Korean J Lab Med.  2006 Aug;26(4):233-240. 10.3343/kjlm.2006.26.4.233.

FLT3 Gene Mutations as a Prognostic Factor for Acute Myeloid Leukemia

• Chang SH
• Lee NY
• Kim DH
• Sohn SK
• Suh JS

• KMID: 2238828
• DOI: http://doi.org/10.3343/kjlm.2006.26.4.233

Abstract

BACKGROUND: Two distinct types of fms-like tyrosine kinase 3 (FLT3) gene mutations have been identified in acute myeloid leukemia (AML): D835 and internal tandem duplication (ITD) mutations. These mutations are known to cause the proliferation of leukemic cells and inhibit the apoptosis of leukemic cells due to ligand-independent activation of their receptors. Therefore, the current study attempted to investigate the frequency of FLT3 gene mutations and their prognostic implications for AML in terms of treatment response, survival, and relapse.
METHODS
Polymerase chain reaction (PCR) was performed to detect D835 and ITD mutations in 84 newly diagnosed AML patients from February 2001 to October 2004. Restriction fragment length polymorphism (RFLP) and direct sequencing were performed to analyze the D835 mutations. The results were examined based on a comparison with previously known prognostic factors, and the treatment outcomes analyzed according to the existence of the mutations in relation to the event free survival (EFS), overall survival (OS), and complete remission (CR) rates.
RESULTS
D835 and IDT mutations were detected in 4.7% (4/84) and 19.0% (16/84), respectively, of the AML patients. The FLT3 gene mutations were not found to be associated with previously known prognostic factors, such as the WBC count, age, and cytogenetic risk group, but were associated with the lactate dehydrogenase levels. The EFS and OS rates were also significantly lower in the FLT3 gene mutation group, especially in AML with normal karyotypes.
CONCLUSIONS
FLT3 gene mutations were observed in 23.8% of AML patients and appeared to have a prognostic implication on patient survival. Accordingly, the presence of FLT3 gene mutations, which could be tested easily by using PCR/RFLP methods, should be investigated routinely at the time of diagnosis.

Keyword

FLT3; Acute myeloid leukemia; Prognostic implications

MeSH Terms

Apoptosis
Cytogenetics
Diagnosis
Disease-Free Survival
fms-Like Tyrosine Kinase 3
Humans
Karyotype
L-Lactate Dehydrogenase
Leukemia, Myeloid, Acute*
Polymerase Chain Reaction
Polymorphism, Restriction Fragment Length
Recurrence
L-Lactate Dehydrogenase
fms-Like Tyrosine Kinase 3

Figure

• 

  Fig. 1. Results of D835 mutations in the FLT3 gene. The amplified product (lane 1) of wild type was digested to two bands (68 bp and 46 bp) by EcoRV in lane 2. When amplified products contained D835 mutations, undigested bands (114 bp) were visualized on low melting point agarose gel electrophoresis (lane 3 and 4). Lane SM, molecular size markers (100 bp DNA ladder).

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  Fig. 2. Sequence analysis in 3 patients with D835 mutations in the FLT3 gene. The results revealed that the first nucleotide G of codon 835 was substituted with T. Abbreviation: FLT3, fms-like tyrosine kinase 3.

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  Fig. 3. Results of ITD mutations in the FLT3 gene. The amplified product of wild type was shown in lane 5. When amplified products contained ITD mutations, another bands were visualized on low melting point agarose gel electrophoresis (lane 1–4). Lane SM, molecular size marker (100 bp DNA ladder).

• 

  Fig. 4. Event free (A) and overall (B) survival in patients with AML according to the FLT3 mutation status.

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  Fig. 5. Event free (A) and overall (B) survival rate in patients with normal karyotype in AML according to the FLT3 mutation status. Abbreviations: AML, acute myeloid leukemia; FLT3, fms-like tyrosine kinase 3; ITD, internal tandem duplication; FLT3+, FLT3 mutation; FLT3-, no FLT3 mutation.

Reference

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