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Published on: March 26, 2018
Delineation and molecular characterization of acute myeloid leukemia patients with coduplication of FLT3 and MLL
Lene Hyldahl Olesen1, Charlotte Guldborg Nyvold, Anni Aggerholm
1Department of Hematology, Aarhus University Hospital, Denmark.
Abstract:
Partial tandem (PTD) and internal tandem duplications (ITD) of the MLL or FLT3 genes respectively, have been demonstrated in acute myeloid leukemia (AML). While occurrence of each of these PTD/ITD seem to confer an unfavorable prognosis, the literature contains only sparse information of the occurrence and the prognosis of simultaneous PTD/ITD of these genes. We have therefore attempted to determine the presence and its consequence in AML and with the further aim of characterizing such patients with respect to other genetic aberrations and to prototype variables in this disease. We analyzed blast cells from 250 adult patients treated at the same institution during a 15-year period for FLT3 ITD and MLL PTD and the duplications were found in 24% and 4%, respectively. The four co-duplicated cases (2%) did not differ with respect to sex, age, FAB-type, or immunophenotype, promoter methylation of p15, E-cadherin (CDH1), Estrogen receptor, MDR1, expression of apoptosis-related or multidrug resistance-related genes, though a trend toward decreased gene expression of MDR1 was observed. Two of the patients had a normal karyotypic analysis, while the remaining two showed aberrations in chromosome 11, one with trisomy 11 and the other with a der (11). The extensive molecular characterization of FLT3/MLL coduplicated patients presented here indicates that, even though they do not differ molecularly from the groups of patients with single ITDs, their prognosis and overall survival is universally poor. More patients are needed to determine whether coduplication has independent clinical implications compared to patients with single ITD/PTD.
Insights
Simultaneous internal tandem duplications (ITD) of FLT3 and partial tandem duplications (PTD) of MLL in acute myeloid leukemia (AML) are rare but associated with a poor prognosis. Further research is needed to confirm independent clinical implications.
Area of Science:
- Hematology
- Molecular Biology
- Oncology
Background:
- Internal tandem duplications (ITD) of FLT3 and partial tandem duplications (PTD) of MLL are known genetic alterations in acute myeloid leukemia (AML).
- These individual genetic aberrations are associated with an unfavorable prognosis in AML patients.
- Limited data exists regarding the co-occurrence and prognostic impact of simultaneous FLT3 ITD and MLL PTD.
Purpose of the Study:
- To determine the frequency and clinical significance of co-occurring FLT3 ITD and MLL PTD in adult AML.
- To characterize patients with both genetic alterations concerning other molecular aberrations and clinical variables.
- To evaluate the prognostic impact of simultaneous FLT3 ITD and MLL PTD on patient survival.
Main Methods:
- Analysis of blast cells from 250 adult AML patients over a 15-year period.
- Detection of FLT3 ITD and MLL PTD using molecular techniques.
- Assessment of other genetic aberrations, including karyotyping and gene methylation/expression profiling.
- Correlation of genetic findings with clinical parameters and patient survival.
Main Results:
- FLT3 ITD and MLL PTD were found in 24% and 4% of patients, respectively.
- Four cases (2%) exhibited co-occurrence of both FLT3 ITD and MLL PTD.
- Co-duplicated cases showed no significant differences in FAB-type, immunophenotype, or methylation status of key genes (p15, CDH1, Estrogen receptor, MDR1).
- A trend towards decreased MDR1 gene expression was observed in co-duplicated cases.
- Two co-duplicated patients had normal karyotypes, while two had chromosome 11 aberrations.
- Patients with FLT3/MLL coduplication had a universally poor prognosis and overall survival.
Conclusions:
- Co-occurrence of FLT3 ITD and MLL PTD in AML is infrequent.
- Despite molecular similarities to patients with single ITDs, coduplicated patients exhibit universally poor survival.
- Larger studies are required to ascertain if coduplication has independent prognostic value compared to single ITD/PTD.
