Identification of RUNX1/AML1 as a classical tumor suppressor gene

Abstract

Based on our previous results indicating the presence of a tumor suppressor gene (TSG), chromosome 21 was analysed for loss of heterozygosity (LOH) in 18 patients with acute myeloid leukemia (17, AML-M0; one, AML-M1). Allelotyping at polymorphic loci was performed on purified material, allowing unequivocal detection of allelic loss and homozygous deletions. Six AML-M0 patients shared a common region of LOH harboring a single gene: RUNX1 (AML1), the most frequent site of translocations in acute leukemia and a well-known fusion oncogene. Fluorescence in situ hybridization allowed the identification of deletions with breakpoints within RUNX1 in two patients as the cause of LOH. In the four others the LOH pattern and the presence of two karyotypically normal chromosomes 21 were in line with mitotic recombination. Further molecular and cytogenetic analyses showed that this caused homozygosity of primary RUNX1 mutations: two point mutations, a partial deletion and, most significantly, a complete deletion of RUNX1. These findings identify RUNX1 as a classical TSG: both alleles are mutated or absent in cancer cells from four of the 17 AML-M0 patients examined. In contrast to AML-M0, the AML-M1 patient was trisomic for chromosome 21 and has two mutated and one normal RUNX1 allele, suggesting that the order of mutagenic events leading to leukemia may influence the predominant tumor type.

Transcriptional dysregulation during myeloid transformation in AML

“…In addition, RUNX1 point mutations were reported in sporadic and familial myeloid leukemia (Osato et al, 1999;Song et al, 1999). Subsequent studies have confirmed the occurrence of RUNX1 point mutations in AML, predominantly in the M0 subtype (Preudhomme et al, 2000;Langabeer et al, 2002;Matsuno et al, 2003;Roumier et al, 2003;Silva et al, 2003). Whereas mutations in the C-terminal domain were believed for some time to cluster within the RUNT domain, mutations in the C-terminal region, outside the RUNT domain, have also been identified, predominantly in MDS-AML (Harada et al, 2003).…”

Expression levels of the runt-related transcription factor�1 and�3 genes in the development of acute myeloid leukemia

“…However, the significance of the RUNX1 gene in cancer development is not fully known. Previous studies have suggested that the RUNX1 gene functions as a tumor suppressor in AML (25), and that loss of the RUNX1 gene may lead to weak differentiation and leukemia development (26). One previous study has reported that a normal expression level of RUNX1 gene inhibits cell proliferation and promotes differentiation of hematopoietic progenitor cells (21).…”

Kinetic analysis of genomewide gene expression reveals molecule circuitries that control T cell activation and Th1/2 differentiation

“…The level of expression of this gene was reduced on TCR stimulation and is preferentially recovered in differentiating Th2 cells. Based on previous studies that identify runx1 as a tumor suppressor (34) and affecting T cell differentiation in thymus (35), it likely plays a role in limiting Th2 cells in later stage. The Th1-selective transcription factors can also be divided into two groups based on their transcription profiles.…”