Candidate genes showing haploinsufficiency in the 5q- syndrome included the tumour suppressor gene SPARC and RPS14, a component of the 40S ribosomal subunit.
In addition, we identified a block in the processing of pre-ribosomal RNA in RPS14-deficient cells that is functionally equivalent to the defect in Diamond-Blackfan anaemia, linking the molecular pathophysiology of the 5q- syndrome to a congenital syndrome causing bone marrow failure.
A systematic RNA interference screen to interrogate the function of each gene in the common deleted region (CDR) for the 5q- syndrome identified RPS14 as a critical haploinsufficiency disease gene for the erythroid failure, which is a characteristic of this syndrome.
This review examines the potential role of several genes, including RPS14, in the pathogenesis of the 5q- syndrome and recent advances in clinical management, with particular emphasis on the role and mechanism of action of lenalidomide.
A mouse model of the human 5q- syndrome has now been created by chromosomal engineering involving a large-scale deletion of the Cd74-Nid67 interval (containing RPS14).
In 5q- syndrome haploinsufficiency of the ribosomal gene RPS14 appears to cooperate with loss of two micro-RNAs miR-145 and miR-146 to induce key features of the disease.
Haploinsufficiency of the ribosomal protein S14RPS14 gene, located in the common deleted region of chromosome 5q, is a potential causal factor of 5q- syndrome.
We found that p53 accumulates selectively in the erythroid lineage in primary human hematopoietic progenitor cells after expression of shRNAs targeting RPS14, the ribosomal protein gene deleted in the 5q-syndrome, or RPS19, the most commonly mutated gene in DBA.
Recurrent deletions of 5q in myeloid malignancies encompass two separate regions: deletion of 5q33, which is associated with the 5q− syndrome and haploinsufficiency of RPS14, and deletion of a more proximal locus at 5q31.
Heterozygous loss of the RPS14 gene on 5q leads to activation of p53 in the erythroid lineage and the macrocytic anemia characteristic of the 5q-syndrome.
A mouse model of the human 5q- syndrome has been generated by large-scale deletion of the Cd74-Nid67 interval (containing Rps14) and the crossing of these '5q- mice' with p53-deficient mice ameliorated the erythroid progenitor defect.
A mouse model of the human 5q- syndrome has been generated by large-scale deletion of the Cd74-Nid67 interval (containing Rps14) and the crossing of these '5q- mice' with p53-deficient mice ameliorated the erythroid progenitor defect.
Haploinsufficiency of the ribosomal protein gene RPS14 plays a critical role in the development of anemia in the 5q- syndrome, and haploinsufficiency of CUX1 is important in some patients with MDS and AML with complete or partial loss of chromosome 7.
Combined Rps14/Csnk1a1/miR-145/146a deficiency recapitulated the cardinal features of the 5q- syndrome, including (1) more severe anemia with faster kinetics than Rps14 haploinsufficiency alone and (2) pathognomonic megakaryocyte morphology.