Haploinsufficiency of RPS14 and RPS24 in 5q-Syndrome

Abstract 4964

The 5q-syndrome is a subtype of myelodysplastic syndrome, a rare disorder caused by the loss of a part of the long arm of chromosome 5, being firstly described in 1974 by Van Den Berghe; the cytogenetic characterization reports 4 types of deletion of chromosome 5 (q13-q31), (q13-q33), (q22-q25), (q32-q33) in a critical deletion region (CDR 1 and 2), that shows a reduction in gene expression of 50–60%, the aploinsufficiency includes the tumor suppressor genes, the regulation of gene splicing and apoptosis, the growth inhibitory protein, and the PDGF and p53 pathway. The CDR1 deletion involves genes encoding the 40S ribosomal subunit (D55479-CDC23, EGR1, CDC25C), while the CDR2 deletion includes several genes (SPARC, WIG-1, BMI-1, MEGF-1, RPS14, RPS24) encoding the transcription factor Egr-1/K20×20, the cytoskeletal remodeling protein, and the alphacatenin.

The mechanism of the aploinsufficiency remains unresolved, but we have observed the characteristic changes Cys224-with Arg234, and the down-regulation of micro RNA-genes RPL28, EF1D, and up-regulation of several pro-apoptotic genes BAX and CAPS3, that is caused by a defect in ribosomal protein function, which is characterized by macrocytic anemia, thrombocytosis, megakaryocyte hyperplasia with nuclear hypolobation, erythroblastopenia associated with displastic abnormalities of hematopoietic stem cells/progenitor cells (HSCs/HPCs), hypogranular neutrophils or pseudo Chediak-Higashi large granules, ringed sideroblasts, excess of blasts, and increased malignancy (acute myeloid leukemia).

In accordance of what recent data are currently suggesting we have also observed the mutation of the JaK2 gene and FLT3; this means that many other candidate genes may play a role in this disease and in the risk for clonal evolution and in the progression of acute myeloid leukemia.