LPL is the strongest prognostic factor in a comparative analysis of RNA-based markers in early chronic lymphocytic leukemia

Abstract

The online version of this article has a Supplementary Appendix. BackgroundThe expression levels of LPL, ZAP70, TCL1A, CLLU1 and MCL1 have recently been proposed as prognostic factors in chronic lymphocytic leukemia. However, few studies have systematically compared these different RNA-based markers. Design and MethodsUsing real-time quantitative PCR, we measured the mRNA expression levels of these genes in unsorted samples from 252 newly diagnosed chronic lymphocytic leukemia patients and correlated our data with established prognostic markers (for example Binet stage, CD38, IGHV gene mutational status and genomic aberrations) and clinical outcome. ResultsHigh expression levels of all RNA-based markers, except MCL1, predicted shorter overall survival and time to treatment, with LPL being the most significant. In multivariate analysis including the RNA-based markers, LPL expression was the only independent prognostic marker for overall survival and time to treatment. When studying LPL expression and the established markers, LPL expression retained its independent prognostic strength for overall survival. All of the RNA-based markers, albeit with varying ability, added prognostic information to established markers, with LPL expression giving the most significant results. Notably, high LPL expression predicted a worse outcome in good-prognosis subgroups, such as patients with mutated IGHV genes, Binet stage A, CD38 negativity or favorable cytogenetics. In particular, the combination of LPL expression and CD38 could further stratify Binet stage A patients. ConclusionsLPL expression is the strongest RNA-based prognostic marker in chronic lymphocytic leukemia that could potentially be applied to predict outcome in the clinical setting, particularly in the large group of patients with favorable prognosis.Key words: LPL, RNA-based markers, chronic lymphocytic leukemia, prognosis.Citation: Kaderi MA, Kanduri M, Buhl AM, Sevov M, Cahill N, Gunnarsson R, Jansson M, Smedby KE, Hjalgrim H, Jurlander J, Juliusson G, Mansouri L, and Rosenquist R. LPL is the strongest prognostic factor in a comparative analysis of RNA-based markers in early chronic lymphocytic leukemia.

CLLU1 expression has prognostic value in chronic lymphocytic leukemia after first-line therapy in younger patients and in those with mutated IGHV genes

“…The prognostic value of CLLU1 mRNA expression has previously been investigated in four retrospective studies, 13,15,16,20 including between 59 and 252 patients each and at a median follow-up from diagnosis of between 43 and 102 months. The end-points in all four studies were time to first treatment and overall survival from diagnosis.…”

“…[9][10][11] In particular, the expression of genes such as CLLU1, ADAM29 and LPL have recently been associated with different outcomes in CLL. [12][13][14][15][16][17] CLLU1 located at chromosome 12q22, encodes a novel transcript, which has been identified as a marker specific to CLL. 18 In particular, high CLLU1 expression (CLLU1-H) is significantly more frequent in unmutated IGHV and CD38 + CLL.…”

“…It was perhaps to be expected that CLLU1 expression would not be an independent predictor of overall survival in a multivariate model which included IGHV mutation status, because of the correlation between these two variables. However, Kaderi et al 16 also found that CLLU1 expression did not independently predict overall survival, in 252 newly diagnosed patients (median follow-up of 102 months), in a multivariate model including other RNA-based markers. They found that LPL expression was the most significant of the markers included and, like CLLU1 expression, it was particularly able to discriminate between subgroups within the groups with good prognosis, such as those with mutated IGHV genes.…”

Biochemistry and pathophysiology of intravascular and intracellular lipolysis

“…Interestingly, LPL is frequently overexpressed in invasive cervical squamous cell carcinomas (Carter et al 2012). Most impressively, patients with chronic lymphocytic leukemia (CLL) whose leukemia cells express high levels of LPL transcripts have a lower survival rate (Van Bockstaele et al 2007;Maloum et al 2009;Kaderi et al 2011). One study indicated that high LPL transcript levels in CLL are associated with increased LPL protein production; however, enzymatic activity assays suggested that much of the LPL could be inactive (Mansouri et al 2010).…”

<i>SEPT10</i> Expression in Chronic Lymphocytic Leukemia. Correlation with Clinical and Biological Prognostic Factors

“…Thus, the study of this gene may be important for a better understanding of the disease variability, and could be used in combination with other markers, adding further information to those provided by established prognostic factors. In this line, an association between SEPT10 and LPL [9], which overexpression was related to adverse clinical outcome in CLL [25], have been previously described, suggesting that SEPT10 could direct LPL to the cell surface by establishing a link between proteoglycans (the cell surface LPL receptor) and the actin cytoskeleton [5,9]. The understanding of biological mechanism of the disease will contribute to future risk stratification strategies with potential value in treatment decisions.…”