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RNA-based Prognostic Markers in Chronic Lymphocytic Leukemia
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology. (Molekylär hematologi)
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Chronic lymphocytic leukemia (CLL) is a heterogeneous disease where a significant proportion of patients will develop an aggressive disease. Today, the mutational status of the immunoglobulin heavy variable (IGHV) genes is one of the strongest prognostic markers in CLL, where unmutated IGHV genes correlate with poor outcome. In addition, IGHV3-21 gene usage is associated with poor prognosis independent of mutational status. Recently, several genes were shown to be differently expressed between IGHV mutated and unmutated CLL and were suggested as prognostic markers. The aim of this thesis was to examine the applicability of these RNA-based prognostic markers in CLL.

In papers I and II, the prognostic significance of LPL and TCL1A mRNA expression in CLL was investigated in 140 and 144 patients, respectively. High expression was found to be associated with inferior clinical outcome for both markers. However, CLL cases with mutated IGHV3-21 genes displayed low levels of LPL expression, indicating that LPL cannot identify this poor-risk patient group. In contrast, high TCL1A expression was detected in all IGHV3-21 cases. To elucidate the functionality of LPL in CLL, LPL lipase activity was measured in 33 cases. The lipase activity was found to be invariably low, implying an alternative function for LPL in CLL.

In paper III, a comprehensive analysis of five RNA-based markers (LPL, TCL1A, ZAP70, CLLU1 and MCL1) was performed in 252 CLL patients. All RNA-based markers except MCL1 predicted clinical outcome, with LPL being the strongest. Moreover, LPL expression independently predicted overall survival when adjusted for established markers. All of the RNA-based markers added additional prognostic information to established markers, e.g. high LPL expression predicted an inferior outcome in patients with mutated IGHV genes or good-risk cytogenetics.

For clinical application, over time stability of prognostic markers is crucial. In paper IV, the expression of LPL, TCL1A, ZAP70 and MCL1 was investigated in samples taken at diagnosis and at a follow-up of seven years in 104 CLL patients. LPL was found to be the most stable marker, displaying high correlation between the sequential samples, whereas ZAP70 and MCL1 varied significantly. TCL1A expression increased at follow-up, which may indicate disease progression as TCL1A promotes cell survival.

In summary, this thesis highlights the applicability of RNA-based markers in CLL prognostication, both as single markers or in combination with established markers. In particular, LPL was shown to be the strongest RNA-based marker in terms of prognostic strength and stability.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis , 2010. , p. 79
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 624
Keyword [en]
Chronic lymphocytic leukemia, prognostic markers, RNA-based markers, LPL
National Category
Medical Genetics Hematology
Research subject
Medical Science
Identifiers
URN: urn:nbn:se:uu:diva-133250ISBN: 978-91-554-7950-3 (print)OAI: oai:DiVA.org:uu-133250DiVA, id: diva2:360682
Public defence
2010-12-17, Rudbecksalen, Rudbecklaboratoriet, Dag Hammarskjöldsväg 20, Uppsala, 13:00 (English)
Opponent
Supervisors
Funder
Available from: 2010-11-25 Created: 2010-11-04 Last updated: 2018-01-12Bibliographically approved
List of papers
1. Lipoprotein lipase is differentially expressed in prognostic subsets of chronic lymphocytic leukemia but displays invariably low catalytical activity
Open this publication in new window or tab >>Lipoprotein lipase is differentially expressed in prognostic subsets of chronic lymphocytic leukemia but displays invariably low catalytical activity
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2010 (English)In: Leukemia research: a Forum for Studies on Leukemia and Normal Hemopoiesis, ISSN 0145-2126, E-ISSN 1873-5835, Vol. 34, no 3, p. 301-306Article in journal (Refereed) Published
Abstract [en]

Lipoprotein lipase (LPL) expression has been shown to correlate with IGHV mutational status and to predict outcome in chronic lymphocytic leukemia (CLL). We here investigated the prognostic impact of LPL expression in relation to other prognostic markers including IGHV3-21 usage in 140 CLL patients. Additionally, we studied the catalytic activity of LPL in CLL cells. A significant difference in LPL mRNA expression was detected in IGHV unmutated compared to mutated CLL patients (p<0.001). However, the poor-prognostic mutated/stereotyped IGHV3-21 patients did not differ from other mutated CLL cases. Clinical outcome was significantly different in CLL cases with high versus low LPL expression (p<0.001), and LPL expression exceeded mutation status/IGHV3-21 usage as an independent prognostic marker. Finally, LPL protein expression correlated significantly with mRNA expression and was higher in IGHV unmutated versus mutated CLL (p=0.018), although the majority of synthesized protein was catalytically inactive indicating a non-catalytical function in CLL.

Keyword
LPL expression, LPL catalytical activity, IGHV mutational status, IGHV3 21 usage, Chronic lymphocytic leukemia, Prognosis
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-121105 (URN)10.1016/j.leukres.2009.07.032 (DOI)000274529600008 ()19709746 (PubMedID)
Available from: 2010-03-18 Created: 2010-03-18 Last updated: 2017-12-12Bibliographically approved
2. IGHV3-21 gene usage is associated with high TCL1 expression in chronic lymphocytic leukemia
Open this publication in new window or tab >>IGHV3-21 gene usage is associated with high TCL1 expression in chronic lymphocytic leukemia
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2010 (English)In: European Journal of Haematology, ISSN 0902-4441, E-ISSN 1600-0609, Vol. 84, no 2, p. 109-116Article in journal (Refereed) Published
Abstract [en]

T-cell leukemia/lymphoma protein 1 (TCL1) was recently shown to display an expression pattern in chronic lymphocytic leukemia (CLL) corresponding to molecular subtypes, where poor-risk patients demonstrated higher expression levels. Here, we examined the mRNA expression pattern of TCL1 in 144 patients with CLL, including 67 immunoglobulin heavy-chain variable (IGHV) mutated, 58 IGHV unmutated and 19 patients with IGHV3-21 usage. A higher TCL1 expression level was detected in patients with CLL with unmutated vs. mutated IGHV genes (P < 0.001), whereas no difference was demonstrated within the IGHV3-21 cohort (i.e., mutated vs. unmutated and stereotyped vs. non-stereotyped complementarity determining region 3). The IGHV3-21 subgroup displayed high TCL1 mRNA expression, differing significantly from other IGHV mutated cases (P < 0.001), although 11/19 had mutated IGHV genes. Furthermore, high TCL1 expression levels were associated with significantly shorter overall survival (P < 0.001). Altogether, we show that TCL1 mRNA expression may predict clinical outcome in CLL and that the IGHV3-21 subset, regardless of mutational status, displays high TCL1 expression.

National Category
Hematology
Identifiers
urn:nbn:se:uu:diva-121110 (URN)10.1111/j.1600-0609.2009.01369.x (DOI)000273301600003 ()19889012 (PubMedID)
Available from: 2010-03-18 Created: 2010-03-18 Last updated: 2017-12-12Bibliographically approved
3. LPL is the strongest prognostic factor in a comparative analysis of RNA-based markers in early chronic lymphocytic leukemia
Open this publication in new window or tab >>LPL is the strongest prognostic factor in a comparative analysis of RNA-based markers in early chronic lymphocytic leukemia
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2011 (English)In: Haematologica (online), ISSN 0390-6078, E-ISSN 1592-8721, Vol. 96, no 8, p. 1153-1160Article in journal (Refereed) Published
Abstract [en]

BACKGROUND:

The 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 METHODS:

Using 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.

RESULTS:

High 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.

CONCLUSIONS:

LPL 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.

National Category
Medical and Health Sciences Medical Genetics Cancer and Oncology
Research subject
Clinical Genetics; Medical Genetics; Oncology
Identifiers
urn:nbn:se:uu:diva-111078 (URN)10.3324/haematol.2010.039396 (DOI)000294722700013 ()21508119 (PubMedID)
Available from: 2009-12-02 Created: 2009-12-02 Last updated: 2018-01-12Bibliographically approved
4. Longitudinal study of RNA-based prognostic markers in chronic lymphocytic leukemia reveals LPL as the most stable
Open this publication in new window or tab >>Longitudinal study of RNA-based prognostic markers in chronic lymphocytic leukemia reveals LPL as the most stable
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

Several genes display differential expression in prognostic subsets in chronic lymphocytic leukemia (CLL), including LPL, TCL1, ZAP70 and MCL1. CLL patients commonly have an indolent course with low stage disease and long survival, and in this study we aimed to investigate the stability of RNA-based prognostic markers in such an indolent cohort over time. mRNA expression of LPL, TCL1, ZAP70 and MCL1 was measured in sequential unsorted samples obtained from 96 CLL patients at both diagnosis and a median follow-up of seven years. LPL was the only RNA-based marker that did not demonstrate any significant changes in expression in diagnostic vs. follow-up samples. Furthermore, an 82% concordance between both time-points was observed when grouping cases based on high or low expression. LPL expression was not affected by treatment and in addition, LPL expression in follow-up samples could predict overall survival. In contrast, TCL1 expression was found to increase at follow-up, especially in cases displaying low expression at diagnosis. As TCL1 promotes cell survival this increase could possibly be of importance for progression of the disease. Both ZAP70 and MCL1 mRNA expression were found to vary significantly during the disease course. In summary, using unsorted CLL samples, we have demonstrated that LPL is superior to other RNA-based markers based on stability over time. These findings fully endorse the use of LPL analysis at any time point of the disease.

Keyword
Chronic lymphocytic leukemia, prognostic markers, RNA-based markers, LPL, longitudinal
National Category
Medical Genetics Hematology
Research subject
Medical Science
Identifiers
urn:nbn:se:uu:diva-133249 (URN)
Available from: 2010-11-04 Created: 2010-11-04 Last updated: 2018-01-12

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