The human LASP1 gene is fused to MLL in an acute myeloid leukemia with t(11;17)(q23;q21)

Strehl, Sabine; Slany, Robert K.; Fuchs, Uta; König, Margit; Haas, Oskar A.

doi:10.1038/sj.onc.1206042

Cited by 47 publications

(34 citation statements)

References 27 publications

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“…Two additional observations underscore the importance of LASP-1 in cancer. First, altered expression of LASP-1 is associated with the MLL gene in acute myeloid leukaemia (Strehl et al, 2003). Second, recent studies have shown LASP-1 to be transcriptionally upregulated in response to the morphogen Sonic Hedgehog (Ingram et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

Overexpression of LASP-1 mediates migration and proliferation of human ovarian cancer cells and influences zyxin localisation

Grünewald

Kämmerer

Winkler³

et al. 2007

Br J Cancer

108

135

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LIM and SH3 protein 1 (LASP-1), initially identified from human breast cancer, is a specific focal adhesion protein involved in cell proliferation and migration. In the present work, we analysed the effect of LASP-1 on biology and function of human ovarian cancer cell line SKOV-3 using small interfering RNA technique (siRNA).Transfection with LASP-1-specific siRNA resulted in a reduced protein level of LASP-1 in SKOV-3 cells. The siRNA-treated cells were arrested in G 2 /M phase of the cell cycle and proliferation of the tumour cells was suppressed by 60 -90% corresponding to around 70% of the cells being transfected successfully as seen by immunofluorescence. Moreover, transfected tumour cells showed a 40% reduced migration. LASP-1 silencing is accompanied by a reduced binding of the LASP-1-binding partner zyxin to focal contacts without changes in actin stress fibre and microtubule organisation or focal adhesion morphology as observed by immunofluorescence. In contrast, silencing of zyxin is not influencing cell migration and had neither influence on LASP-1 expression nor actin cytoskeleton and focal contact morphology suggesting that LASP-1 is necessary and sufficient for recruiting zyxin to focal contacts.The data provide evidence for an essential role of LASP-1 in tumour cell growth and migration, possibly through influencing zyxin localization.

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Section: Discussionmentioning

confidence: 99%

Overexpression of LASP-1 mediates migration and proliferation of human ovarian cancer cells and influences zyxin localisation

Grünewald

Kämmerer

Winkler³

et al. 2007

Br J Cancer

108

135

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“…Apparent translocations fused MLL to sequence located on chromosome bands 3q26, 3p25, 4q31-32, 4p15, 6q21, 7q31-32, 9q21-22, 12q21 (2 clones), 14q21, 15q12-13, 17q24 (3 clones), and Xq22-23. Although several of these chromosomal bands contain known partner genes of MLL (3q25-26-GMPS, 6q21-AF6q21, 17q24-LASP1, and Xq22-23-Septin6 [56][57][58][59] ), the partner sequences in the induced clones did not match known MLL partners.…”

Section: Ipcr Analysis Of Etoposide-induced Mll Repair Productsmentioning

confidence: 99%

Therapy-related acute myeloid leukemia–like MLL rearrangements are induced by etoposide in primary human CD34+ cells and remain stable after clonal expansion

Libura

Slater

Felix

et al. 2005

Blood

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Rearrangements involving the MLL gene on chromosome band 11q23 are a hallmark of therapy-related acute myeloid leukemias following treatment with topoisomerase II poisons including etoposide. Therapy-related and de novo genomic translocation breakpoints cluster within a well-characterized 8.3-kb fragment of MLL. Repair of etoposidestabilized DNA topoisomerase II covalent complexes may initiate MLL rearrangements observed in patients. We used a culture system of primary human hematopoietic CD34 ؉ cells and inverse polymerase chain reaction to characterize the spectrum of stable genomic rearrangements promoted by etoposide exposure originating within an MLL translocation hotspot in therapy-related leukemia. Alterations to the region were observed at a readily detectable frequency in etoposidetreated cells. Illegitimate repair events after minimal repair included MLL tandem duplications and translocations, with minor populations of deletions or insertions. In stably repaired cells that proliferated for 10 to 14 days, the significant majority of illegitimate events were MLL IntroductionGenome integrity is controlled by multiple damage surveillance pathways, cell-cycle checkpoints, and repair mechanisms. [1][2][3] Despite these safeguards, illegitimate repair of chromosomal doublestrand breaks (DSBs), such as those produced by chemotherapy agents that target topoisomerase II (topo II), can promote chromosomal rearrangements and, ultimately, tumorigenesis. Topo II is an essential cellular enzyme that catalyzes changes in DNA topology via its cleavage-religation equilibrium. Topo II-targeted drugs that are poisons of this enzyme stabilize topo II-DNA covalent complexes, most often by decreasing the rate of religation in a dose-dependent manner. Disruption of the cleavage-religation reaction results in accumulation of DSBs, p53 activation, and induction of apoptosis or repair. 4,5 Chromosomal DSBs are potent inducers of recombination, stimulating the exchange of homologous sequences between 2 DNA duplexes 1000-fold 6-8 not only between sister chromatids, but also between homologs, and sequence repeats on heterologous chromosomes. 9-12 DSBs may be repaired by homologous recombination or nonhomologous end joining (NHEJ), and both repair mechanisms have been associated with chromosomal translocations, a hallmark of leukemias, lymphomas, and soft-tissue sarcomas. [13][14][15] There is clear evidence that exposure to chemotherapy or irradiation can result in subsequent development of therapy-related leukemias, which occur in 1% to 15% of patients exposed to DNA-damaging agents in anticancer regimens. 16,17 Exposure to topo II poisons such as etoposide is predominantly associated with therapy-related leukemias characterized by rearrangements of the MLL gene on chromosome band 11q23. 16 MLL spans 100 kb, encodes a 430-kDa protein homologous to the Drosophila trithorax gene, and has important functions in embryogenesis and hematopoiesis. 18,19 Mixed-lineage leukemia (MLL) is a critical transcriptional regulator and numerous tr...

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“…이중 4개의 MLL 결합파트너 유 전자가 17번 염색체 장완에 존재하는 것으로 보고되었는데 ALL1 fused gene from chromosome 17 (AF17 혹은 MLLT6, 17q21 에 위치), LIM and SH3 protein (LASP1 혹은 MLN50, 17q21 에 위치), MLL septin-like fusion (MSF 혹은 SEPT9, 17q25 에 위치) 및 RARA (17q21에 위치) 유전자이다 [10][11][12][13].…”

Section: 김경은•김성현•한진영unclassified

“…현재까지 APL의 변이형에서 보이는 t(11;17)(q23;q21)의 염 색체 변이를 나타내면서 형태학적으로는 APL이 아닌 AMoL으 로 진단된 증례가 전 세계적으로 7-8예 정도 보고되고 있다 [7,[10][11][12][13][14][15][16][17]. …”

Section: 김경은•김성현•한진영unclassified

Acute Monocytic Leukemia with t(11;17)(q23;q21) Involving a Rearrangement of Mixed Lineage Leukemia Gene

Kim

Han

2006

Ann Lab Med

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329A case of acute monocytic leukemia (AMoL) by French-American-British (FAB) classification in a 63-year-old male showed the abnormal karyotype 46,XY,t(11;17)(q23;q21), previously reported as a variant translocation in acute promyelocytic leukemia (APL). Fluorescence in situ hybridization (FISH) analysis identified a mixed lineage leukemia (MLL) gene rearrangement, but not visible disruptions of promyelocytic leukemia (PML) or retinoic acid receptor alpha (RARA) genes. We suggest that a certain gene proximal to RARA was rearranged in this case onto a gene close to MLL on chromosome 11q. Now, a few cases of AMoL with a similar translocation have been reported in the literature, and these cases emphasize the importance of cytogenetic and FISH studies in addition to morphology, cytochemistry, and immunophenotype in classifying acute myeloid leukemia (AML).( Korean J Lab Med 2006;26:329-33)

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The human LASP1 gene is fused to MLL in an acute myeloid leukemia with t(11;17)(q23;q21)

Cited by 47 publications

References 27 publications

Overexpression of LASP-1 mediates migration and proliferation of human ovarian cancer cells and influences zyxin localisation

Overexpression of LASP-1 mediates migration and proliferation of human ovarian cancer cells and influences zyxin localisation

Therapy-related acute myeloid leukemia–like MLL rearrangements are induced by etoposide in primary human CD34+ cells and remain stable after clonal expansion

Acute Monocytic Leukemia with t(11;17)(q23;q21) Involving a Rearrangement of Mixed Lineage Leukemia Gene

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