Erythroid inhibition by the leukemic fusion AML1-ETO is associated with impaired acetylation of the major erythroid transcription factor GATA-1.
Human acute myeloid leukemias with the t(8;21) translocation express the AML1-ETO fusion protein in the hematopoietic stem cell compartment and show impairment in erythroid differentiation. This clinical finding is reproduced in multiple murine and cell culture model systems in which AML1-ETO specifically interferes with erythroid maturation. Using purified normal human early hematopoietic progenitor cells, we find that AML1-ETO impedes the earliest discernable steps of erythroid lineage commitment. Correspondingly, GATA-1, a central transcriptional regulator of erythroid differentiation, undergoes repression by AML1-ETO in a nonconventional histone deacetylase-independent manner. In particular, GATA-1 acetylation by its transcriptional coactivator, p300/CBP, a critical regulatory step in programming erythroid development, is efficiently blocked by AML1-ETO. Fusion of a heterologous E1A coactivator recruitment module to GATA-1 overrides the inhibitory effects of AML1-ETO on GATA-1 acetylation and transactivation. Furthermore, the E1A-GATA-1 fusion, but not wild-type GATA-1, rescues erythroid lineage commitment in primary human progenitors expressing AML1-ETO. These results ascribe a novel repressive mechanism to AML1-ETO, blockade of GATA-1 acetylation, which correlates with its inhibitory effects on primary erythroid lineage commitment.
Department of Pathology, University of Virginia School of Medicine, Charlottesville, Virginia 22908, USA.
Youngjin
Y
Choi
Kamaleldin E
KE
Elagib
Lorrie L
LL
Delehanty
Adam N
AN
Goldfarb
D000107:Acetylation; D018952:Antigens, CD34 / Q000096:biosynthesis / Q000276:immunology; D018955:CD36 Antigens / Q000096:biosynthesis / Q000276:immunology; D002454:Cell Differentiation / Q000502:physiology; D002460:Cell Line; D019070:Cell Lineage; D050676:Core Binding Factor Alpha 2 Subunit / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D015672:Erythroid Precursor Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D050982:GATA1 Transcription Factor / Q000378:metabolism*; D006801:Humans; D020014:K562 Cells; D015514:Oncogene Proteins, Fusion / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D000075142:RUNX1 Translocation Partner 1 Protein; D015533:Transcriptional Activation; D014162:Transfection; D016335:Zinc Fingers / Q000502:physiology; D050880:p300-CBP Transcription Factors / Q000378:metabolism
C107844:AML1-ETO fusion protein, human; D018952:Antigens, CD34; D018955:CD36 Antigens; D050676:Core Binding Factor Alpha 2 Subunit; D050982:GATA1 Transcription Factor; C494688:GATA1 protein, human; D015514:Oncogene Proteins, Fusion; D000075142:RUNX1 Translocation Partner 1 Protein; D050880:p300-CBP Transcription Factors