Although CLL is considered to be an indolent disease, the rate of progression, disease complications, time to initiation of treatment, and life expectancy vary considerably. Two clinical staging systems, Rai and Binet, based on bulk of disease and presence or absence of anemia and thrombocytopenia, are widely used to predict patients' prognosis. In addition, several immunophenotype, cytogenetic, and molecular markers that have emerged in recent years can be used to identify high risk asymptomatic patients. Ig VH gene mutational status [i.e., the sequence of DNA coding for the V portion of the Ig heavy (H) chain] seems to play a role in disease progression and outcome. Patients whose CLL clone has unmutated VH genes are at increased risk for progressive disease. Although VH gene status is highly predictive of disease outcome in CLL, it is a technically difficult assay. CD38 was originally thought to be a reliable marker for VH gene status, but further studies have cast doubt on this conclusion. Its expression is, however, an independent predictor of aggressive disease, poor outcome, and shortened survival. Another surrogate marker for VH gene mutational status is ZAP-70 protein (Z-associated protein of molecular weight 70 kDa), a tyrosine kinase that appears to be normally expressed in T cells and natural-killer cells. It is highly overexpressed in CLL tumor cells with unmutated VH genes. However, methods of assessing ZAP-70 are not yet standardized. Another prognostic marker recently reported is microRNA expression profile. MicroRNAs are a recently identified class of regulatory RNAs that function by targeting specific messenger RNAs for degradation or inhibition of translation and therefore decreasing the expression of the specific proteins. A specific micro-RNA expression was found to correlate with low or high levels of ZAP-70 expression and with mutational status of IgVH.
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