Other candidates for prognostic markers
In addition to the more extensively studied prognostic markers discussed in the Review, many molecular and biological factors have been described to correlate with an adverse outcome in patients with chronic lymphocytic leukemia (CLL).1,2 A detailed assessment of these factors is beyond the scope of this Review, and we apologize to all authors of these articles that their work cannot be cited because of space limitations.
The different molecules and factors include the proangiogenic molecule VEGF,3,4 soluble CD44,5–7soluble CD26,8,9 circulating CD20,10 and CD49d,11,12 as well as insulin-like growth factor 1,13 matrix metalloproteinase9,14,15 Bcl2,16–20Tcell leukemia 1,21 and soluble intracellular adhesion molecule 1.22–25 Other candidates for prognostic markers in CLL are short telomere length26–29and high telomerase activity,29–31 expression of myeloid cell leukemia sequence 1,32 activation-induced cytidine deaminase mRNA33 and hematopoietic lineage cell-specific protein 1,34 as well as a higher level of circulating endothelial cells.35 In addition, the expression of lipoprotein lipase and ADAM29,36–38 overexpression of TOSO39 and PEG1O,40 as well as CLLU1 expression41,42 and RelA DNA binding43 were all associated with rapid disease progression or impaired overall survival. Furthermore, the cytokines interleukin (IL)-622,44,45IL846,47and IL1044 and tumor necrosis factor-α48 could potentially serve as novel serum markers.
The area of research on epigenetic markers and microRNAs led to the unexpected and fascinating discovery of an interplay between protein-coding genes and noncoding RNAs, that was found to be causally involved in cancer initiation, progression, dissemination, and chemotherapy resistance.49,50These microRNAs might not only be causal in the pathogenesis of CLL, but could also explain the predictive value of a variety of prognostic markers. For instance, a low expression of miR29c and miR223was found to correlate with the two adverse prognostic factors ZAP70and lipoprotein lipase and to be associated with an inferior treatment-free survival and overall survival.51
This large number of prognostic factors needs further investigation and a systematic comparison to other factors in larger clinical cohorts in order to assess the true prognostic and clinical value of these markers with regards to survival.
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