The molecular pathogenesis of down syndrome-associated diseases and the promising potential therapeutic targets

Abstract

Trisomy 21, the most common origin of Down syndrome, is an extra copy of chromosome 21 in all cells generated by a chromosomal non-disjunction during meiosis. The increased transcription of the oncogenes and tumor suppressor genes located on the human chromosome 21 determines transcriptional alterations of several molecular pathways involved in the Down syndrome associated diseases related to cell cycle alteration, leukemia, tumors and cancer. The elucidation of the molecular mechanisms involved in the Down syndrome-associated diseases could promise potential therapeutic targets.Trisomy 21 or Down syndrome determined by the triplication of human chromosome 21, is the most frequent genetic disorder with hard impact on public health. The genetic overdosage, caused by the trisomy 21, determines transcriptional alterations of most genes on human chromosome 21 and their overdosage determine transcriptional variations of several genes located on other chromosomes affecting several molecular pathways involved in cell cycle alteration, leukaemia, tumors and cancer [1].The increased transcription of the oncogenes and tumor suppressor genes located on the human chromosome 21 have important roles in leukemia, tumors and cancer that are related to cell cycle alterations. The chromosome 21 oncogene AML1 (Acute myeloid leukaemia 1) also known as RUNX1 or CBFA2 is an established regulator of hematopoiesis and megakaryopoiesis and the hereditary loss-offunction mutations of AML1 cause the autosomal dominant familial platelet disorder with a predisposition to develop acute myeloid leukemia as is also seen in mouse models [2,3]. AML1 transcripts are downregulated in Down syndrome megakaryoblasts compared to non-Down syndrome megakaryoblasts suggesting that AML1 is linked to the megakaryocytic lineage [4]. It was found that AML1 inhibits NF-κB signaling through interaction with IκB kinase complex in the cytoplasm and that the inhibition of NF-κB signaling in leukemic cells with mutated AML1 efficiently blocks their growth and development of leukemia. This suggest AML1 function as a cytoplasmic attenuator of NF-κB signaling in the repression of myeloid tumors and indicate that NF-κB signaling is one of the promising therapeutic targets of hematologic malignancies with AML1 abnormality [5].The chromosome 21 gene TIAM1 (T-cell lymphoma invasion and metastasis 1) has been identified to have important roles in the progression of epithelial cancers. In human breast carcinomas, a close correlation was observed between increased TIAM1 expression and increased tumor grade [6] suggesting that increased TIAM1 expression and/or activity may promote progression of breast carcinoma. Tumors that do occur in Tiam mutant mice are more likely to progress suggesting that, in skin carcinogenesis, Tiam1 is an inhibitor of tumor development [7]. Colon carcinoma cell lines selected for increased metastatic potential in nude mice express more TIAM1 protein than their parental line [8,9]. This indicate that TIAM1 may have a role in the progression and met...