AML1 Interconnected Pathways of Leukemogenesis

Abstract

The AML1 transcription factor, identified by the cloning of the translocation t(8;21) breakpoint, is one of the most frequent targets for chromosomal translocations in leukemia. Furthermore, polysomies and point mutations can also alter AML1 function. AML1, also called CBF alpha 2, PEBP alpha 2 or RUNX1, is thus implicated in a great number of acute leukemias via a variety of pathogenic mechanisms and seems to act either as an oncogene or a tumor suppressor gene. Characterization of AML1 knockout mice has shown that AML1 is necessary for normal development of all hematopoietic lineages and alterations in the overal functional level of AML1 can have a profound effect on hematopoiesis. Numerous studies have shown that AML1 plays a vital role in the regulation of expression of many genes involved in hematopoietic cell development, and the impairment of AML1 function disregulates the pathways leading to cellular proliferation and differentiation. However, heterozygous AML1 mutations alone may not be sufficient for the development of leukemia. A cumulative process of mutagenesis involving additional genetic events in functionally related molecules, may be necessary for the development of leukemia and may determine the leukemic phenotype. We review the known AML1 target genes, AML1 interacting proteins, AML1 gene alterations and their effects on AML1 function, and mutations in AML1-related genes associated with leukemia. We discuss the interconnections between all these genes in cell signaling pathways and their importance for future therapeutic developments.

Identification and characterization of novel AML1-ETO fusion transcripts in pediatric t(8;21) acute myeloid leukemia: a report from the Children's Oncology Group

“…To determine the function of the novel in-frame A1bE and A1cE transcripts identified in primary t(8;21) AML samples, complete cDNAs for these forms were cotransfected into HeLa cells, along with a promoter reporter construct for GM-CSF, a known AML1 target gene (Michaud et al, 2003). Unlike AML1b, the A1E fusion proteins had no significant transactivating effects on the GM-CSF promoter, consistent with previously reported results (Frank et al, 1995).…”

“…Functional role of the novel in-frame A1E fusion proteins To assess the functional roles of the novel in-frame A1E transcripts, cDNAs for these forms (in pcDNA3) were co-transfected with a promoter reporter construct for granulocyte-macrophage colony-stimulating factor (GM-CSF; a known AML1 target gene) (Michaud et al, 2003) into HeLa cells. Extracts were prepared and cellular A1E proteins were assayed on western blots and promoter activity measured by luciferase assays.…”

“…The AML1 gene encodes a DNA-binding protein that regulates hematopoietic gene expression (Michaud et al, 2003;Peterson and Zhang, 2004) and has the potential to encode multiple transcript and protein isoforms (termed AML1a, AML1b and AML1c), due to differential use of promoters (distal P1 and proximal P2, respectively) and alternate splicing of upstream exons (Miyoshi et al, 1995). AML1a and AML1b transcripts are both transcribed from the P2 promoter and encode identical N-terminal regions; however, AML1a lacks the C-terminal transactivation domain present in AML1b.…”

ELA2 is regulated by hematopoietic transcription factors, but not repressed by AML1-ETO

“…Linggi et al, 2002). Since neutrophil elastase (NE) is an early marker of lineage commitment along the myeloid path, ELA2 was investigated as a possible target of AML1 and AML1-ETO (Nuchprayoon et al, 1994;Michaud et al, 2003;Peterson and Zhang, 2004).…”

The role of the proto-oncogene ETS2 in acute megakaryocytic leukemia biology and therapy

“…AML1 (also known as RUNX1, a DNA-binding subunit of the transcription complex termed core-binding factor 20,21 ) is located in the 'critical Down syndrome region' on chromosome 21 and is an established regulator of hematopoiesis and megakaryopoiesis. [21][22][23] AML1 haploinsufficiency in humans impairs some aspect of megakaryopoiesis, as is also seen in mouse models.…”