Genomewide

GEP experiments using either the Lymphochip or Affymetrix arrays have shown that all CLL samples have a remarkably consistent profile, independent of IGHV mutational status, consistent with their origination from memory B cells. In this regard, CLL differs from other B-cell diseases such as DLBCL, where the profile differs markedly from case to case. CLL

expresses genes not expressed in normal memory B cells, including ROR1 receptor tyrosine kinase and CD200, and conversely, lacks expression of other genes normally expressed in normal memory cells, such as histone H2AX and RAD9. The biological relevance of these observations remains to be determined; some of these may be of direct pathological significance in the development of CLL.

Despite the relative constancy of the CLL gene signature, a number of genes were identified whose expression segregated with the presence or absence of mutations. As mentioned earlier, ZAP70 expression correlated most strongly with the unmutated IGHV subset of CLL. Other genes differentially expressed between the two subsets of disease included BCL7A, FGFR1 , and PAK1 . Many of the genes that were more highly expressed in unmutated CLL were induced during activation of blood B cells.

More recent GEP experiments have focussed on responses of CLL to irradiation-induced DNA damage and defining pathways that mediate resistance.3342

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