Trisomy 13 correlates with RUNX1 mutation and increased FLT3 expression in AML-M0 patients

Silva, Fernando P.G.; Lind, Anne-Li; Brouwer-Mandema, Geeske; Valk, Peter J.M.; Giphart-Gassler, Micheline

doi:10.3324/haematol.11296

Cited by 28 publications

(33 citation statements)

References 19 publications

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“…In fact, the only mutation associated with mutations in RUNX1 was trisomy 13, as observed by us and others. 19,34 Trisomy 13 is also correlated with higher FLT3 expression and is probably another factor contributing to proliferative advantage in AML-M0.…”

Section: Discussionmentioning

confidence: 99%

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Genome wide molecular analysis of minimally differentiated acute myeloid leukemia

et al. 2009

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Section: Discussionmentioning

confidence: 99%

“…8,19 KIT D816V mutations (exon 17) were screened using the HinfI restriction assay. 20 All patients were screened for these mutations.…”

Section: Mutation Screeningmentioning

confidence: 99%

Genome wide molecular analysis of minimally differentiated acute myeloid leukemia

et al. 2009

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“…Since AML M0 is cytogenetically diverse, the study by Silva et al is limited by the influence of multiple cytogenetic aberrations including complex karyotype and trisomy 13. 8,20 Furthermore, Silva et al limited their mutation screening to the RUNT-domain of RUNX1, which likely resulted in an underestimation of the RUNX1 mutation burden. In contrast, our study of RUNX1 mutations in CN-AML is not biased by the impact of cytogenetic aberrations on gene expression and an underestimation of RUNX1 mutations (the complete coding sequence of RUNX1 gene was sequenced).…”

Section: © F E R R a T A S T O R T I F O U N D A T I O Nmentioning

confidence: 99%

RUNX1 mutations in cytogenetically normal acute myeloid leukemia are associated with a poor prognosis and up-regulation of lymphoid genes

et al. 2012

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The online version of this article has a Supplementary Appendix. BackgroundThe RUNX1 (AML1) gene is a frequent mutational target in myelodysplastic syndromes and acute myeloid leukemia. Previous studies suggested that RUNX1 mutations may have pathological and prognostic implications. Design and MethodsWe screened 93 patients with cytogenetically normal acute myeloid leukemia for RUNX1 mutations by capillary sequencing of genomic DNA. Mutation status was then correlated with clinical data and gene expression profiles. ResultsWe found that 15 out of 93 (16.1%) patients with cytogenetically normal acute myeloid leukemia had RUNX1 mutations. Seventy-three patients were enrolled in the AMLCG-99 trial and carried ten RUNX1 mutations (13.7%). Among these 73 patients RUNX1 mutations were significantly associated with older age, male sex, absence of NPM1 mutations and presence of MLL-partial tandem duplications. Moreover, RUNX1-mutated patients had a lower complete remission rate (30% versus 73% P=0.01), lower relapse-free survival rate (3-year relapse-free survival 0% versus 30.4%; P=0.002) and lower overall survival rate (3-year overall survival 0% versus 34.4%; P<0.001) than patients with wild-type RUNX1. RUNX1 mutations remained associated with shorter overall survival in a multivariate model including age and the European LeukemiaNet acute myeloid leukemia genetic classification as covariates. Patients with RUNX1 mutations showed a unique gene expression pattern with differential expression of 85 genes. The most prominently up-regulated genes in patients with RUNX1-mutated cytogenetically normal acute myeloid leukemia include lymphoid regulators such as HOP homeobox (HOPX), deoxynucleotidyltransferase (DNTT, terminal) and B-cell linker (BLNK), indicating lineage infidelity. ConclusionsOur findings firmly establish that RUNX1 mutations are a marker of poor prognosis and provide insights into the pathogenesis of RUNX1 mutation-positive acute myeloid leukemia. (ClinicalTrials.gov identifier NCT00266136)Key words: RUNX1, mutations, prognosis, acute myeloid leukemia. Haematologica 2012;97(12):1909-1915. doi:10.3324/haematol.2012 This is an open-access paper. CitationRUNX1 mutations in cytogenetically normal acute myeloid leukemia are associated with a poor prognosis and up-regulation of lymphoid genes ABSTRACT© F e r r a t a S t o r t i F o u n d a t i o n

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“…RUNX1 DNA-specific polymerase chain reaction (PCR) products corresponding to the Runt domain and to the COOH-terminal regions (exons 3 to 8) were obtained using previously described flanking intronic forward/reverse primers. 23 After purification on QIAquick column (Qiagen), PCR fragments were sequenced on both strands according to standard methods. The sequence of each identified mutation was confirmed on another independent PCR product.…”

Section: Identification Of Runx1 Mutationsmentioning

confidence: 99%

RUNX1 DNA-binding mutations and RUNX1-PRDM16 cryptic fusions in BCR-ABL+ leukemias are frequently associated with secondary trisomy 21 and may contribute to clonal evolution and imatinib resistance

Roche‐Lestienne

Deluche²,

Corm

et al. 2008

Blood

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Trisomy 13 correlates with RUNX1 mutation and increased FLT3 expression in AML-M0 patients

Cited by 28 publications

References 19 publications

Genome wide molecular analysis of minimally differentiated acute myeloid leukemia

Genome wide molecular analysis of minimally differentiated acute myeloid leukemia

RUNX1 mutations in cytogenetically normal acute myeloid leukemia are associated with a poor prognosis and up-regulation of lymphoid genes

RUNX1 DNA-binding mutations and RUNX1-PRDM16 cryptic fusions in BCR-ABL+ leukemias are frequently associated with secondary trisomy 21 and may contribute to clonal evolution and imatinib resistance

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