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- Gunnarsson, Rebeqa, et al.
(författare)
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Array-based genomic screening at diagnosis and during follow-up in chronic lymphocytic leukemia
- 2011
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Ingår i: Haematologica. - : Ferrata Storti Foundation (Haematologica). - 1592-8721 .- 0390-6078. ; 96:8, s. 1161-1169
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Tidskriftsartikel (refereegranskat)abstract
- Background High-resolution genomic microarrays enable simultaneous detection of copy-number aberrations such as the known recurrent aberrations in chronic lymphocytic leukemia [del(11q), del(13q), del(17p) and trisomy 12], and copy-number neutral loss of heterozygosity. Moreover, comparison of genomic profiles from sequential patients' samples allows detection of clonal evolution. Design and Methods We screened samples from 369 patients with newly diagnosed chronic lymphocytic leukemia from a population-based cohort using 250K single nucleotide polymorphism-arrays. Clonal evolution was evaluated in 59 follow-up samples obtained after 5-9 years. Results At diagnosis, copy-number aberrations were identified in 90% of patients; 70% carried known recurrent alterations, including del(13q) (55%), trisomy 12 (10.5%), del(11q) (10%), and del(17p) (4%). Additional recurrent aberrations were detected on chromosomes 2 (1.9%), 4 (1.4%), 8 (1.6%) and 14 (1.6%). Thirteen patients (3.5%) displayed recurrent copy-number neutral loss of heterozygosity on 13q, of whom 11 had concurrent homozygous del(13q). Genomic complexity and large 13q deletions correlated with inferior outcome, while the former was linked to poor-prognostic aberrations. In the follow-up study, clonal evolution developed in 8/24 (33%) patients with unmutated IGHV, and in 4/25 (16%) IGHV-mutated and treated patients. In contrast, untreated patients with mutated IGHV (n=10) did not acquire additional aberrations. The most common secondary event, del(13q), was detected in 6/12 (50%) of all patients with acquired alterations. Interestingly, aberrations on, for example, chromosome 6q, 8p, 9p and 10q developed exclusively in patients with unmutated IGHV. Conclusions Whole-genome screening revealed a high frequency of genomic aberrations in newly diagnosed chronic lymphocytic leukemia. Clonal evolution was associated with other markers of aggressive disease and commonly included the known recurrent aberrations.
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| 2. |
- Norin, Stefan
(författare)
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Clinical prognostic markers in chronic lymphocytic leukemia
- 2011
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of mature B lymphocytes in blood, bone marrow and lymphoid tissues. The clinical course for the individual patient is still unpredictable despite decades of research on prognostic markers and staging systems. The aim of this thesis was to review the value of existing prognostic tools in order to develop new clinical prognostic markers for CLL and to assess the impact of clonal evolution and transformation in CLL in relation to biological markers and given therapy. Paper I: This is a long-term follow-up of the first trial of subcutaneous alemtuzumab as first-line therapy in CLL. In order to assess duration of response, infectious complications and incidence of Richter transformation, a comparison was made with historical controls. Median time to treatment failure was 28 months for the alemtuzumab-treated patients compared to 17 months for the control group (not significant). Infectious complications were not more common in the alemtuzumab-treated patients despite profound and prolonged T-cell suppression. The rate of Richter transformation was similar between the groups. Paper II: Clinical data of 77 patients included in five phase II trials at Karolinska University Hospital were analyzed to find out whether the use of computed tomography (CT) could add prognostic information to the Rai and Binet clinical staging systems. A high nodal tumor burden evaluated by CT correlated with a shorter time to next therapy and a trend towards shorter survival. Massive splenomegaly was associated with shorter overall survival and therapy-free survival. Paper III: The expression of the estrogen receptors (ER) α, β1 and its splice variant β2 was evaluated in peripheral blood mononuclear cells (PBMC) from CLL patients and normal controls using immunocytochemistry. The expression of ERα was generally low whereas most PBMCs expressed ERβ1 in both patients and controls. ERβ2 expression was significantly more common in CLL. Patients with high expression (> 50% of PBMC) of ERβ1 and/or ERβ2 were more likely to need therapy during follow-up. Paper IV: Paraffin-embedded splenic tissue samples were obtained from 62 patients with CLL or SLL to assess whether chromosomal aberrations in the spleen have a prognostic impact. The cytogenetic abnormalities 11q-, 13q-, 17p- and trisomy 12 were assessed by interphase FISH and compared with samples from blood and/or bone marrow. Patients with 11q- and 17p- deletions in the spleen had significantly shorter overall and therapy-free survival. Clonal evolution seemed to occur in some cases.
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| 3. |
- Yakimchuk, Konstantin, et al.
(författare)
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Up-regulated estrogen receptor β2 in chronic lymphocytic leukemia
- 2012
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Ingår i: Leukemia and Lymphoma. - : Informa UK Limited. - 1042-8194 .- 1029-2403. ; 53:1, s. 139-144
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Tidskriftsartikel (refereegranskat)abstract
- The estrogen receptors alpha (ERα) and beta (ERβ) have been demonstrated in mouse models to be important for immune system regulation, and are differentially expressed in lymphoid organs. One ERβ splice variant, ERβ2, inhibits the ERα-mediated estrogen effect, and expression might predict response to selective estrogen receptor modulators. We studied the expression of ERα, ERβ1 and ERβ2 in peripheral blood mononuclear cells from 26 patients with chronic lymphocytic leukemia (CLL) and 30 normal controls using immunocytochemistry. ERα expression was generally low, while ERβ1 was expressed in 65% of patients with CLL and in 83% of controls (NS). In contrast, nuclear staining for ERβ2 was positive in 69% of patients with CLL, but in only 17% of controls (p < 0.001). In CLL, ERβ2 was found in B- but not in T-lymphocytes. Our data show the expression of ERβ1 and ERβ2 in the majority of patients with CLL, suggesting that the ERs are important in CLL and might be used as therapeutic targets.
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