An FLT3 gene-expression signature predicts clinical outcome in normal karyotype AML

Bullinger, Lars; Döhner, Konstanze; Kranz, Raphael; Stirner, Christoph; Fröhling, Stefan; Scholl, Claudia; Kim, Young H.; Schlenk, Richard F.; Tibshirani, Robert; Döhner, Hartmut; Pollack, Jonathan R.

doi:10.1182/blood-2007-09-115055

Cited by 86 publications

(63 citation statements)

References 45 publications

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“…Initial studies have provided remarkable results by identifying novel AML subgroups and prognostic gene expression signatures. [7][8][9][10][11] Furthermore, a recent gene expression study observed differential expression of genes coding for the DNA methylation enzymes (regulators) DNMT3A and DNMT3B. 7 Because DNA methylation is recognized as a key regulatory element of gene expression, [12][13][14] these findings point to a potential pathogenic role of aberrant DNA methylation patterns in distinct subgroups of AML patients.…”

Section: Introductionmentioning

confidence: 99%

Quantitative DNA methylation predicts survival in adult acute myeloid leukemia

Bullinger

Ehrich

Döhner

et al. 2010

Blood

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Acute myeloid leukemia (AML) is characterized by molecular heterogeneity that is not fully reflected in the current classification system. Recent insights point toward a significant role of aberrant DNA methylation in leukemogenesis. Therefore, we investigated the prognostic impact of DNA methylation in AML. To screen for promoter methylation in AML we applied a combination of base-specific cleavage biochemistry and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS), a powerful methodology allowing for quantitatively investigating DNA methylation status in a large series of both promoter regions and leukemia samples. We analyzed 92 genomic regions in 182 patient samples, correlated findings with clinical and molecular data, and validated the results in an independent cohort of 74 AML samples. Using this approach, we were able to identify novel leukemia subgroups based on distinct DNA methylation patterns. Furthermore, we defined a methylation-based outcome predictor for patient survival (P < .01) that in multivariable analysis provided independent prognostic information (hazard ratio, 1.52; 95% CI, 1.06-2.16). Here, we report the first large-scale methylation-based outcome predictor in AML, and thereby our findings support the use of genomic methylation markers for improved molecular classification and prognostication in adult AML. (Blood. 2010;115:636-642)

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Section: Introductionmentioning

confidence: 99%

Quantitative DNA methylation predicts survival in adult acute myeloid leukemia

Bullinger

Ehrich

Döhner

et al. 2010

Blood

Self Cite

148

117

View full text Add to dashboard Cite

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“…19 For example, in CN-AML patients predicted to have a FLT3-ITD mutation based on the resulting gene expression patterns, the class prediction profiles outperformed the presence of the molecular marker FLT3-ITD with regard to impact on clinical outcome. 20 Furthermore, in CEBPAmutated CN-AMLs, only CEBPA double mutants, but not single mutants, seem to exhibit a characteristic gene expression profile. 21 In addition to its role in class prediction, GEP has proved to be a very powerful means for the discovery of novel leukemia subclasses (class discovery).…”

Section: Gep In Adult Amlmentioning

confidence: 99%

Gene expression profiling in MDS and AML: potential and future avenues

et al. 2011

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“…21 Additionally, a previous gene expression profiling study showed that not all FLT3-ITD cells harbor a respective ITD-specific gene expression pattern, suggesting that other alterations in FLT3 or other genes such as JM domain point mutation or TKD (K663Q) mutation would have to account for the FLT3 pathway activation signature in these cases. 22 Higher mutant/wild-type allelic ratio of FLT3-ITD mutation has been shown to correlate with more aggressive disease, higher early relapse rate in the first year and decreased overall survival. 21,23 Unfortunately, these data were not available for our patients and were not reported in this study; we could not, therefore, identify any potential variation in the MRD detection between patients with high and low allele burden.…”

Section: -17mentioning

confidence: 99%