Somatic heterozygous mutations in ETV6 (TEL) and frequent absence of ETV6 protein in acute myeloid leukemia

Doorn-Khosrovani, Sahar van Waalwijk van Barjesteh; Spensberger, Dominik; Knegt, Yvonne de; Tang, Michelle; Löwenberg, Bob; Delwel, Ruud

doi:10.1038/sj.onc.1208588

Cited by 65 publications

(64 citation statements)

References 43 publications

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“…To test whether this paradigm occurs in AML, we examined a focal CNA on chromosome 12p12.3 that occurred in 3 AML patients. This region contains the ETV6 (TEL) gene, which is known to be mutated and translocated in patients with AML (19,20). We identified 3 of 180 samples with nonsynonymous singlenucleotide variants in ETV6 in the absence of a CNA (P4A, R105Q, and R202Q); none of these samples had CNAs at 12p12.3.…”

Section: Identification Of Translocations and Genementioning

confidence: 99%

Acquired copy number alterations in adult acute myeloid leukemia genomes

Walter

Payton²,

Ries³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

224

175

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Cytogenetic analysis of acute myeloid leukemia (AML) cells has accelerated the identification of genes important for AML pathogenesis. To complement cytogenetic studies and to identify genes altered in AML genomes, we performed genome-wide copy number analysis with paired normal and tumor DNA obtained from 86 adult patients with de novo AML using 1.85 million feature SNP arrays. Acquired copy number alterations (CNAs) were confirmed using an ultra-dense array comparative genomic hybridization platform. A total of 201 somatic CNAs were found in the 86 AML genomes (mean, 2.34 CNAs per genome), with French-AmericanBritish system M6 and M7 genomes containing the most changes (10 -29 CNAs per genome). Twenty-four percent of AML patients with normal cytogenetics had CNA, whereas 40% of patients with an abnormal karyotype had additional CNA detected by SNP array, and several CNA regions were recurrent. The mRNA expression levels of 57 genes were significantly altered in 27 of 50 recurrent CNA regions <5 megabases in size. A total of 8 uniparental disomy (UPD) segments were identified in the 86 genomes; 6 of 8 UPD calls occurred in samples with a normal karyotype. Collectively, 34 of 86 AML genomes (40%) contained alterations not found with cytogenetics, and 98% of these regions contained genes. Of 86 genomes, 43 (50%) had no CNA or UPD at this level of resolution. In this study of 86 adult AML genomes, the use of an unbiased high-resolution genomic screen identified many genes not previously implicated in AML that may be relevant for pathogenesis, along with many known oncogenes and tumor suppressor genes. AML ͉ array CGH ͉ genomics ͉ SNP arrayA cute myeloid leukemia (AML) is a heterogeneous group of diseases currently classified by abnormalities in bone marrow morphology, karyotype, acquired gene mutations, and alterations in gene expression (1-3). Although the identification of specific gene mutations has resulted in improved treatments and outcomes for some AML patients (4), enormous clinical heterogeneity exists and may reflect the presence of as-yet undetected initiating and cooperating mutations. Therefore, the discovery of somatic mutations in the genomes of AML patients with normal and abnormal karyotypes will advance our understanding of the genetics underlying AML and should lead to more specific therapies and better patient classification schemes.The discovery of previously uncharacterized genes mutated in acute lymphoblastic leukemia (ALL) was recently reported using SNP array technology for DNA copy number analysis (5). SNP array platforms can detect genomic amplifications, deletions, SNP loss of heterozygosity (LOH), and regions of uniparental disomy (UPD) (copy-neutral LOH events) in cancer cells. Early studies using SNP arrays and array comparative genomic hybridization (CGH) platforms have suggested that both copy number alterations (CNAs) and UPD are common in AML genomes (6-12). However, these studies used low-resolution arrays, often used reference DNA that was not obtained from the same patient's n...

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Section: Identification Of Translocations and Genementioning

confidence: 99%

Acquired copy number alterations in adult acute myeloid leukemia genomes

Walter

Payton²,

Ries³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

224

175

View full text Add to dashboard Cite

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“…These chromosomal aberrations were observed in nearly 30 percent of AML cases [18,19]. In addition to these major structural aberrations, numerous somatic mutations were found to be associated with AML including mutations in the NPM1, KRAS2, CEBPA, ETV6, JAK2, and TET2 genes [20][21][22][23][24][25][26].…”

Section: Types and Progression Pathways Of Leukemiamentioning

confidence: 99%

Role of autophagy in the progression and suppression of leukemias

Ekiz

Can

Baran

2012

Critical Reviews in Oncology/Hematology

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Autophagy is a physiological process in which cellular components are degraded by the lysosomal machinery. Thereby, organelles are recycled and monomers are produced in order to maintain energy production. Current studies indicate autophagy might suppress or augment survival of cancer cells. Therefore, by elucidating the role of autophagy in cancer pathogenesis, novel therapeutic intervention points may be revealed. Leukemia therapy has advanced in recent years; but a definitive cure is still lacking. Since autophagy often is deregulated in this particular type of cancer, it is clear that future findings will have clinical implications. This review will discuss the current knowledge of autophagy in blood cancers. © 2011 Elsevier Ireland Ltd

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“…Mutations in ETV6 have only been reported previously in five AML patients (M1 and M2) and in prostate cancer. 5 We found insertions in patients 6 and 58, and a point mutation in patient 21 ( Figure 3; Table 1). Mutations in patient 6 were biallelic, including a frameshift mutation in one allele, resulting in a truncated protein, and an insertion in the remaining allele ( Figure 3; Table 1).…”

Section: Letters To the Editormentioning

confidence: 99%

“…ETV6-mutant proteins with truncation and insertions comparable to ours (Table 1; Figure 3) were shown to have impaired transcriptional repression activity. 5 Interestingly, all our mutants resulted in loss of the ETS domain or its binding activity, but not of the pointed (PNT) domain (Figure 3). Similar mutants reported by Barjesteh van Waalwijk van Doorn-Khosrovani et al 5 showed a dominantnegative effect when ETV6 wild-type constructs were cotransfected with higher amounts of mutant construct.…”

Section: Letters To the Editormentioning

confidence: 99%

“…[1][2][3][4] Recently, heterozygous mutations of ETV6, resulting in loss of repressor activity, were found in AML, adding to the view that ETV6 might have tumor-suppressor characteristics. 5 Whereas translocations and deletions involving ETV6 have been reported in AML-M0, ETV6 mutations were never investigated specifically in this subtype. 4,6 To better understand the role of ETV6 in AML-M0, we studied 52 M0 patients using cytogenetic techniques complemented with single-nucleotide polymorphism (SNP) arrays and sequencing of ETV6, as described in the Supplementary Information.…”

Section: Etv6 Mutations and Loss In Aml-m0mentioning

confidence: 99%

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ETV6 mutations and loss in AML-M0

et al. 2008

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individuals. This was performed in a number of studies for flow cytometry (Kern et al.; 6 San Miguel et al. Instead, we look at bone marrows that are regenerating after heavy chemotherapy. The expression of presumed leukemiaspecific genes or the frequency of presumed leukemia specific phenotypes can be very different in such samples compared to steady-state healthy bone marrow.For instance, the gene CSPG4 was identified as a possible MRD marker. 4 It was highly expressed in AML samples but not in healthy bone marrow. However, we found that it was useless as an MRD marker because expression of CSPG4 was also high in bone marrow that was free of leukemia but was regenerating after chemotherapy. 4 Therefore, to determine the real sensitivity and specificity of an MRD analysis, it is mandatory to analyze a large number of leukemia-free, regenerating bone marrows.A second problem of analyzing serial dilutions of leukemic cells in samples of healthy bone marrow is that this does not really simulate the situation of minimal residual disease. The important clinical question is the amount of leukemic stem cells that is still present in the patient. If the leukemic phenotype that is used for flow cytometry is present on the majority of leukemic cells but not on leukemic stem cells, the sensitivity could be lower than anticipated. If the expression of a leukemia-associated gene, like WT1, is particularly high in leukemic stem cells, the sensitivity might be much better than anticipated and vice versa. ConclusionsMonitoring MRD has become a strong diagnostic tool in acute leukemia. It is widely used for clinical decision-making in acute lymphoblastic leukemia, chronic myeloid leukemia and acute promyelocytic leukemia. Various methods have been developed to monitor MRD in AML and we should proceed to put them into clinical practice.Sensitivity is an important issue in the comparison of these methods. When the term is used, it should always be clear whether we are talking about the LPT or the real sensitivity and specificity of our diagnostic test.The LPT is easy to determine and for most methods of monitoring MRD, is in the range of 10 À4 -10 À6 . These figures have a very limited meaning because for clinical decisionmaking LPT cannot be used as the cutoff for high versus low MRD. At such a low threshold, the specificity of monitoring MRD (likelihood of a negative test result in a truly negative patient) is too low due to false positive healthy and regenerating bone marrows.If we use, for instance, a threshold of 10 À3 for clinical decision-making, it does not matter whether the LPT is 10 À4 or 10 À6 . What really matters is the sensitivity and specificity of the diagnostic test at the threshold of 10 À3 . We should put less effort into determining LPTs and more effort into determining sensitivity and specificity of our methods at the clinically relevant thresholds.Because of the many issues that influence the quality of each method of monitoring MRD, the best way of really comparing two methods is to simultaneously apply ...

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Somatic heterozygous mutations in ETV6 (TEL) and frequent absence of ETV6 protein in acute myeloid leukemia

Cited by 65 publications

References 43 publications

Acquired copy number alterations in adult acute myeloid leukemia genomes

Acquired copy number alterations in adult acute myeloid leukemia genomes

Role of autophagy in the progression and suppression of leukemias

ETV6 mutations and loss in AML-M0

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