Genetic Heterogeneity in Chronic Lymphocytic Leukemia: What Can Conventional Cytogenetics Add?

Hernández‐Rivas, José‐Ángel; Marín, Isabel González-Gascón y

doi:10.1159/000477997

Cited by 3 publications

(4 citation statements)

References 6 publications

(7 reference statements)

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“…It is of special interest the fact that a higher dysregulation of ILT2 expression on NK cells was observed in patients carrying a del(11q) and trisomy 12, which have been associated with enhanced clonal aggressiveness and worse evolution (2–6). The minimal region of deletion on 11q22.3–23.1 observed in CLL patients often involves the Radixin (RDX) and Ataxia telangiectasia mutated (ATM) genes.…”

Section: Discussionmentioning

confidence: 99%

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Ig-Like Transcript 2 (ILT2) Blockade and Lenalidomide Restore NK Cell Function in Chronic Lymphocytic Leukemia

et al. 2018

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One of the cardinal features of chronic lymphocytic leukemia (CLL) is its association with a profound immunosuppression. NK cell function is markedly impaired in CLL patients, who show a significant dysregulation of the expression of activating and inhibitory receptors. Here, we analyzed the role of the novel inhibitory receptor Ig-like transcript 2 (ILT2, also termed LIR-1, LILRB1) in the regulation of NK cells in CLL. Our results show that ILT2 expression was significantly decreased on leukemic cells and increased on NK cells of CLL patients, particularly in those with advanced disease and with bad prognostic features, such as those carrying chromosome del(11q). The immunomodulatory drug lenalidomide may regulate the expression of ILT2 and its ligands in CLL since it significantly increased the expression of ILT2 and partially reestablished the expression of its ligands on leukemic cells. Furthermore, lenalidomide significantly increased the activation and proliferation of NK cells, which was strongly enhanced by ILT2 blockade. Combining ILT2 blockade and lenalidomide activated NK cell cytotoxicity resulting in increased elimination of leukemic cells from CLL patients. Overall, we describe herein the role of an inhibitory receptor involved in the suppression of NK cell activity in CLL, which is restored by ILT2 blockade in combination with lenalidomide, suggesting that it may be an interesting therapeutic strategy to be explored in this disease.

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Section: Discussionmentioning

confidence: 99%

“…This clinical heterogeneity is associated with a heterogeneous array of chromosomic, genetic, and molecular defects (1). Thus, patients harboring chromosome del(17p) or del(11q) have been associated with a poor clinical outcome (2–4), but CLL patients with del(13q) have been associated with a more favorable prognosis (5, 6).…”

Section: Introductionmentioning

confidence: 99%

Ig-Like Transcript 2 (ILT2) Blockade and Lenalidomide Restore NK Cell Function in Chronic Lymphocytic Leukemia

et al. 2018

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“…This is supported by numerous studies reporting on multiple neoplastic "subclones" coexisting within the CLL population, which have arisen from clonal populations harboring different genetic aberrations or acquisition of additional abnormalities over time (16,(46)(47)(48)(49). Small subclones independently emerging in CLL +12 may include BCL2 translocations [e.g., t(14;18)(q32;q21) or t(2;18)(p11.2;q21)] and deletions of TP53/del(17p), usually consisting of 0.5-7.5% of cells (10,(48)(49)(50). These subclones are associated with disease progression or relapse and can therefore present as independent risk and prognostic factors (10,11,14,46,(48)(49)(50).…”

Section: Immuno-flowfish For Detection Of Subclones In Cllmentioning

confidence: 99%

“…Small subclones independently emerging in CLL +12 may include BCL2 translocations [e.g., t(14;18)(q32;q21) or t(2;18)(p11.2;q21)] and deletions of TP53/del(17p), usually consisting of 0.5-7.5% of cells (10,(48)(49)(50). These subclones are associated with disease progression or relapse and can therefore present as independent risk and prognostic factors (10,11,14,46,(48)(49)(50). Specifically, patients with >60% of cells with +12 had a worse outcome in terms of overall and disease-free survival.…”

Section: Immuno-flowfish For Detection Of Subclones In Cllmentioning

confidence: 99%

“Immuno‐flowFISH” for the Assessment of Cytogenetic Abnormalities in Chronic Lymphocytic Leukemia

et al. 2019

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Imaging flow cytometry is emerging as a diagnostic tool for the assessment of leukemia. It has the functionality of standard flow cytometry and generates high‐resolution digital images of each cell with quantifiable numerical data. We demonstrate the use of an automated high‐throughput method for performing fluorescence in situ hybridization (FISH) on immunophenotyped whole cells in suspension and analyzed by imaging flow cytometry, a technique called “Immuno‐flowFISH”. The aim of this study was to demonstrate the application of immuno‐flowFISH for the detection of chromosomal abnormalities in CLL, specifically trisomy 12 and del(17p). Mononuclear cells were isolated and immunophenotyped with fluorescently conjugated CD3, CD5, and CD19 monoclonal antibodies. Following fixation, cells were permeabilized, dsDNA denatured and hybridized with chromosome 12 or 17 enumeration (CEP 12 and CEP17) and 17p12 locus‐specific FISH probes. Cells were analyzed on the Amnis ImageStream®X Mark II to assess the number and percent FISH‐positive CLL cells and the ratio of FISH spot counts for CD5/CD19‐positive CLL cells to CD3/CD5‐positive T cells (FISH “mean spot ratio”). Deletion of 17p was detected in about 8% of cases to date, with del(17p) ranged from 3.5–22.8% and the FISH “mean spot ratio” 0.86–0.96. Immuno‐flowFISH also detected a minimal residual disease case with +12 with a limit of detection of 0.13% and a rare case that presented with atypical phenotype and cytogenetics. Immuno‐flowFISH could detect del(17p) in phenotypically identified CD5/CD19‐positive B‐cells. The 100‐fold increase in analyzed cells, as well as the addition of cell phenotype increased the sensitivity and specificity over current clinical FISH testing. Furthermore, immuno‐flowFISH analysis demonstrated specific utility in unique clinical scenarios such as residual disease and atypical biology cases which may be of significant benefit with regards to prognostication and MRD analysis. The method will assist in therapeutic decision making and disease monitoring for many hematological malignancies. © 2019 International Society for Advancement of Cytometry

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Imaging flow cytometry to assess chromosomal abnormalities in chronic lymphocytic leukaemia

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Chuah

et al. 2018

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Genetic Heterogeneity in Chronic Lymphocytic Leukemia: What Can Conventional Cytogenetics Add?

Cited by 3 publications

References 6 publications

Ig-Like Transcript 2 (ILT2) Blockade and Lenalidomide Restore NK Cell Function in Chronic Lymphocytic Leukemia

Ig-Like Transcript 2 (ILT2) Blockade and Lenalidomide Restore NK Cell Function in Chronic Lymphocytic Leukemia

“Immuno‐flowFISH” for the Assessment of Cytogenetic Abnormalities in Chronic Lymphocytic Leukemia

Imaging flow cytometry to assess chromosomal abnormalities in chronic lymphocytic leukaemia

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