Adult acute myeloid leukemia with trisomy 11 as the sole abnormality is characterized by the presence of five distinct gene mutations: MLL-PTD, DNMT3A, U2AF1, FLT3-ITD and IDH2

Eisfeld, A-K; Kohlschmidt, Jessica; Mrózek, Krzysztof; Blachly, James S.; Nicolet, Deedra; Kroll, Karl; Orwick, Shelley; Carroll, Andrew J.; Stone, Richard; Chapelle, Albert de la; Byrd, John C.; Bloomfield, Clara D.

doi:10.1038/leu.2016.196

Cited by 16 publications

(14 citation statements)

References 12 publications

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“…Low somatic mutation burden compared with other tumor types is also a distinguishing feature of AML . Thus, to categorize other genomic alterations that co‐occur with FLT3 ‐ITD, a targeted 80‐gene panel was utilized. At diagnosis, 15 genes classified as tumor suppressors, transcription factors, cohesin complex genes, methylation‐related genes, chromatin remodeling genes, kinases, Ras pathway genes, and signaling genes, were observed to contain mutations with a variant allele frequency (VAF) of 0.10 or greater ( Figure b, Table ).…”

Section: Resultsmentioning

confidence: 99%

“…Eighty protein‐coding genes were sequenced for mutation status using targeted amplicon sequencing with the MiSeq platform (Illumina). DNA libraries were prepared and analyzed as previously described by Eisfeld et al . The average targeted gene panel coverage was 775X.…”

Section: Methodsmentioning

confidence: 99%

“…The objective of the present study was to gain a deeper understanding of the clonal heterogeneity between diagnosis and relapse in larger cohort of pediatric patients with CN FLT3 ‐ITD–positive AML, with hopes of gaining insight into therapy shortcomings. Given the low somatic mutational burden reported for AML, samples were sequenced by RNASeq and a next‐generation sequencing gene panel consisting of 80 genes for chimeric transcripts and co‐occurring mutations, respectively.…”

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confidence: 99%

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Uncovering the Genomic Landscape in Newly Diagnosed and Relapsed Pediatric Cytogenetically Normal FLT3‐ITD AML

Buelow

Pounds

Wang

et al. 2019

Clinical Translational Sci

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Fms-like tyrosine kinase 3 (FLT3) internal tandem duplication (ITD) mutations, common in pediatric acute myeloid leukemia (AML), associate with early relapse and poor prognosis. Past studies have suggested additional cooperative mutations are required for leukemogenesis in FLT3-ITD+ AML. Using RNA sequencing and a next-generation targeted gene panel, we broadly characterize the co-occurring genomic alterations in pediatric cytogenetically normal (CN) FLT3-ITD+ AML to gain a deeper understanding of the clonal patterns and heterogeneity at diagnosis and relapse. We show that chimeric transcripts were present in 21 of 34 (62%) of de novo samples, 2 (6%) of these samples included a rare reoccurring fusion partner BCL11B. At diagnosis, the median number of mutations other than FLT3 per patient was 1 (range 0-3), which involved 8 gene pathways; WT1 and NPM1 mutations were frequently observed (35% and 24%, respectively). Fusion transcripts and high variant allele frequency (VAF) mutants, which included WT1, NPM1, SMARCA2, RAD21, and TYK2, were retained from diagnosis to relapse. We did observe reduction in VAF of simple or single mutation clones, but VAFs were preserved or expanded in more complex clones with multiple mutations. Our data provide the first insight into the genomic complexity of pediatric CN FLT3-ITD+ AML and could help stratify future targeted treatment strategies.Pediatric acute myeloid leukemia (AML) is a rare heterogeneous disease that accounts for 30% of all childhood leukemia. 1,2 It is distinct from the adult counterpart in both their genomic alterations and therapeutic response. 3 However, in both settings, pediatric and adult AML have relatively low somatic mutation burden compared with other tumor types. 4,5 Fms-like tyrosine kinase 3 (FLT3) internal tandem duplication (ITD) mutations are among the most common

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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confidence: 99%

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Uncovering the Genomic Landscape in Newly Diagnosed and Relapsed Pediatric Cytogenetically Normal FLT3‐ITD AML

Buelow

Pounds

Wang

et al. 2019

Clinical Translational Sci

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“…Interestingly, spliceosome mutations were predominantly enriched in patients with gains of chromosomal material, with almost half of these patients harboring one or more such mutations. With the exception of patients with sole trisomy 11 (subgroup #21), who most frequently harbored U2AF1 mutations (43%), 44 SRSF2 was the most often mutated spliceosome gene in patients with unbalanced chromosomal abnormalities. It was mutated in 17% of patients with unbalanced abnormalities, and in 18–50% of patients with sole gain of specific chromosomes, being especially frequent in patients with sole trisomy 13 (50% Figures 1 and 2 ).…”

Section: Resultsmentioning

confidence: 99%

The mutational oncoprint of recurrent cytogenetic abnormalities in adult patients with de novo acute myeloid leukemia

et al. 2017

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Recurrent chromosomal abnormalities and gene mutations detected at the time of diagnosis of acute myeloid leukemia (AML) are associated with particular disease features, treatment response and survival of AML patients, and are used to denote specific disease entities in the World Health Organization classification of myeloid neoplasms and acute leukemia. However, large studies that integrate cytogenetic and comprehensive mutational information are scarce. We created a comprehensive oncoprint of mutations associated with recurrent cytogenetic findings by combining the information on mutational patterns of 80 cancer- and leukemia-associated genes with cytogenetic findings in 1603 adult patients with de novo AML. We show unique differences in the mutational profiles among major cytogenetic subsets, identify novel associations between recurrent cytogenetic abnormalities and both specific gene mutations and gene functional groups, and reveal differences in cytogenetic and mutational features between patients younger than 60 years and those aged 60 years or older. The identified associations between cytogenetic and molecular genetic data may help guide mutation testing in AML, and result in more focused application of targeted therapy in patients with de novo AML.

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“…In patients with acute myeloid leukemia, trisomy 11 is not uncommon and is associated with an intermediate or poor risk, with a median duration of complete remission of 17.5 months (range: 8.7-49.8 months), and with a median overall survival of 14.3 months (range: 0.5-50.7 months) 13 . In addition, a study of acute myeloid leukemia with clonal isolated trisomy 11 revealed mutational landscapes that included the partial tandem duplication of KMT2A (formerly MLL), the internal tandem duplication of FLT3, and mutations in DNMT3A, U2AF1, IDH2 14 . However, the presence of those genetic alterations has not been established for mds and cmml.…”

Section: Discussionmentioning

confidence: 99%

Adult Chronic Myelomonocytic Leukemia with Trisomy 11: A Case Report

et al. 2017

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Chronic myelomonocytic leukemia (cmml) is an indolent disease in the category of myelodysplastic and myeloproliferative neoplasms, which can often evolve into acute leukemic neoplasms. Although cytogenetic abnormalities such as trisomy 8 or absence of chromosome Y are well known, few reports about cmml with trisomy 11 have been published. Here, we report a case of cmml with trisomy 11 as the sole chromosomal abnormality, resulting in a very poor outcome.Based on a bone marrow specimen, cmml-1 with trisomy 11 was diagnosed in a 79-year-old man presenting with anemia and atypical peripheral blood cells. Because of the patient's age, he was followed without receiving anticancer treatment. Two months after his diagnosis, the patient's leucocytosis and anemia rapidly worsened, with increasing numbers of immature peripheral cells, which was strongly suggestive of leukemic transformation. Because of acute kidney injury superimposed on chronic kidney disease that led to poor performance status, cytotoxic chemotherapy was not considered feasible, and the patient was transferred to a hospice care facility.

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Adult acute myeloid leukemia with trisomy 11 as the sole abnormality is characterized by the presence of five distinct gene mutations: MLL-PTD, DNMT3A, U2AF1, FLT3-ITD and IDH2

Cited by 16 publications

References 12 publications

Uncovering the Genomic Landscape in Newly Diagnosed and Relapsed Pediatric Cytogenetically Normal FLT3‐ITD AML

Uncovering the Genomic Landscape in Newly Diagnosed and Relapsed Pediatric Cytogenetically Normal FLT3‐ITD AML

The mutational oncoprint of recurrent cytogenetic abnormalities in adult patients with de novo acute myeloid leukemia

Adult Chronic Myelomonocytic Leukemia with Trisomy 11: A Case Report

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