Hematopoiesis in the fetal liver is impaired by targeted mutagenesis of a gene encoding a non-DNA binding subunit of the transcription factor, polyomavirus enhancer binding protein 2/core binding factor

Abstract

The Pebpb2 gene encodes a non-DNA binding subunit of the heterodimeric transcription factor, polyomavirus enhancer binding protein 2͞core binding factor (PEBP2͞CBF), and is rearranged in inversion of chromosome 16 associated with human acute myeloid leukemia. To investigate its physiological function, Pebpb2 was mutated by a targeting strategy to generate a null mutant. The homozygous mutation in mice proved lethal in embryos around embryonic day 12.5, apparently due to massive hemorrhaging in the central nervous system. In addition, definitive hematopoiesis in the liver was severely impaired. The observed phenotype was indistinguishable from that reported for homozygous disruption of AML1, which encodes a DNA binding subunit of PEBP2͞CBF. Thus, the results indicate that the two subunits function together as a heterodimeric PEBP2͞CBF in vivo and that PEBP2͞CBF plays an essential role in the development of definitive hematopoiesis.

The AML1-ETO fusion protein promotes the expansion of human hematopoietic stem cells

“…Both mice lack definitive hematopoiesis and die in utero, and embryonic stem cells from these null mice are unable to contribute to definitive hematopoiesis in chimeric mice. [3][4][5][6][7] These findings demonstrate that AML1/CBF␤ is required for the development of hematopoietic stem cells.…”

“…Both mice lack definitive hematopoiesis and die in utero, and embryonic stem cells from these null mice are unable to contribute to definitive hematopoiesis in chimeric mice. [3][4][5][6][7] These findings demonstrate that AML1/CBF␤ is required for the development of hematopoietic stem cells.The (8;21) translocation is associated with approximately 40% of myeloid leukemias of the French-American-British (FAB) M2 subtype and rearranges the AML1 gene on chromosome 21q22 and the ETO gene on chromosome 8q22, generating an AML1-ETO fusion protein that contains the first 177 amino acids of AML1 (including the DNA-binding domain but lacking the transcriptional activation domain of AML1) and almost the full length of the ETO protein. The role of AML1-ETO in the pathogenesis of AML has been intensely studied.…”

Potential involvement of the AML1-MTG8 fusion protein in the granulocytic maturation characteristic of the t(8;21) acute myelogenous leukemia revealed by microarray analysis

“…13,25,26 Targeted disruption of AML1 and CBF␤ has demonstrated that both are essential for definitive hematopoiesis of all lineages in mouse fetal liver. [27][28][29][30] The MTG8 protein contains two putative zinc fingers and several proline-rich regions, 9,31 and interacts with the nuclear receptor corepressor (N-CoR)/mSin3/histone deacetylase (HDAC) complex, [32][33][34] suggesting that MTG8 functions as a transcriptional corepressor.…”

The t(8;21) fusion protein, AML1/ETO, transforms NIH3T3 cells and activates AP-1

“…The consensus DNA sequence recognized by AML1, TGT/cGGT (Meyers et al, 1993), is contained in the promoter and enhancer regions of many hematopoietic-speci®c genes . Although murine genes encoding AML2 and AML3 have been identi®ed (Levanon et al, 1994), an essential role for AML1 in hematopoiesis was demonstrated by AML1 (Okuda et al, 1996;Wang et al, 1996a) and CBFb (Niki et al, 1997;Sasaki et al, 1996;Wang et al, 1996b) knock-out experiments. Mice that lack AML1 or CBFb have absent fetal liver hematopoiesis and die between days E11.5-13.5 with a distinct pattern of central nervous system hemorrhage.…”