Clonal chromosomal aberrations in bone marrow cells of Fanconi anemia patients: gains of the chromosomal segment 3q26q29 as an adverse risk factor

Tönnies, Holger; Huber, Sylvia; Kühl, Jörn‐Sven; Gerlach, Antje; Ebell, Wolfram; Neitzel, Heidemarie

doi:10.1182/blood-2002-10-3243

Cited by 110 publications

(88 citation statements)

References 15 publications

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“…37 We know from Fanconi anemia that patients with 3q26 aberrations have a higher risk of developing AML and if monosomy 7 develops, this occurs in the 3q26 aberrant clone as a second event. 42 Therefore, as both MLL-AF6 and monosomy 7 are associated with poor outcome in pediatric AML, 37,38,43 this may underscore that EVI1 has a role in these leukemias. However, direct evidence demonstrating an oncogenic effect of EVI1 þ overexpression in these types of leukemia could not be derived from our study and further evidence is currently lacking.…”

Section: Discussionmentioning

confidence: 99%

EVI1 overexpression in distinct subtypes of pediatric acute myeloid leukemia

et al. 2010

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Overexpression of the ecotropic virus integration-1 (EVI1) gene (EVI1 þ ), localized at chromosome 3q26, is associated with adverse outcome in adult acute myeloid leukemia (AML). In pediatric AML, 3q26 abnormalities are rare, and the role of EVI1 is unknown. We studied 228 pediatric AML samples for EVI1 þ using gene expression profiling and RQ-PCR. EVI1 þ was found in 20/213 (9%) of children with de novo AML, and in 4/8 with secondary AML. It was predominantly found in MLLrearranged AML (13/47), monosomy 7 (2/3), or FAB M6/7 (6/10), and mutually exclusive with core-binding factor AML, t(15;17), and NPM1 mutations. Fluorescent in situ hybridization (FISH) was performed to detect cryptic 3q26 abnormalities. However, none of the EVI1 þ patients harbored structural 3q26 alterations. Although significant differences in 4 years pEFS for EVI1 þ and EVI1À pediatric AML were observed (28%±11 vs 44%±4, P ¼ 0.04), multivariate analysis did not identify EVI1 þ as an independent prognostic factor. We conclude that EVI1 þ can be found in B10% of pediatric AML. Although EVI1 þ was not an independent prognostic factor, it was predominantly found in subtypes of pediatric AML that are related with an intermediate to unfavorable prognosis. Further research should explain the role of EVI1 þ in disease biology in these cases. Remarkably, no 3q26 abnormalities were identified in EVI1 þ pediatric AML.

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Section: Discussionmentioning

confidence: 99%

EVI1 overexpression in distinct subtypes of pediatric acute myeloid leukemia

et al. 2010

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“…Interestingly, loss of 6q material is a frequent aberration in nonHodgkin lymphoma and is also occasionally found in myelodysplastic syndromes (MDS) (Steinemann et al, 2003;Mitelman et al, 2006). Gain of 3q is associated with clonal evolution from Fanconi anemia to MDS (To¨nnies et al, 2003). 13q amplifications have recently been linked to overexpression of an oncogenic micro-RNA cluster in B-cell lymphomas (He et al, 2005).…”

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confidence: 99%

Genome-wide single-nucleotide polymorphism analysis in juvenile myelomonocytic leukemia identifies uniparental disomy surrounding the NF1 locus in cases associated with neurofibromatosis but not in cases with mutant RAS or PTPN11

et al. 2007

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Juvenile myelomonocytic leukemia (JMML) is a malignant hematopoietic disorder whose proliferative component is a result of RAS pathway deregulation caused by somatic mutation in the RAS or PTPN11 oncogenes or in patients with underlying neurofibromatosis type 1 (NF-1), by loss of NF1 gene function. To search for potential collaborating genetic abnormalities, we used oligonucleotide arrays to analyse over 116 000 single-nucleotide polymorphisms across the genome in 16 JMML samples with normal karyotype. Evaluation of the SNP genotypes identified large regions of homozygosity on chromosome 17q, including the NF1 locus, in four of the five samples from patients with JMML and NF-1. The homozygous region was at least 55 million base pairs in each case. The genomic copy number was normal within the homozygous region, indicating uniparental disomy (UPD). In contrast, the array data provided no evidence for 17q UPD in any of the 11 JMML cases without NF-1. We used arraybased comparative genomic hybridization to confirm 17q disomy, and microsatellite analysis was performed to verify homozygosity. Mutational analysis demonstrated that the inactivating NF1 lesion was present on both alleles in each case. In summary, our data indicate that a mitotic recombination event in a JMML-initiating cell led to 17q UPD with homozygous loss of normal NF1, provide confirmatory evidence that the NF1 gene is crucial for the increased incidence of JMML in NF-1 patients, and corroborate the concept that RAS pathway deregulation is central to JMML pathogenesis.

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“…Для АФ характерны перестройки: add1q, add3q, моносомия 7. В редких случаях клональная амплификация 3q26-q29 может быть отмечена до развития МДС или ОМЛ, од-нако риск прогрессирования в ОМЛ у таких пациентов крайне высок [58,59].…”

Section: редкие болезниunclassified