Molecular Pathogenesis of MDS.
Clonal disorders of hematopoiesis, such as myelodysplastic syndromes (MDS) and myeloproliferative diseases (MPD), affect both hematopoietic stem cells and progenitor cells within the erythroid, platelet and granulocytic lineages and can have devastating consequences in children and adults. The genetic features of these diseases often include clonal, nonrandom chromosomal deletions (e.g., 7q-, 5q-, 20q-, 6q-, 11q- and 13q-) that appear to inactivate tumor suppressor genes required for the normal development of myeloid cells (reviewed in Bench and Fenaux). These putative tumor suppressors have proved to be much more difficult to identify than oncogenes activated by chromosomal translocations, the other major class of chromosomal lesions in MDS and MPD. Although MDS and MPD are almost certainly caused by mutations in stem/progenitor cells, the role of inactivated tumor suppressor genes in this process remains poorly understood. In a small portion of myeloid diseases, mutations have been identified in genes encoding factors known to be required for normal hematopoiesis, such as PU.1, RUNX1, CTNNA1 (alpha-catenin) and c/EBPalpha, and implicating these genes as tumor suppressors. Nonetheless, the identities of most deletion-associated tumor suppressors in these diseases remains elusive, despite complete sequencing of the human genome. The deleted regions detected by cytogenetic methods are generally very large, containing many hundreds of genes, thus making it hard to locate the critical affected gene or genes. It is also unclear whether dysfunctional myelopoiesis results from haploinsufficiency, associated with the deletion of one allele, or from homozygous inactivation due to additional point mutations or microdeletions of the retained wild-type allele. In general MDS have proved surprisingly resistant to conventional treatments. Targeted therapeutic advances in MDS will likely depend on a full comprehension of underlying molecular mechanisms, in particular the tumor suppressor genes lost through clonal, nonrandom chromosomal deletions, such as the 7q- and (del)5q.
Look
A Thomas
AT
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115-6084, USA. thomas_look@dfci.harvard.edu
D000328:Adult; D002869:Chromosome Aberrations / Q000145:classification*; D002872:Chromosome Deletion; D005784:Gene Amplification; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D006410:Hematopoiesis / Q000235:genetics; D006801:Humans; D007621:Karyotyping; D009190:Myelodysplastic Syndromes / Q000235:genetics*; D009196:Myeloproliferative Disorders / Q000235:genetics; D011379:Prognosis; D014157:Transcription Factors / Q000235:genetics
D014157:Transcription Factors