The Role of Haploinsufficiency of rps14 and p53 Activation in the Molecular Pathogenesis of the 5q- Syndrome

Jacqueline Boultwood

doi:10.4081/pr.2011.s2.e10

Abstract

In recent years we have gained great insight into the molecular pathogenesis of the 5q- syndrome, a distinct subtype of myelodysplasia. The demonstration of haploinsufficiency of the ribosomal gene RPS14 (mapping to the commonly deleted region) and the finding that this is the cause of the erythroid defect in the 5qsyndrome represent major advances. A mouse model of the human 5q- syndrome generated by large-scale deletion of the Cd74-Nid67 interval (containing RPS14) further supports a critical role for RPS14 haploinsufficiency. It is widely accepted that ribosomal deficiency results in p53 activation and defective erythropoiesis and the crossing of the ‘5q- mice’ with p53 deficient mice ameliorated the erythroid progenitor defect. Emerging data suggests that the p53 activation observed in the mouse model may also apply to the human 5q- syndrome.

Highlights

The demonstration of haploinsufficiency of the ribosomal gene RPS14 and the finding that this ly is the cause of the erythroid defect in the 5qn syndrome represent major advances
We have recently demonstrated haploinsufficiency of the ribosomal gene RPS14 in the CD34+ cells of patients with the 5q- syncently described in a patient with non-classical Diamond-Blackfan anaemia (DBA).[17]
The 5q- syndrome is were studied by an RNA-mediated interference triguingly both disorders show haploinsuffinow recognized as a distinct clinical entity (RNAi)- based approach by Ebert et al and it ciency for ribosomal proteins, RPS19 and according to the WHO classification and is was shown that partial loss of function RPS14 respectively, required for the maturadefined by a medullary blast count of

Summary

Introduction

The demonstration of haploinsufficiency of the ribosomal gene RPS14 (mapping to the commonly deleted region) and the finding that this ly is the cause of the erythroid defect in the 5qn syndrome represent major advances.

Results

Conclusion