Leukemia  1997 Sep;11(9):1442-6 

Tandem duplications of the FLT3 receptor gene are associated with leukemic
transformation of myelodysplasia.

Horiike S, Yokota S, Nakao M, Iwai T, Sasai Y, Kaneko H, Taniwaki M, Kashima K,
Fujii H, Abe T, Misawa S.

Department of Internal Medicine III, Kyoto Prefectural University of Medicine,
Japan.

We recently reported an internal tandem duplication of the human flt3 receptor
gene (FLT3) as a somatic mutation in 17% of acute myelogenous leukemia (AML).
The present study revealed the duplication at the juxtamembrane and the first
tyrosine kinase domains of FLT3 in seven of 92 (8%) patients with
myelodysplastic syndrome (MDS) and AML with trilineage myelodysplasia
(AML/TMDS), the diseases which may represent neoplastic changes of pluripotent
stem cells. A tandem duplication of exon 11 of FLT3 was harbored by two of 58
(3%) patients with MDS and five of 34 (15%) with overt leukemia, including
MDS-derived leukemia, AML/TMDS and therapy-related leukemia. Although the
duplicated regions varied within exon 11 in each case, they occurred in-frame,
and altered mRNA expressions were demonstrated by reverse-transcription
polymerase chain reaction. Two cases of MDS with a FLT3 duplication transformed
to overt leukemia within a few months. Longitudinal analyses in two other
patients with leukemia revealed that the duplication was a late genetic event
during the disease course; one of whom showed two independent duplications of
FLT3 at the terminal therapy-resistant phase. Of seven patients with the FLT3
duplication, six had abnormal karyotypes, and four harbored a point mutation of
the N-RAS and/or TP53 genes. Patients with FLT3 mutations have poor prognoses.
This study uncovered the fact that the accumulation of genetic events, including
FLT3 duplication, correlates with leukemic transformation from antecedent
myelodysplasia and with subsequent disease progression.

PMID: 9305595 [PubMed - indexed for MEDLINE]