fall 2008: volume 13, issue 2 newsletter of the myelodysplastic syndromes foundation From the Guest Editor’s Desk The Molecular Basis of the 5q- syndrome presence of the del(5q) as the sole karyotypic abnormality.4 The 5q- syndrome now joins the list of other leukemias in having both a postulated cause and a good therapy. Curiously perhaps the “therapy” (lenalidomide) arrived before the “postulated cause” (the RPS14 gene) was published but the relationship between lenalidomide and RPS14 is not clear and so there remains Contents Dr. Jacqueline Boultwood and much to be learned about all aspects of this Professor James S. Wainscoat prototypic MDS. From the Operating Director’s Desk 4 Leukaemia Research Fund Foundation Initiatives 5 Molecular Haematology Unit Mapping the Commonly Deleted Region and Identifying Young Investigator Grants Program 6 Nuffield Department of Clinical Laboratory Sciences Candidate Genes Meeting Highlights/Announcements 8 John Radcliffe Hospital The del(5q) in the 5q- syndrome is Patient Services 11 Oxford, United Kingdom considered to mark the location for a gene(s) the loss of which may affect Patient Forums and Support Groups 12 important processes such as growth My Story 16 The 5q- Syndrome control and normal hematopoiesis.2 The The 5q- syndrome was first described in basis for research on deletions such as the Patient Tributes 22 1974 by Van den Berghe who reported the del(5q) in the 5q- syndrome is well known. Nutritional Health 23 consistent association of the deletion of the The first step is to characterize the long arm of chromosome 5 [del(5q)] with Drug News 28 deletions and to identify the commonly the following hematological features: deleted region (CDR) i.e. the region of Patient Registries and Referrals 31 macrocytosis, anemia, normal or high deletion shared by all patients as this MDS Centers of Excellence 32 platelet count and hypolobulated mega- localizes the gene(s) for further study. Over karyocytes in the bone marrow.1 From the the years several genes and genomic Information on Clinical Trials 35 earliest studies a good prognosis and a regions have been put forward as Educational Resources 37 marked female preponderance have also significant in the 5q- syndrome or related been reported.2,3 The 5q- syndrome is the leukemias characterized by the del(5q). Our Foundation Publications 42 most distinct of all the myelodysplastic group in Oxford identified the CDR of the Contributions to the Foundation 43 syndromes. However, the strong genotype- 5q- syndrome5,6 and have since narrowed phenotype relationship present in the the CDR to the approximately 1.5 Mb In Memorium 44 5q- syndrome is not observed in other MDS interval at 5q32 flanked by D5S413 and the General Information 48 or acute myeloid leukemia (AML) GLRA1 gene.7 We subsequently generated a characterized by chromosomal deletions. transcription map of the CDR and noted The 5q- syndrome is now recognized as a several promising candidate genes map distinct clinical entity according to the within this region, including the tumor WHO classification and is defined by a suppressor gene SPARC, and RPS14,a medullary blast count of <5% and the component of the 40S ribosomal subunit.5,7,8 1 The next step in our research was the The anemia in DBA and the 5q- syndrome 5q- syndrome share a related molecular sequencing of all the 44 genes that map is due to a failure of erythropoiesis and basis in that they are all disorders of within the CRD in a group of patients with intriguingly both disorders show haplo- defective ribosomal biogenesis. the 5q- syndrome. The gene sequencing is insufficiency for ribosomal proteins, RPS19 Several of the bone marrow failure critical to understanding the pathogenesis and RPS14 respectively, required for the syndromes are associated with defects in 11,13 of the 5q- syndrome —if Knudsen’s two maturation of 40S ribosomal subunits. factors associated with ribosome synthesis16 hit model applied to this disorder there These abnormalities may lead to impairment and the demonstration of RPS14 as a would be loss of one allele of a gene and a of ribosome biogenesis and subsequent 5q- syndrome gene adds to the body of mutation of the remaining copy of the reduction of protein translation capacity, a evidence suggesting that defective ribosomal 9 same gene. We have sequenced all the defect which may be of particular biogenesis may have a more general genes in the CDR and no mutations have importance for developing erythroid cells, relevance in leukemogenesis. been identified. This is a key step in whose survival and division require large determining the molecular basis of the amounts of protein synthesis. Indeed, we Lenalidomide 5q- syndrome since it brings forward the have recently shown that CD34+ cells from The good prognosis of patients with consideration of haploinsufficiency (a gene patients with the 5q- syndrome have a the 5q- syndrome is well known, and the dosage effect resulting from the loss of defect in the expression of many genes rate of leukemic transformation is low. one allele of a gene) as the basis of the involved in ribosome biogenesis and in the Nevertheless most patients become 5q- syndrome. There has been growing control of translation, suggesting that the transfusion dependent and do not respond recognition of haploinsufficiency as a cancer 5q- syndrome represents a disorder of well to erythropoietin. The introduction of 10 14 model over the last decade: our research aberrant ribosome biogenesis. lenalidomide (a derivative of thalidomide) indicates that this is the correct model for The data of Ebert et al data strongly for the treatment of the 5q- syndrome has the 5q- syndrome. suggest that the RPS14 gene is an had a major impact. A majority of patients important gene in relation to the erythroid Candidate Gene RPS14 treated with lenalidomide for the 5q- differentiation defect of the 5q- syndrome.12 syndrome become transfusion independent We recently demonstrated haploin- However, whether it is a causal gene in and enter into a cytogenetic remission. This sufficiency of the ribosomal gene RPS14 relation to producing a clonal hematopoietic remarkable result is all the more surprising in the CD34+ cells of patients with the disorder, and whether haploinsufficiency of in view of the fact that lenalidomide was not 5q- syndrome and commented upon its an additional gene or genes is involved developed for this purpose. The results of relevance to the 5q- syndrome from an remain important questions. Haploin- lenalidomide in the 5q- syndrome and analogy with Diamond-Blackfan Anaemia sufficiency of other genes localized within related MDS are described in a series of (DBA) which is caused in around a quarter the CDR such as the tumor suppressor gene seminal papers by List et al.17,18 of cases by haploinsufficiency for the related SPARC could play a role in establishing 11 The US Food and Drug Administration ribosomal gene RPS19. Most recently the 15 clonal dominance. Clearly mouse knockout (FDA) approved the use of lenalidomide genes in the 5q- syndrome CDR were models might prove very informative in studied by an RNA-mediated interference “for the treatment of patients with relation to all these questions. (RNAi)- based approach: partial loss of transfusion-dependent anemia due to function (hapolinsufficiency) of RPS14 in The del(5q) is the most commonly low- or intermediate-1-risk myelodysplastic normal hematopoietic stem cells resulted reported deletion in de novo MDS and is syndromes associated with a deletion 5q in a block in erythroid differentiation with found in 10–15% of all patients. The cytogenetic abnormality with or without relative preservation of megakaryocyte relationship between the 5q- syndrome additional cytogenetic abnormalities”.In differentiation, closely mirroring the defects and the other myeloid malignancies with contrast the European Medicines Agency observed in the 5q- syndrome.12 More- the del(5q) is a complex question. The (EMEA) has refused marketing authorization over, forced expression of an RPS14 cDNA del(5q) in the 5q- syndrome is for lenalidomide intended for the treatment in primary bone marrow cells from patients cytogenetically indistinguishable from the of anemia due to MDS. The EMEA wishes to with the 5q- syndrome rescued the del(5q) found in other MDS and AML and it have further evidence pertaining to whether phenotype, suggesting that RPS14 is a should be recognized that in the majority treatment with lenalidomide increases the 5q- syndrome gene. A block in the processing of patients with the del(5q) and a myeloid risk of progression to AML. of pre-ribosomal in RPS14-deficient cells malignancy, one allele of RPS14 will be was found thus linking the pathogenesis of deleted. An exciting possibility is that MDS the 5q- syndrome to DBA.12 and AML patients with the del(5q) and the 2 The mechanism of action of lenalidomide 08. Boultwood J, Pellagatti A, Cattan H, et al. 18. List A, Dewald G, Bennett J, et al. remains uncertain although it is known to Gene expression profiling of CD34+ Lenalidomide in the myelodysplastic have effects on T-cell co-stimulation, cells in patients with the 5q- syndrome. syndrome with chromosome 5q angiogenesis inhibition. and modulation of Br J Haematol. 2007;139(4):578–589. deletion. N Engl J Med. 2006;355(14): 19 apoptosis. We have provided evidence in 09. Knudson A. Alfred Knudson and his 1456–1465. favor of the SPARC gene as a candidate two-hit hypothesis. (Interview by Ezzie 19. Ortega J and List A. Immunomodulatory target gene for lenalidomide and Hutchinson). Lancet Oncol. 2001;2(10): drugs in the treatment of myelo- interestingly similar evidence has emerged 642–645. dysplastic syndromes. Curr Opin Oncol. from studies of Non Hodgkins Lymphoma 2007;19(6):656–659.