LEF-1 is a prosurvival factor in chronic lymphocytic leukemia and is expressed in the preleukemic state of monoclonal B-cell lymphocytosis

Gutierrez, Albert; Tschumper, Renee C.; Wu, Xiaosheng; Shanafelt, Tait D.; Eckel‐Passow, Jeanette E.; Huddleston, P.M.; Slager, Susan L.; Kay, Neil E.; Jelinek, Diane F.

doi:10.1182/blood-2010-02-269878

Cited by 137 publications

(158 citation statements)

References 31 publications

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“…16,17 A recent study demonstrated that LEF1 is not only overexpressed in chronic lymphocytic leukemia/small lymphocytic lymphoma, but also in its preleukemic state of monotypic B lymphocytosis. 7 These findings suggest that LEF1 may have a role in the pathogenesis of chronic lymphocytic leukemia.…”

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confidence: 75%

“…16,17 A recent study shows that LEF1 is not only overexpressed in chronic lymphocytic leukemia, but also in the CD5 þ /CD19 þ cells from patients with monoclonal B-cell lymphocytosis, suggesting a role of LEF1 in early leukemogenesis of chronic lymphocytic leukemia. 7 So far, the data on LEF1 expression in B-cell lymphoma are limited, and the evaluation has been through molecular or other methods primarily used in research settings. Our study assessed LEF1 expression by immunohistochemistry in a large series of chronic lymphocytic leukemia/small lymphocytic lymphoma as well as other types of B-cell lymphomas.…”

Section: Discussionmentioning

confidence: 99%

“…[3][4][5][6][7] Our study represents the first attempt to assess LEF1 expression by immunohistochemistry that allows us to evaluate a large series of chronic lymphocytic leukemia/small lymphocytic lymphoma as well as other types of B-cell lymphomas. Given the central role of LEF/TCF in WNT/b-catenin signaling, the expression of b-catenin was also examined in order to investigate whether the pro-survival effect of LEF1 in chronic lymphocytic leukemia/small lymphocytic lymphoma is through mediating nuclear response to WNT signaling.…”

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confidence: 99%

“…[3][4][5][6][7] This pathway regulates cell fate determination during development as well as cell proliferation and survival. The ultimate mediator of this pathway is a nuclear complex of LEF/T-cell factor (TCF) and b-catenin that work together to regulate the transcription of a variety of WNT target genes.…”

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Nuclear overexpression of lymphoid-enhancer-binding factor 1 identifies chronic lymphocytic leukemia/small lymphocytic lymphoma in small B-cell lymphomas

et al. 2011

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Lymphoid-enhancer-binding factor 1 (LEF1), coupling with b-catenin, functions as a key nuclear mediator of WNT/b-catenin signaling, which regulates cell proliferation and survival. LEF1 has an important role in lymphopoiesis, and is normally expressed in T and pro-B cells but not mature B cells. However, gene expression profiling demonstrates overexpression of LEF1 in chronic lymphocytic leukemia, and knockdown of LEF1 decreases the survival of the leukemic cells. So far, the data on LEF1 expression in B-cell lymphomas are limited. This study represents the first attempt to assess LEF1 by immunohistochemistry in a large series (290 cases) of B-cell lymphomas. Strong nuclear staining of LEF1 was observed in virtually all neoplastic cells in 92 of 92 (100%) chronic lymphocytic leukemia/small lymphocytic lymphomas including two CD5À cases, with strongest staining in cells with Richter's transformation. LEF1 also highlighted the morphologically inconspicuous small lymphocytic lymphoma component in three composite lymphomas. All 53 mantle cell lymphomas, 31 low-grade follicular lymphomas and 31 marginal zone lymphomas, including 3 CD5 þ cases, were negative. In 12 grade 3 follicular lymphomas, LEF1 was positive in a small subset (5-15%) of cells. Diffuse large B-cell lymphoma, however, demonstrated significant variability in LEF1 expression with overall positivity in 27 of 71 (38%) cases. Our results demonstrate that nuclear overexpression of LEF1 is highly associated with chronic lymphocytic leukemia/small lymphocytic lymphoma, and may serve as a convenient marker for differential diagnosis of small B-cell lymphomas. The expression of b-catenin, the coactivator of LEF1 in WNT signaling, was examined in 50 chronic lymphocytic leukemia/small lymphocytic lymphomas, of which 44 (88%) showed negative nuclear staining. The findings of universal nuclear overexpression of LEF1 but lack of nuclear b-catenin in the majority of chronic lymphocytic leukemia/small lymphocytic lymphoma suggest that the pro-survival function of LEF1 in this disease may be independent of WNT/b-catenin signaling.

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confidence: 75%

Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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Nuclear overexpression of lymphoid-enhancer-binding factor 1 identifies chronic lymphocytic leukemia/small lymphocytic lymphoma in small B-cell lymphomas

et al. 2011

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“…In the present work, LEF-1 was found to be one of critical transcription factors for the activity of Crlz1 promoter. As LEF-1 has been reported to be expressed stage-specifically from pro-B to pre-B cells during B cell development (Gutierrez et al, 2010;Reya et al, 2000) and play a role to open its target chromatin with β-catenin in the Wnt (wingless-type MMTV integration site) signaling pathway (Heo et al, 2010;Mosimann et al, 2009), the involvement of LEF-1 in the regulation of Crlz1 promoter activity could provide a potential explanation for the molecular mechanism for the pre-B cell stage-specific activity of Crlz1 promoter, i.e., for the pre-B cell stage-specific histone hyperacetylation and chromatin opening of Crlz1 promoter and thereby its subsequent gene expression (Lim et al, 2006). Therefore, it is possible that the initial binding of pre-B cell stage-specific LEF-1 to the distal region of Crlz1 promoter might open the promoter chromatin to start to activate the promoter specifically in the pre-B cell stage, while multiple bindings of relatively ubiquitous Ets family members such as Fli-1 and GABP to its proximal region might further amplify the Crlz1 promoter activity by multiple additive interactions.…”

Section: Discussionmentioning

confidence: 99%

A Strong Promoter Activity of Pre-B Cell Stage-Specific Crlz1 Gene Is Caused by One Distal LEF-1 and Multiple Proximal Ets Sites

Park

Son

Kang

2011

Molecules and Cells

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The promoter of pre-B cell stage-specific Crlz1 gene, whose protein translocates the cytoplasmic core binding factor β (CBFβ) into the nucleus and thereby allows its heterodimerization with Runx, has a very strong activity, which is about 25% of cytomegalovirus (CMV) promoter activity and comparable to the EF-1α promoter activity. Its transcription start site was mapped at 155 nt upstream of translation initiation codon. 5′-truncation analysis of charged amino acids rich leucine zipper 1 (Crlz1) promoter revealed that one distal region from -612 to -536 and one proximal region from -198 to -100 as numbered from the transcription start site were critical for the promoter activity. The 3′-truncation analysis of the promoter revealed that the basal promoter sequence around the transcription start site, which should be necessary for the assembly of transcription initiation complex and the start of RNA polymerase II, was also essential, although not sufficient by itself. When transcription factor binding sites within those two critical regions were searched by in vivo footprinting, one distal LEF-1 and multiple proximal Ets consensus-like sites were found to be footprinted. Indeed, the protein causing a footprint over the distal region was found to be LEF-1, and the ones causing three footprints over the proximal region were found to be such Ets family members as Fli-1 and GABP, as verified by EMSA and ChIP analyses. Furthermore, those LEF-1 and Ets sites were shown to drive additively a strong transcription of Crlz1 gene.

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Interaction between miRNAs and signaling cascades of Wnt pathway in chronic lymphocytic leukemia

Bhattacharya

Sharma

et al. 2020

J of Cellular Biochemistry

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Chronic lymphocytic leukemia (CLL), a severe problem all over the world and represents around 25% of all total leukemia cases, is generating the need for novel targets against CLL. Wnt signaling cascade regulates cell proliferation, differentiation, and cell death processes. Thus, any alteration of the Wnt signaling pathway protein cascade might develop into various types of cancers, either by upregulation or downregulation of the Wnt signaling pathway protein components. In addition, it is reported that activation of the Wnt signaling pathway is associated with the transcriptional activation of microRNAs (miRNAs) by binding to its promoter region, suggesting feedback regulation. Considering the protein regulatory functions of various miRNAs, they can be approached therapeutically as modulatory targets for protein components of the Wnt signaling pathway. In this article, we have discussed the potential role of miRNAs in the regulation of Wnt signaling pathway proteins related to the pathogenesis of CLL via crosstalk between miRNAs and Wnt signaling pathway proteins. This might provide a clear insight into the Wnt protein regulatory function of various miRNAs and provide a better understanding of developing advanced and promising therapeutic approaches against CLL.

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LEF-1 is a prosurvival factor in chronic lymphocytic leukemia and is expressed in the preleukemic state of monoclonal B-cell lymphocytosis

Cited by 137 publications

References 31 publications

Nuclear overexpression of lymphoid-enhancer-binding factor 1 identifies chronic lymphocytic leukemia/small lymphocytic lymphoma in small B-cell lymphomas

Nuclear overexpression of lymphoid-enhancer-binding factor 1 identifies chronic lymphocytic leukemia/small lymphocytic lymphoma in small B-cell lymphomas

A Strong Promoter Activity of Pre-B Cell Stage-Specific Crlz1 Gene Is Caused by One Distal LEF-1 and Multiple Proximal Ets Sites

Interaction between miRNAs and signaling cascades of Wnt pathway in chronic lymphocytic leukemia

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