Characterization of additional genetic events in childhood acute lymphoblastic leukemia with TEL/AML1 gene fusion: a molecular cytogenetics study

S.K., Edmond; Wan, T. S. K.; Cheuk, Adam; Fung, L. F.; Chan, Godfrey C. F.; Chan, Sau Yan; Ha, Sy; Li, Chan

doi:10.1038/sj.leu.2402202

Cited by 62 publications

(54 citation statements)

References 36 publications

(29 reference statements)

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“…14 To the best of our knowledge, only eight ETV6/RUNX1-positive ALLs with partial Xq gains, as identified by metaphase CGH or multicolor FISH, have been described. [15][16][17][27][28][29] All the gains in these cases were generated through unbalanced translocations involving Xq, none of which were seen by conventional cytogenetics. Notably, all cases with Xq gain in the present study were males, as were six of the previously published cases; 16,17,[27][28][29] the gender of the remaining two cases was not reported.…”

Section: Discussionmentioning

confidence: 96%

Combined high-resolution array-based comparative genomic hybridization and expression profiling of ETV6/RUNX1-positive acute lymphoblastic leukemias reveal a high incidence of cryptic Xq duplications and identify several putative target genes within the commonly gained region

et al. 2007

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Seventeen ETV6/RUNX1-positive pediatric acute lymphoblastic leukemias were investigated by high-resolution array-based comparative genomic hybridization (array CGH), gene expression profiling and fluorescence in situ hybridization. Comparing the array CGH and gene expression patterns revealed that genomic imbalances conferred a great impact on the expression of genes in the affected regions. The array CGH analyses identified a high frequency of cytogenetically cryptic genetic changes, for example, del(9p) and del(12p). Interestingly, a duplication of Xq material, varying between 30 and 60 Mb in size, was found in 6 of 11 males (55%), but not in females. Genes on Xq were found to have a high expression level in cases with dup(Xq); a similar overexpression was confirmed in t(12;21)-positive cases in an external gene expression data set. By studying the expression profile and the proposed function of genes in the minimally gained region, several candidate target genes (SPANXB, HMGB3, FAM50A, HTATSF1 and RAP2C) were identified. Among them, the testis-specific SPANXB gene was the only one showing a high and uniform overexpression, irrespective of gender and presence of Xq duplication, suggesting that this gene plays an important pathogenetic role in t(12;21)-positive leukemia.

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Section: Discussionmentioning

confidence: 96%

Combined high-resolution array-based comparative genomic hybridization and expression profiling of ETV6/RUNX1-positive acute lymphoblastic leukemias reveal a high incidence of cryptic Xq duplications and identify several putative target genes within the commonly gained region

et al. 2007

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“…Some of these events could be reflected on the chromosomal level as nonrandom secondary abnormalities and comprise, in particular, the deletion of the nonrearranged TEL allele, the duplications of the normal chromosome 21 and the der(21)t(12;21) as well as more unspecific ones such as 6q deletions and 9p abnormalities. [21][22][23][24][25][26][27][28][29][30][31][32] Since the t(12;21) is virtually undetectable with conventional cytogenetic procedures, the two preferred screening methods are those with reverse transcriptase polymerase chain reaction (RT-PCR) and fluorescence in situ hybridization (FISH). 1-6, 9-13,17,21-33 The latter technology has the advantage that it enables the identification and quantification of the most common and, thus, most relevant secondary changes on a single cell level.…”

Section: Introductionmentioning

confidence: 99%

Incidence and relevance of secondary chromosome abnormalities in childhood TEL/AML1+ acute lymphoblastic leukemia: an interphase FISH analysis

Attarbaschi

Mann

König³

et al. 2004

Leukemia

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The aim of the present study was to determine the frequency and clinical relevance of the most common secondary karyotype abnormalities in TEL/AML1 þ B-cell precursor acute lymphoblastic leukemia (ALL) as assessed with fluorescence in situ hybridization (FISH) analyses. Screening of 372 patients who were enrolled in two consecutive Austrian childhood ALL multicenter trials identified 94 (25%) TEL/AML1 þ cases. TEL deletions, trisomy 21 and an additional der(21)t(12;21) were detected in 52 (55%), 13 (14%) and 14 (15%) TEL/AML1 þ patients, respectively. The 12p aberrations (P ¼ 0.001) and near tetraploidy (P ¼ 0.045) were more common in TEL/AML1 þ patients, whereas the incidence of diploidy, pseudodiploidy, hypodiploidy, low hyperdiploidy, near triploidy, del(6q), chromosome 9 and 11q23 abnormalities was similar among TEL/ AML1 þ and TEL/AML1À patients. None of the TEL/AML1 þ patients had a high hyperdiploid karyotype. Univariate analysis indicated that among TEL/AML1 þ patients those with a deletion of the nontranslocated TEL allele had a worse prognosis than those without this abnormality (P ¼ 0.034). We concluded that the type and incidence of the most common secondary aberrations in TEL/AML1 þ ALL can be conveniently identified with little additional effort during interphase screening with appropriate TEL and AML1 FISH probes. We also provided preliminary evidence that the deletion of the nontranslocated TEL allele may adversely influence the clinical course of TEL/AML1 þ ALL.

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“…16 It has also been shown that the coiled-coil region of ETO could oligomerize with AML1-ETO protein, thus recruiting the nuclear corepressor N-CoR responsible for transcriptional repression of AML1 target genes and resulting in impaired differentiation of primary hematopoietic precursors. 17,18 Recently, we and others have reported other mechanisms of inactivation of AML1 in hematological malignancies, through point mutations of the gene in AML and in MDS [19][20][21][22][23][24][25] or through gene amplification, [26][27][28][29][30][31][32] a rare event mainly observed in acute lymphoblastic leukemia (ALL). In this review, we focused on those two other mechanisms of AML1 deregulation in hematological malignancies.…”

Section: Introductionmentioning

confidence: 99%

New mechanisms of AML1 gene alteration in hematological malignancies

et al. 2003

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The human AML1 gene (also named CBFA2 or RUNX1), located in the 21q22 chromosomal band, encodes for one of the two subunits forming a heterodimeric transcription factor, the human core binding factor (CBF). AML1 protein contains a highly evolutionary conserved domain of 128 amino acids called runt domain, responsible for both heterodimerization with the ␤ subunit of CBF and for DNA binding. AML1 is normally expressed in all hematopoietic lineages and acts to regulate the expression of various genes specific to hematopoiesis playing a pivotal role in myeloid differentiation. AML1 is one of the genes most frequently deregulated in leukemia through different mechanisms including translocation, mutation and amplification. Translocations lead to the formation of fusion genes encoding for chimerical proteins such as AML1-ETO which induces leukemogenesis. Recently, new mechanisms of AML1 deregulation by point mutations or amplification have been reported. To our knowledge, 51 patients (among 805 studied) with AML1 point mutations have been described. Forty of them have acute myeloid leukemia (AML) most often M0 AML. In this subtype of AML, the frequency of AML1 mutation is significantly higher; 21.5% of patients mutated (34/158). Mutations have also been found with lower frequency in other FAB subtype AML (6 cases), in myeloproliferative disorders (6 cases), in myelodysplastic syndrome (3 cases) and rarely in acute lymphoblastic leukemia (1 case). AML1 gene amplification has been found essentially in childhood ALL (12 cases) and more rarely in myeloid malignancies (4 cases). Here, we reviewed all these cases of AML1 point mutations and amplification and focused on the mechanisms of AML1 deregulation induced by these alterations.

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Characterization of additional genetic events in childhood acute lymphoblastic leukemia with TEL/AML1 gene fusion: a molecular cytogenetics study

Cited by 62 publications

References 36 publications

Combined high-resolution array-based comparative genomic hybridization and expression profiling of ETV6/RUNX1-positive acute lymphoblastic leukemias reveal a high incidence of cryptic Xq duplications and identify several putative target genes within the commonly gained region

Combined high-resolution array-based comparative genomic hybridization and expression profiling of ETV6/RUNX1-positive acute lymphoblastic leukemias reveal a high incidence of cryptic Xq duplications and identify several putative target genes within the commonly gained region

Incidence and relevance of secondary chromosome abnormalities in childhood TEL/AML1+ acute lymphoblastic leukemia: an interphase FISH analysis

New mechanisms of AML1 gene alteration in hematological malignancies

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