Detailed analysis of FLT3 expression levels in acute myeloid leukemia.
OBJECTIVE
FLT3 mutations are found in up to 30% of cases of acute myeloid leukemia (AML). Although new FLT3 mutations are being increasing by investigated, the role of FLT3 expression levels in wild type as well as in mutated FLT3 has only been infrequently addressed.


METHODS
To further evaluate the role of FLT3 in AML we investigated FLT3 expression levels in 207 adult AML patients and 8 healthy donors by real-time polymerase chain reaction (PCR). The expression levels were correlated with clinical parameters, FAB types, cytogenetics, flow cytometry, microarray analysis, FLT3 mutations, further molecular aberrations and prognosis.


RESULTS
FLT3 expression levels were different in certain FAB types with increasing levels in the following order: M3<M3v<M6<M2<M4eo<M4<M0<M1<M5a<M5b. These results correlate with the FLT3 receptor surface expression (CD135) detected by flow cytometry (p<0.001), showing the highest CD135 expression in FAB M5. Independent analysis of FLT3 expression in cytogenetic AML subgroups showed the lowest levels in t(15;17) and the highest in the t(11q23) positive AML. In addition, FLT3 expression levels correlated with high percentages of bone marrow blasts (p<0.001) and high leukocyte counts (p<0.001). On the molecular level, no differences in FLT3 expression levels were detected between AML with and without any FLT3 mutation as well as for FAB M5 with or without MLL abnormalities (p=0.495). Furthermore, no significant difference could be found between the group of t(11q23) and MLL-PTD (p=0.180) or between MLL-PTD positive and MLL negative normal karyotypes (p=0.859). In patients with normal cytogenetics no impact or overall survival or event-free survival could be detected (p=0.128 and p=0.305, respectively) regardless of FLT3 muatation status, whereas investigating the group of patients with normal cytogenetics and wild-type FLT3, a clear tendency for a worse overall (p=0.059) and event free (p=0.087) survival was found.


CONCLUSIONS
FLT3 expression levels are correlated with clinical data, genetic subgroups as well as prognosis. Furthermore, our data indicate that FLT3 expression and signaling are closely associated with FAB M5.
Kuchenbauer
Florian
F
Department of Internal Medicine III, Ludwig-Maximilians University of Munich, University Hospital Grosshadern, Munich, Germany.
Kern
Wolfgang
W
Schoch
Claudia
C
Kohlmann
Alexander
A
Hiddemann
Wolfgang
W
Haferlach
Torsten
T
Schnittger
Susanne
S
D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018952:Antigens, CD34 / Q000096:biosynthesis / Q000235:genetics; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D001853:Bone Marrow / Q000473:pathology; D002869:Chromosome Aberrations; D018572:Disease-Free Survival; D004790:Enzyme Induction; D005260:Female; D020440:Gene Duplication; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D007621:Karyotyping; D007948:Leukemia, Monocytic, Acute / Q000235:genetics / Q000473:pathology; D007951:Leukemia, Myeloid / Q000145:classification / Q000201:enzymology* / Q000235:genetics / Q000401:mortality; D007958:Leukocyte Count; D015993:Life Tables; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D016133:Polymerase Chain Reaction; D011379:Prognosis; D016016:Proportional Hazards Models; D012333:RNA, Messenger / Q000096:biosynthesis / Q000378:metabolism; D012334:RNA, Neoplasm / Q000096:biosynthesis / Q000378:metabolism; D016019:Survival Analysis; D020080:Tandem Repeat Sequences; D051941:fms-Like Tyrosine Kinase 3 / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics
D018952:Antigens, CD34; D000970:Antineoplastic Agents; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3