Opposing effects of two zinc finger genes, EVI-1 and GATA-1, on all-trans retinoic acid-induced NB4 cell granulocytic differentiation

Abstract

In hematopoietic stem cells, lineage specific differentiation is determined in part by specific transcription factors which stabilize a particular lineage network and activate differentiation programs. In myeloid and erythroid lineages, distinct transcription factors are expressed in committed progenitors and more differentiated cells. Zinc finger transcription factors, EVI-1 and GATA-1, are expressed in hematopoietic stem cells. Abnormal EVI-1 expression is associated with some human acute myeloid leukemias (AML). It has been shown that enforced EVI-1 expression blocked erythroid specific transcription factor, GATA-1, mediated transcriptional activation and erythroid differentiation. The regulation and the function of the EVI-1 in myeloid differentiation and possible antagonism of erythroid/myeloid lineage transcription factors in lineage commitment and differentiation were studied in NB4, a human acute promyelocytic leukemia (APL) cell line. EVI-1 and GATA-1 were stably expressed in NB4 cells by transfection and effects evaluated on granulocyte differentiation induced by all-trans retinoic acid (ATRA). The results showed that EVI-1 expressing NB4 clones differentiate more rapidly and more completely than control clones. In contrast, GATA-1 expressing NB4 clones showed delayed differentiation. These findings demonstrate that EVI-1 expression promotes and GATA-1 expression delays ATRA-induced NB4 cell granulocytic differentiation, suggesting that EVI-1 plays an important role in myeloid differentiation and EVI-1 and GATA-1 antagonize each other in erythroid/myeloid commitment and differentiation.