Fluorescent-labeled DNA probes applied to novel biological aspects of B-cell chronic lymphocytic leukemia

Fink, Stephanie; Paternoster, Sarah F.; Smoley, Stephanie A.; Flynn, Heather C.; Geyer, Susan; Shanafelt, Tait D.; Lee, You Kyoung; Jelinek, Diane F.; Kay, Neil E.; Dewald, Gordon W.

doi:10.1016/j.leukres.2004.07.012

Cited by 29 publications

(32 citation statements)

References 30 publications

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“…18,19 Experimental deregulation of human (transgenic) TCL1 in murine B cells causes B-cell proliferations resembling aggressive human CLL, 25 demonstrating that TCL1 overexpression is a causal event in the development of CLL. The event(s) responsible for deregulation of TCL1 in human CLL are, in the absence of detectable chromosomal aberrations involving its locus, 20 largely unknown. In previous in situ and in vitro studies, we demonstrate that TCL1 in CLL and in other B-cell tumors underlies dynamic (down)-regulations in strong association with (humoral) T-cell mediated factors.…”

Section: Discussionmentioning

confidence: 99%

“…18 Upon BCR engagement, TCL1 and AKT co-recruit to BCR membrane-activation complexes, with TCL1 expression levels predicting BCR signaling and growth responses. 19 However, chromosomal aberrations that constitutively activate TCL1, as seen in T-cell prolymphocytic leukemia, have not been identified in CLL, 20 and the mechanism(s) regulating TCL1 expression in CLL remain largely unknown except for reports on posttranscriptional TCL1 regulation by micro (mi)-RNAs. 21 The association of higher TCL1 levels in those CLL with the del(11q23) aberration 19 recently has been explained by concurrent losses of miRNA-34b/miRNA-34c.…”

Section: Introductionmentioning

confidence: 99%

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Stromal cells modulate TCL1 expression, interacting AP-1 components and TCL1-targeting micro-RNAs in chronic lymphocytic leukemia

et al. 2012

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The tissue microenvironment in chronic lymphocytic leukemia (CLL) has an increasingly recognized role in disease progression, but the molecular mechanisms of cross talk between CLL cells and their microenvironment remain incompletely defined. Bone marrow stromal cells (BMSC) protect CLL cells from apoptosis in a contact-dependent fashion, and have been used for the identification of key pathways such as the CXCR4 --CXCL12 axis. To further dissect the molecular impact of BMSC on survival and the molecular activation signature of CLL cells, we co-cultured CLL cells with different BMSC. Gene expression profiling of CLL cells revealed that the lymphoid proto-oncogene TCL1 was among the top genes upregulated in CLL cells by BMSC. TCL1 mRNA and protein upregulation by BMSC was paralleled by decreases of TCL1-interacting FOS/JUN, and confirmed by qRT-PCR, immunoblotting, immunoprecipitations, and flow cytometry. Stroma mediated increases in TCL1 were also associated with decreased levels of TCL1-regulatory micro-RNAs (miR-29b, miR-181b, miR-34b). These findings demonstrate that the microenvironment has a proactive role in the regulation of the known signaling enhancer and pro-survival molecule TCL1 in CLL. This provides a further rationale for therapeutically targeting the cross talk between CLL and BMSC.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Stromal cells modulate TCL1 expression, interacting AP-1 components and TCL1-targeting micro-RNAs in chronic lymphocytic leukemia

et al. 2012

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“…Genomic losses from the 14q32/IGH region have been occasionally detected in CLL and other B cell lymphomas, 4,[21][22][23] generating difficulties in evaluation of FISH results. 24 Recently, Fink et al 22 postulated that loss of the IGHV signal in CLL represents usage of a telomeric IGHV gene segment, as 9 of 11 of their cases expressed distally located V H 1-69, V H 3-72, and V H 3-74.…”

Section: Discussionmentioning

confidence: 99%

Telomeric IGH Losses Detectable by Fluorescence in Situ Hybridization in Chronic Lymphocytic Leukemia Reflect Somatic VH Recombination Events

Włodarska¹,

Matthews

Veyt³

et al. 2007

The Journal of Molecular Diagnostics

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Chromosomal translocations affecting the immunoglobulin loci, particularly immunoglobulin heavy chain (IGH) genes complex at 14q32, are a hallmark of B cell malignancies.1,2 They usually result in deregulated expression of involved oncogenes (eg, BCL1, CMYC, and PAX5) juxtaposed to the regulatory elements of IGH. As some of these translocations are associated with specific subtypes of mature B cell lymphoma and have prognostic significance, their detection is of clinical importance. In daily practice, IGH translocations have been routinely analyzed by fluorescence in situ hybridization (FISH) using either a common LSI IGH dual-color, break-apart rearrangement assay or dual-color, dual-fusion oncogene-specific probe, such as LSI IGH/CCND1, IGH/ BCL2, and IGH/CMYC.The IGH-mediated translocations are relatively rare in B cell chronic lymphocytic leukemia (CLL), [3][4][5] which is the most common form of leukemia in adults and shows a highly variable clinical course. The CLL cells display a phenotype of mature activated B lymphocytes expressing CD19, CD5, and CD23 and having reduced levels of membrane IgM, IgD, and CD79b. The co-expression of CD19 and CD5, however, is also characteristic for mantle cell lymphoma (MCL), which, in contrast to CLL, is usually an aggressive disease hallmarked by the t(11;14)(q13; q32)/IGH-CCND1 rearrangement. Differential diagnosis between CLL and leukemic MCL is sometimes challenging. 5 Given that up to 30% of MCL cases have immunophenotypic features characteristic of B-CLL, albeit usually with atypical, pleomorphic morphology, 6 immunophenotyping alone is insufficient to exclude a diagnosis of MCL. Therefore, in the Belfast City Hospital (Belfast, Northern Ireland) all suspected CLL cases have been routinely examined by rapid interphase FISH with the LSI IGH/CCND1 assay to identify t(11;14)-positive MCL cases, in addition to examination for CLL typical cytogenetic aberrations. During this analysis, a subset of CLL

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“…3,[10][11][12] TCL1 has also been shown to be highly expressed in most Bcell tumors, however, chromosome aberrations that constitutively activate TCL1 are not found and thus its role as a B-cell oncogene is unclear. [13][14][15][16][17][18] However, when driven by IgH Em enhancer elements, human TCL1 overexpression in mice produces B-cell tumors preceded in some cases by preneoplastic CD5 þ /IgM þ B-cell expansions that resemble early chronic lymphocytic leukemia (CLL). 15,19,20 To clarify TCL1's role in human CLL, we present here the first complete assessment of the regulation of TCL1 in the different molecular and immunophenotypic subsets of CLL.…”

Section: Introductionmentioning

confidence: 99%

TCL1 shows a regulated expression pattern in chronic lymphocytic leukemia that correlates with molecular subtypes and proliferative state

et al. 2005

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Expression of the human oncogene TCL1 in transgenic mice produces B-cell tumors that resemble chronic lymphocytic leukemia (CLL) suggesting its role in B-cell tumorigenesis. To clarify the expression pattern and regulation of TCL1 in CLL, we assessed 213 primary tumors by immunohistochemistry (IHC), flow-cytometry and/or Western blot, using a new monoclonal antibody. TCL1 protein was detectable in the majority of CLL (90% by IHC) but showed marked variations across cases with virtual absence in approximately 10% of tumors. Higher TCL1 levels correlated with markers of the 'pre-germinal center' CLL subtype including unmutated VH status (P ¼ 0.005), ZAP70 expression (P ¼ 0.007), and presence of chromosome 11q22-23 deletions (P ¼ 0.04). Intratumoral heterogeneity in TCL1 levels was also prominent and explained in part by markedly lower TCL1 expression in proliferating tumor cells. In vitro exposure of CLL cells to interleukin-4 (but not other growth factors) produced progressive and irreversible decrease in TCL1 protein levels in association with the onset of proliferation. TCL1 expression patterns in CLL are complex and highly dynamic and appear to reflect both the histogenetic subtypes of the disease and the growth parameters of individual tumors. The observed regulation pattern suggests that TCL1 may exert its effects predominantly in the unmutated/ZAP70-positive tumor subset.

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Fluorescent-labeled DNA probes applied to novel biological aspects of B-cell chronic lymphocytic leukemia

Cited by 29 publications

References 30 publications

Stromal cells modulate TCL1 expression, interacting AP-1 components and TCL1-targeting micro-RNAs in chronic lymphocytic leukemia

Stromal cells modulate TCL1 expression, interacting AP-1 components and TCL1-targeting micro-RNAs in chronic lymphocytic leukemia

Telomeric IGH Losses Detectable by Fluorescence in Situ Hybridization in Chronic Lymphocytic Leukemia Reflect Somatic VH Recombination Events

TCL1 shows a regulated expression pattern in chronic lymphocytic leukemia that correlates with molecular subtypes and proliferative state

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