fetal and adult erythropoiesis. 7,8 With regard to its role in erythropoiesis, conflicting hypotheses are reported. Fisher et al 9,10 brought argument, suggesting that PU.1 is required for erythropoiesis in adult bone marrow but not in fetal liver.…”

“…Fisher et al 9,10 brought argument, suggesting that PU.1 is required for erythropoiesis in adult bone marrow but not in fetal liver. Others showed that PU.1 is involved in the self-renewal of fetal erythroid progenitors, 7 whereas its role in erythroid progenitors from the adult seemed to be excluded. 5 A dysregulation of PU.1 activity can lead to murine malignant hemopathies.…”

Subtle distinct regulations of late erythroid molecular events by PI3K/AKT-mediated activation of Spi-1/PU.1 oncogene autoregulation loop

“…spi-1/pu.1 gene disruption results in lethality (Scott et al, 1994). It is essential for controlling the balance between self-renewal and differentiation in hematopoietic progenitor cells, and functions in a concentration-dependent manner to promote differentiation of the lymphoid and myeloid lineages (Back et al, 2004;Fisher et al, 2004 and references therein). Furthermore, Spi-1/PU.1 is expressed at low levels in erythroid progenitor cells and subsequently downregulated on terminal differentiation.…”

“…Furthermore, Spi-1/PU.1 is expressed at low levels in erythroid progenitor cells and subsequently downregulated on terminal differentiation. It acts to maintain the self-renewal capacity of immature erythroid precursors and to prevent differentiation in the erythroid lineage (Back et al, 2004;Fisher et al, 2004).…”