Genetic deletions in AML and MDS

Abstract

Chromosomal deletions are common molecular events in myeloid malignancies. Heterozygous deletions may contain a tumor suppressor gene that undergoes homozygous inactivation or may contain one or more genes that alter the disease phenotype through haploinsufficiency. The most common karyotypic abnormality in myelodysplastic syndrome (MDS) is deletion of chromosome 5q. A subset of patients with del(5q) as a sole cytogenetic abnormality has a consistent set of clinical features, termed the 5q- syndrome. While no tumor suppressor genes have been identified on 5q that are homozygously inactivated, recent studies have highlighted several genes and micro RNAs (miRNAs) that cause the phenotype of the 5q- syndrome through allelic insufficiency. For example, deletion of one allele of the RPS14 gene causes a severe defect in erythropoiesis, analogous to the congenital syndrome Diamond Blackfan anemia, which is itself caused by mutations that inactivate one allele of a ribosomal gene. Loss of one allele of miR-145 and miR-146a causes an increase in megakaryocyte production and may contribute to the clonal advantage of cells with del(5q). The functional approaches used to dissect the molecular basis of the 5q deletion in MDS have the potential to identify key genes and therapeutic targets within other chromosomal deletions in hematologic malignancies.