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Published on: September 20, 2016
Gene expression profiling identifies FLT3 mutation-like cases in wild-type FLT3 acute myeloid leukemia
Adrián Mosquera Orgueira1,2,3, Andrés Peleteiro Raíndo1,2,3, Miguel Cid López1,2,3
1Health Research Institute of Santiago de Compostela (IDIS), Santiago, Spain.
Background:
FLT3 mutation is present in 25-30% of all acute myeloid leukemias (AML), and it is associated with adverse outcome. FLT3 inhibitors have shown improved survival results in AML both as upfront treatment and in relapsed/refractory disease. Curiously, a variable proportion of wild-type FLT3 patients also responded to these drugs.
Methods:
We analyzed 6 different transcriptomic datasets of AML cases. Differential expression between mutated and wild-type FLT3 AMLs was performed with the Wilcoxon-rank sum test. Hierarchical clustering was used to identify FLT3-mutation like AMLs. Finally, enrichment in recurrent mutations was performed with the Fisher's test.
Results:
A FLT3 mutation-like gene expression pattern was identified among wild-type FLT3 AMLs. This pattern was highly enriched in NPM1 and DNMT3A mutants, and particularly in combined NPM1/DNMT3A mutants.
Conclusions:
We identified a FLT3 mutation-like gene expression pattern in AML which was highly enriched in NPM1 and DNMT3A mutations. Future analysis about the predictive role of this biomarker among wild-type FLT3 patients treated with FLT3 inhibitors is envisaged.
Insights
A specific gene expression pattern in acute myeloid leukemia (AML) mimics FLT3 mutations, even in wild-type FLT3 cases. This pattern is linked to NPM1 and DNMT3A mutations, suggesting potential therapeutic insights.
Area of Science:
- Hematology
- Molecular Biology
- Oncology
Background:
- FMS-like tyrosine kinase 3 (FLT3) mutations occur in 25-30% of acute myeloid leukemia (AML) cases and are linked to poor prognosis.
- FLT3 inhibitors have demonstrated improved survival in AML patients, both in initial treatment and in relapsed/refractory settings.
- A subset of AML patients with wild-type FLT3 also exhibit responses to FLT3 inhibitors, indicating complex underlying biology.
Purpose of the Study:
- To investigate the molecular underpinnings of FLT3 inhibitor response in AML, particularly in patients without FLT3 mutations.
- To identify gene expression patterns in wild-type FLT3 AML that resemble those found in FLT3-mutated AML.
- To explore the association of this FLT3 mutation-like gene expression pattern with other common AML mutations.
Main Methods:
- Analysis of six transcriptomic datasets from AML patient cohorts.
- Differential gene expression analysis between FLT3-mutated and wild-type FLT3 AML using the Wilcoxon-rank sum test.
- Hierarchical clustering to identify AML cases with a FLT3-mutation-like gene expression profile.
- Fisher's exact test to assess enrichment of recurrent mutations within identified AML subgroups.
Main Results:
- Identification of a distinct gene expression pattern in wild-type FLT3 AML that mimics the expression profile of FLT3-mutated AML.
- This FLT3 mutation-like gene expression pattern was significantly enriched in AML cases harboring NPM1 mutations.
- The pattern was also highly prevalent in cases with DNMT3A mutations, and especially in those with combined NPM1 and DNMT3A mutations.
Conclusions:
- A FLT3 mutation-like gene expression signature has been identified in AML, independent of actual FLT3 mutations.
- This signature is strongly associated with NPM1 and DNMT3A mutations, suggesting a potential molecular link.
- Further research is warranted to evaluate the predictive value of this biomarker in wild-type FLT3 AML patients treated with FLT3 inhibitors.
