Molecular Pathogenesis of the 5q– Syndrome: The Role of RPS14 in Pathogenesis and SPARC in the Hematologic Response to Lenalidomide

The 5q– syndrome is the most distinct of all the myelodysplastic syndromes. Importantly, there is a clear genotype- phenotype association in the 5q– syndrome, and it is believed that the deletion of 5q marks the location for ≥ 1 gene, the loss of which might affect important processes such as growth control and normal hematopoiesis. We identified the commonly deleted region (CDR) of the 5q– syndrome at 5q31-32 and suggest that ≥ 1 of the 44 candidate genes mapping within this interval represents the gene or genes critical to the development of the 5q– syndrome. Pinpointing the causative gene(s) has proven challenging; however, new data that support a role for several candidate genes assigned to this interval are now emerging. We have demonstrated haploinsufficiency of the tumor suppressor gene SPARC in the CD34+ cells of patients with the 5q– syndrome and have shown that lenalidomide upregulates this gene in cultured erythroid progenitors from patients with 5q– syndrome. We have also demonstrated haploinsufficiency of RPS14, a component of the 40S ribosomal subunit, in the 5q– syndrome. In Diamond-Blackfan anemia, haploinsufficiency of the ribosomal gene RPS19 is critical, and we have speculated an analogous role for RPS14 in the 5q– syndrome. New data obtained using a functional genomic approach strongly suggests that haploinsufficiency of RPS14 is critical to the development of the 5q– syndrome. We suggest that reduced expression levels (a gene dosage effect) for ≥ 1 of the genes mapping to the CDR is the pathogenetic basis of the 5q– syndrome.