Common deleted genes in the 5q- syndrome: Thrombocytopenia and reduced erythroid colony formation in SPARC null mice

Division of Hematology/Oncology, Cedars-Sinai Medical Center, School of Medicine, University of California-Los Angeles, Los Angeles, CA, USA.
Leukemia (Impact Factor: 10.43). 10/2007; 21(9):1931-6. DOI: 10.1038/sj.leu.2404852
Source: PubMed


The commonly deleted region (CDR) for the 5q- syndrome has been identified as a 1.5-megabase interval on human chromosome 5q32. We studied, by real-time reverse-transcription (RT)-PCR, the expression of 33 genes within the CDR that are known to be expressed in CD34+ hematopoietic stem cells. Genes in the 5q- samples that showed the most pronounced decrease in expression compared to non-5q- samples were: solute carrier family 36, member 1 (SLC36A1; 89% downregulated), Ras-GTPase-activating protein SH3 domain-binding (G3BP; 79%), antioxidant protein 1 (ATOX1; 76%), colony-stimulating factor-1 receptor precursor (CSF1R; 76%), ribosomal protein S14 (RPS14; 74%), platelet-derived growth factor receptor-beta (PDGFRB; 73%), Nef-associated factor 1 (TNIP1; 72%), secreted protein, acidic and rich in cysteine (SPARC; 71%), annexin VI (ANAX6; 69%), NSDT (66%) and TIGD (60%). We further studied the hematopoietic system in SPARC-null mice. These mice showed significantly lower platelet counts compared to wild-type animals (P=0.008). Although hemoglobin, hematocrit and mean corpuscular volume (MCV) were lower in mice lacking SPARC, differences were not statistically significant. SPARC-null mice showed a significantly impaired ability to form erythroid burst-forming units (BFU-E). However, no significant differences were found in the formation of erythroid colony-forming units (CFU-E), granulocyte/monocyte colony-forming units (CFU-GM) or megakaryocyte colony-forming units (CFU-Mk) in these animals. We conclude that many of the genes within the CDR associated with the 5q- syndrome exhibit significantly decreased expression and that SPARC, as a potential tumor suppressor gene, may play a role in the pathogenesis of this disease.

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    • "Genes in the commonly deleted region of chromosome 5q that are implicated in the pathogenesis of del(5q) MDS [19, 20, 25, 26, 66–68]. del(5q) deletion of the long arm of chromosome 5, MDS myelodysplastic syndromes "
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    ABSTRACT: Deletion of the long arm of chromosome 5, del(5q), is the most prevalent cytogenetic abnormality in patients with myelodysplastic syndromes (MDS). In isolation, it is traditionally associated with favorable prognosis compared with other subtypes of MDS. However, owing to the inherent heterogeneity of the disease, prognosis for patients with del(5q) MDS is highly variable depending on the presence of factors such as additional chromosomal abnormalities, >5 % blasts in the bone marrow (BM), or transfusion dependence. Over recent years, the immunomodulatory drug lenalidomide has demonstrated remarkable efficacy in patients with del(5q) MDS. Advances in the understanding of the pathogenesis of the disease have suggested that lenalidomide targets aberrant signaling pathways caused by haplosufficiency of specific genes in a commonly deleted region on chromosome 5 (e.g., SPARC, RPS14, Cdc25C, and PP2A). As a result, the agent specifically targets del(5q) clones while also promoting erythropoiesis and repopulation of the bone marrow in normal cells. This review discusses recent developments in the understanding of the mechanism of action of lenalidomide, and how this underlies favorable outcomes in patients with del(5q) MDS. In addition, we discuss how improved understanding of the mechanism of disease will facilitate clinicians' ability to predict/monitor response and identify patients at risk of relapse.
    Annals of Hematology 09/2013; 93(1). DOI:10.1007/s00277-013-1863-5 · 2.63 Impact Factor
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    • "; der(7)inv(7)(p13p22)add(7)(q36), del(20)(q11.2) [7] "
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    ABSTRACT: Chromosome 5q deletion can be found in rare cases of myelofibrosis (MF) but the incidence, clinical significance and response to therapies are not well studied. We retrospectively reviewed charts of 939 patients with MF and identified 8 patients [0.8%] who carried 5q deletion. Of the 8, seven had complex cytogenetic abnormalities and one had additional clone with different cytogenetic abnormality. All 8 had significant three-lineage pancytopenia. Three patients took lenalidomide and one (patient with 5q-clone) achieved long-lasting hematologic response. Two patients responded to JAK2 inhibitor therapy. MF patients with 5q deletion often have complex karyotype and poor outcome.
    Leukemia research 02/2013; 37(5). DOI:10.1016/j.leukres.2013.01.003 · 2.35 Impact Factor
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    • "Role of SPARC in 5q-Syndrome. Lehmann et al. [32] further studied the hematopoietic system in SPARC-null mice. These mice showed significantly lower platelet counts compared to wild-type animals. "
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    ABSTRACT: Myelodysplastic syndrome (MDS) with interstitial deletion of a segment of the long arm of chromosome 5q [del(5q)] is characterized by bone marrow erythroid hyperplasia, atypical megakaryocytes, thrombocythemia, refractory anemia, and low risk of progression to acute myeloid leukemia (AML) compared with other types of MDS. The long arm of chromosome 5 contains two distinct commonly deleted regions (CDRs). The more distal CDR lies in 5q33.1 and contains 40 protein-coding genes and genes coding microRNAs (miR-143, miR-145). In 5q-syndrome one allele is deleted that accounts for haploinsufficiency of these genes. The mechanism of erythroid failure appears to involve the decreased expression of the ribosomal protein S14 (RPS14) gene and the upregulation of the p53 pathway by ribosomal stress. Friend leukemia virus integration 1 (Fli1) is one of the target genes of miR145. Increased Fli1 expression enables effective megakaryopoiesis in 5q-syndrome.
    02/2012; 2012(2090-3219):179402. DOI:10.1155/2012/179402
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