-
Blood.
2006 Mar 1;107(5):1791-9. Epub 2005 Oct 27.
KIT-D816 mutations in
AML1-ETO-positive AML are associated with impaired
event-free and overall survival.
Schnittger S,
Kohl TM, Haferlach T, Kern W, Hiddemann W,
Spiekermann K, Schoch C.Laboratory of Leukemia
Diagnostics and Clinical Cooperative Group Leukemia,
Department of Medicine III, University Hospital
Grosshadern, Ludwig-Maximilians University, Munich,
Germany. susanne.schnittger@mll-online.com
Mutations in codon D816 of the
KIT gene represent a recurrent genetic alteration in
acute myeloid leukemia (AML). To clarify the
biologic implication of activation loop mutations of
the KIT gene, 1940 randomly selected AML patients
were analyzed. In total, 33 (1.7%) of 1940 patients
were positive for D816 mutations. Of these 33
patients, 8 (24.2%) had a t(8;21), which was
significantly higher compared with the subgroup
without D816 mutations. Analyses of genetic
subgroups showed that KIT-D816 mutations were
associated with t(8;21)/AML1-ETO and other rare AML1
translocations. In contrast, other activating
mutations like FLT3 and NRAS mutations were very
rarely detected in AML1-rearranged leukemia. KIT
mutations had an independent negative impact on
overall (median 304 vs 1836 days; P = .006) and
event-free survival (median 244 vs 744 days; P =
.003) in patients with t(8;21) but not in patients
with a normal karyotype. The KIT-D816V receptor
expressed in Ba/F3 cells was resistant to growth
inhibition by the selective PTK inhibitors imatinib
and SU5614 but fully sensitive to PKC412. Our
findings clearly indicate that activating mutations
of receptor tyrosine kinases are associated with
distinct genetic subtypes in AML. The KIT-D816
mutations confer a poor prognosis to
AML1-ETO-positive AML and should therefore be
included in the diagnostic workup. Patients with
KIT-D816-positive/AML1-ETO-positive AML might
benefit from early intensification of treatment or
combination of conventional chemotherapy with KIT
PTK inhibitors.
PMID: 16254134 [PubMed - indexed for
MEDLINE]