Molecular pathogenesis of myelodysplastic syndromes with deletion 5q

Abstract

The molecular pathogenesis of deletion 5q (del(5q)) myelodysplastic syndrome (MDS) has recently been realized as a result of major advances in our understanding of the mechanisms responsible for clinical phenotype. Identification of commonly deleted genes such as RPS14, miRNA‐145, HSPA9, CD78, and CSNK1a1 have elucidated the precise biological changes responsible for the anemia, leukopenia, and thrombocytosis that characterizes del(5q) MDS and highlighted the importance of allelic haploinsufficiency in the hematological phenotype. Recent elegant investigations have also identified a critical role of innate immune signaling in del(5q) pathogenesis. TP53 and Wnt/β‐catenin pathways have also been found to be involved in clonal expansion and progression of the disease as well as resistance and poor outcomes to available therapy. Understanding the molecular pathogenesis of the disease has provided a critical foundation in identifying the biological targets of lenalidomide in del(5q) MDS, which has led to the development of novel therapeutic agents in hematologic malignancies as well as potential alternative targets to exploit in patients who have failed lenalidomide treatment.

A paediatric myelodysplastic syndrome with 5q deletion associated with Fanconi anaemia

“…The 5q− cells are haplodeficient in Cdc25C and PP2Aca, key enzymes regulating the G2/M phase checkpoint. Lenalidomide is an immunomodulatory drug characterised by a wide range of effects, and targets these enzymes resulting in G2/M phase arrest and apoptosis in 5q− cells, and growth inhibition of differentiating erythroblasts harbouring 5q− without affecting cytogenetically normal cells 4 . To our knowledge, this is the first reported case of lenalidomide treatment in a child with 5q− syndrome and the second report of this chromosomal abnormality in FA.…”

Transitory response of a myelodysplastic syndrome with deletion of chromosome 5q to thalidomide. Report of one case

“…The commonly deleted region (CDR) includes 1.5 megabases comprising 41 genes located at or near the 5q32-33.4 region. Genes in 5q associated with the MDS pathogenesis include: RPS14 (erythroid phenotype of 5q-syndrome), microRNAs miR-145 and miR-146 (causes elevated platelet counts and selective advantage to the 5q-clone), EGR1 (increases stem-cell self-renewal), CTNNA1 (hypermethylation of the remaining allele is associated with progression to AML), SPARC gene (probably haploinsufficiency could increase adhesion of the clone to the bone marrow) 2,3 .…”

“…Clinically, 5q-syndrome is associated with favorable prognosis and a low risk of transformation to acute myeloid leukemia if receiving lenalidomide, the standard treatment 3 . Thalidomide could have adequate response (up to 20%) as an alternative with lower cost.…”

MicroRNAs from Liquid Biopsy Derived Extracellular Vesicles: Recent Advances in Detection and Characterization Methods

“…Since then, a plethora of studies have attempted to standardize and characterize the non-coding transcriptome of different cancer types to offer suitable biomarker miRNA candidates [13]. Expression level alterations of miRNA can also indirectly reflect chromosomal abnormalities of their originating tumor cells, as a high number of microRNA gene loci are located within chromosomal fragile regions [14][15][16] which are prone to translocations [17,18], amplifications [19], or deletions [20]. This, coupled with a complete mapping of miRNA loci in the genome and the evaluation of their enrichment in different biological fluids, can prove useful tools in evaluating disease status when ctDNA or CTCs are not available.…”