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?Investigating the Proteins Involved in MDS Pathogenesis
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By CourteneyLai, Section Biology
Posted on Fri Apr 30th, 2010 at 12:38:52 PM PST
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Myelodysplastic syndrome (MDS) is a heterogenous group of hematopoietic stem cell disorders that may or may not progress into acute myeloid leukemia.[1] Primarily arising among the elderly, it is thought to be the most common blood malignancy.[2] One subcategory of MDS is known as 5q- syndrome, name so because of its signature of a large-scale chromosomal deletion of the q-region of chromosome 5.[1] The discovery of a commonly deleted region (CDR) within this region, located from q31-33, provided an explanation for the heterogeneity seen within this disease, with variable chromosomal deletions resulting in the wide variety of symptoms seen in patients.[3]
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Recently, an inducible knockout mouse was generated that modeled loss of the CDR in one chromosome, as seen in human MDS.[4] Investigation of the various proteins within this CDR revealed a short region consisting of 8 genes that appeared to recapitulate some of known MDS symptoms, although the effects of losing only one of these genes, RpS14, was investigated, with the normal function of the other 7 genes, as well as the consequences of losing their expression, remaining unknown.[4]
Hoping to shed light on the function of these genes in the body, the expression of each of the 7 genes within this identified region could be systematically knocked down. Pulsed stable isotope labelling with amino acids in cell culture (pSILAC) could be employed on samples from cytogenetically normal versus MDS with 5q- syndrome individuals. By combining the use of pulse-labelled growth media and mass spectrometry, the proteins affected, either down-regulated as seen by decreased levels between the samples, or up-regulated, through changes in de novo protein production, could be identified.[5] This would shed light on the pathways and effects of CDR deletion on MDS patients, potentially leading to therapeutic interventions.
REFERENCES
1. Tefferi, A. and J.W. Vardiman, Myelodysplastic syndromes. N Engl J Med, 2009. 361(19): p. 1872-85.
2. Williamson, P.J., et al., Establishing the incidence of myelodysplastic syndrome. Br J Haematol, 1994. 87(4): p. 743-5.
3. Ebert, B.L., et al., Identification of RPS14 as a 5q- syndrome gene by RNA interference screen. Nature, 2008. 451(7176): p. 335-9.
4. Barlow, J.L., et al., A p53-dependent mechanism underlies macrocytic anemia in a mouse model of human 5q- syndrome. Nat Med. 16(1): p. 59-66.
5. Selbach, M., et al., Widespread changes in protein synthesis induced by microRNAs. Nature, 2008. 455(7209): p. 58-63. |
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