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: Eric Padron, Rami Komrokji, Alan F List
• Journal: Expert review of hematology (Expert Rev Hematol) Vol. 4 Issue 1 Pg. 61-9 (Feb 2011) ISSN: 1747-4094 [Electronic] England
• PMID: 21322779 (Publication Type: Journal Article, Review)

Chemical References

• Antineoplastic Agents
• Thalidomide
• Lenalidomide

Topics

• Anemia, Macrocytic (genetics, metabolism, therapy)
• Antineoplastic Agents (therapeutic use)
• Chromosome Deletion
• Chromosomes, Human, Pair 5 (genetics, metabolism)
• Clinical Trials as Topic
• Gene Deletion
• Humans
• Lenalidomide
• Thalidomide (analogs & derivatives, therapeutic use)