Biomedical subjects

Robert Escher

Publications and source records attributed to Robert Escher.

3 recordsLinked to original sources

PubMed2004

Chromosome band 16q22-linked familial AML: exclusion of candidate genes, and possible disease risk modification by NQO1 polymorphisms.

Analyses of chromosomal translocation and inversion breakpoints in sporadic acute myeloid leukemias have identified many transcription factors as playing a role in leukemogenesis. Studies of families with a Mendelian predisposition to hematological malignancies have identified the gene coding for the transcription factor RUNX1 as a leukemia-predisposing gene involved in the first steps of leukemogenesis. Using two families, another autosomal dominant familial leukemia locus was linked to chromosome band 16q22 where the CBFB gene maps. Although CBFB forms a core-binding factor transcriptional complex with RUNX1, previous analyses have excluded the CBFB gene as the leukemia-predisposing gene in these families. In the current study, we performed an extended molecular analysis in these families of the four other transcription factor genes in the 16q22 critical region as well as of two other genes with a known association with leukemia. Several previously undescribed but nonpathogenic sequence variants were identified. We demonstrated that the transcription factors E2F4, CTCF, NFATC3, and NFAT5, and the genes coding for NAD(P)H:quinone oxido-reductase 1 (NQO1) and for E-cadherin are not responsible for the leukemia susceptibility in these families. The presence of NQO1 polymorphisms may suggest a role for this gene in disease risk modification in these families.

CCCTC-Binding Factor↗

PubMed2004

Two clonal occurrences of tetrasomy 21 in an atypical chronic myeloid leukemia with wild-type RUNX1 alleles. Additional support for a gene dosage effect of chromosome 21 or RUNX1 in leukemia.

Atypical chronic myeloid leukemia (aCML) is a rare leukemic disorder with no specific genetic lesion. Here we demonstrate clonal occurrences of tetrasomy for the long arm of chromosome 21 in a patient with aCML, and a thorough review of the literature provides evidence that this chromosomal anomaly is a so far not recognised recurrent finding in aCML. Further, the timely association of the occurrence of the tetrasomy 21q with acceleration of the leukemia suggests a role for chromosome 21 in leukemic disease progression. The chromosome 21 gene most strongly implicated in both normal and abnormal hematopoiesis is RUNX1. Also, RUNX1 haploinsufficiency due to RUNX1 point mutations characterises the familial platelet disorder with propensity to develop leukemia, and thromboytopenia was a leading feature in the present case. Therefore, an extensive molecular analysis of RUNX1 was performed. However, these analyses did not reveal a mutation, and the results support a gene dosage effect for RUNX1 in myeloid disease similar to observations in lymphoid disease. Patients with aCML and a tetrasomy 21 may form a karyotypically and phenotypically defined subgroup of aCML.

Aneuploidy↗

PubMed2003

AML1 interconnected pathways of leukemogenesis.

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.

Animals↗