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Resources for Hematology Fellows

Case Study: Identifying One of the 5q- Syndrome Genes

The following case study focuses on identifying one of the 5q- syndrome genes. Test your knowledge by reading the question below and making the proper selection.

Which of the following genes or pathways was recently implicated in the pathogenesis of 5q- syndrome? Choose one.

  1. Jak2 tyrosine kinase involved in cytokine signal transduction
  2. p53 tumor suppressor gene
  3. Ribosomal subunit protein 14 (RPS14)
  4. Growth factor oncogene sis encoding for platelet-derived growth factor-beta (PDGF-β)
  5. FLT3 receptor tyrosine kinase


  1. Ribosomal subunit protein 14 (RPS14)


The 5q- syndrome is a subtype of myelodysplastic syndrome (MDS) characterized by a more indolent clinical course compared with other MDS subtypes with more complex cytogenetic abnormalities.1 Putative tumor suppressor gene(s) lost in the 5q31-32 region are thought to be responsible for the hallmark bone marrow features of the 5q- syndrome (i.e., erythroid hypoplasia and dysplastic megakaryocytes).2 At the 2007 ASH Annual Meeting, Dr. Benjamin Ebert, from the laboratory of Dr. Todd Golub at Harvard Medical School, presented his exciting discovery that the partial loss of function of the RPS14 in normal hematopoietic progenitors recapitulates the phenotype of 5q- syndrome.3 Ebert, et al. used RNA-mediated interference, a methodology effective for targeted gene silencing, against 40 candidate genes in normal hematopoietic progenitors and screened by FACS analysis for a shift favoring megakaryocytic differentiation over erythroid differentiation. Partial knockdown of RPS14 caused the most dramatic shift among the genes tested. Furthermore, the partial knockdown created a cellular state of haploinsufficiency, which was sufficient to recapitulate the morphologic features of the 5q- syndrome, including macrocytic anemia and erythroid hypoplasia. Conversely, expression of RPS14 in progenitor cells from patients with 5q- syndrome reversed the characteristic phenotype and increased erythroid differentiation.

Comparisons were made to Diamond-Blackfan anemia, one of the inherited bone marrow failure syndromes resulting from haploinsufficiency of ribosomal protein function.4 Inactivating mutations of RPS19 account for approximately 25 percent of cases. In other cases, identification of mutations in other ribosomal protein genes has been reported. (See 2007 ASH Annual Meeting abstracts #421 and #422.) Similar to 5q- syndrome, it is not clear why erythroid progenitors are particularly sensitive to ribosomal protein gene haploinsufficiency. Some have suggested that these proteins are rate-limiting in erythroid progenitors but not in other hematopoietic progenitors. However, haploinsufficiency of RSP14 alone may not recapitulate the 5q- syndrome completely. There is megakaryocyte dysplasia in 5q- syndrome, which was not reported in the work published by Ebert, et al. Therefore, loss of multiple tumor suppressor genes on the 5q arm are likely responsible.


  1. Giagounidis AA, Germing U, Aul C. Biological and Prognostic Significance of Chromosome 5q Deletions in Myeloid Malignancies. Clin Cancer Res. 2006;12:5-10.
  2. Boultwood J, Fidler C, Strickson AJ, et al. Narrowing and genomic annotation of the commonly deleted region of the 5q- syndrome. Blood. 2002;99:4638-41.
  3. Ebert BL, Pretz J, Bosco J, et al. Identification of RPS14 as a 5q- syndrome gene by RNA interference screen. Nature. 2008;451:335-9.
  4. Alter B. Diagnosis, Genetics, and Management of Inherited Bone Marrow Failure Syndromes. Hematology 2007:29-39.

Case study submitted by Kim-Hien Dao, DO, PhD, of the University of California, San Diego.