title: Biology and treatment of the 5q- syndrome.
abstract: The 5q- syndrome is a unique subtype of myelodysplastic syndromes typified by a relatively indolent course and responsiveness to lenalidomide. Here, we review the salient biologic features of this disease. Hemizygous deletion of a segment of chromosome 5q is believed to be the disease-initiating event. Recent molecular techniques have isolated the common deleted region and characterized key candidate genes contributing to the disease phenotype. Gene-specific RNA interference strategies revealed that haplo-insufficiency for the RPS14 gene, which encodes a ribosomal protein, is a critical effector of the p53-dependent erythroid hypoplasia and apoptotic loss of erythroid precursors. Disease-specific sensitivity to lenalidomide results from the drug's inhibitory effect on two haplodeficient phosphatases, PP2Acα and CDC25c, which are coregulators of the G(2)/M checkpoint. Hyperphosphorylation of MDM2, as a result of inhibition of PP2A phosphatase activity, stabilizes MDM2, permitting p53 degradation and transition to G(2) arrest and clonal suppression. With the emerging data elucidating the pathogenesis of the 5q- syndrome and the success of clinical trials, a cohesive story connecting the biology and pharmacology associated with this subtype of myelodysplastic syndromes has emerged.
authors.affiliation: Hematologic Malignancy Division, H Lee Moffitt Cancer Center, Tampa, FL 33612, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Padron
authors.forename: Rami
authors.initials: R
authors.lastname: Komrokji
authors.forename: Alan F
authors.initials: AF
authors.lastname: List
mesh_terms: D000748:Anemia, Macrocytic / Q000235:genetics / Q000378:metabolism / Q000628:therapy; D000970:Antineoplastic Agents / Q000627:therapeutic use; D002872:Chromosome Deletion; D002895:Chromosomes, Human, Pair 5 / Q000235:genetics / Q000378:metabolism; D002986:Clinical Trials as Topic; D017353:Gene Deletion; D006801:Humans; D000077269:Lenalidomide; D013792:Thalidomide / Q000031:analogs & derivatives / Q000627:therapeutic use
chemical_list: D000970:Antineoplastic Agents; D013792:Thalidomide; D000077269:Lenalidomide