Loss of 5q in myeloid malignancies ? A gain in understanding of biological and clinical consequences

Hemizygous interstitial or terminal deletion of the long arm of chromosome 5 [del(5q)] is a recurrent cytogenetic abnormality in myeloid malignancies, including myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). These deletions cause loss of a large contiguous chromosomal region encompassing more than 30 genes, which results in disease through haploinsufficiency of one or more genes including RPS14. In MDS, del(5q) in isolation is a lower-risk cytogenetic anomaly and is sometimes associated with a unique clinicopathological phenotype, but in AML it represents a higher-risk lesion, often denoting secondary AML arising from prior MDS. Lenalidomide effectively targets the del(5q)-bearing clone in MDS, resulting in sustained erythroid transfusion independence in most patients and cytogenetic remission in a subset of treated patients. Since the initial regu-latory approval of lenalidomide for del(5q) MDS in 2005, translational research endeavors in del(5q)-associated myeloid malignancies have improved our understanding of how allelic haploinsufficiency underlies both the hematological phenotype and selective sensitivity to lenalidomide therapy. This review will focus on the mo-lecular pathogenesis of del(5q) in myeloid malignancies, clinical development of lenalidomide and emerging data on lenalidomide-refractory del (5q) MDS, and possible novel targeted therapeutic strategies.

Automated summary

Hemizygous interstitial or terminal deletion of chromosome 5q is a recurrent cytogenetic abnormality in myeloid malignancies, with differing clinical implications in MDS and AML. Lenalidomide effectively targets the del(5q)-bearing clone, leading to erythroid transfusion independence and cytogenetic remission in some patients, but novel targeted therapeutic strategies are still needed for lenalidomide-refractory cases.