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

Blood Rev. 2021 Mar:46:100735. doi: 10.1016/j.blre.2020.100735. Epub 2020 Jul 23.


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 regulatory 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 molecular 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.

Keywords: AML; Cereblon; Chromosome 5q; Haploinsufficiency; Lenalidomide; MDS; RPS14; TP53.

Publication types

  • Review

MeSH terms

  • Alleles
  • Chromosome Deletion*
  • Chromosomes, Human, Pair 5*
  • Genetic Association Studies
  • Genetic Predisposition to Disease*
  • Haploinsufficiency
  • Humans
  • Myelodysplastic Syndromes / diagnosis
  • Myelodysplastic Syndromes / genetics
  • Myelodysplastic Syndromes / metabolism
  • Myelodysplastic Syndromes / therapy
  • Myeloproliferative Disorders / diagnosis
  • Myeloproliferative Disorders / etiology*
  • Myeloproliferative Disorders / metabolism
  • Myeloproliferative Disorders / therapy