Acute lymphoblastic leukemia (ALL) in infants is characterized by
rearrangements of the mixed lineage leukemia (MLL) gene, drug resistance,
and a poor treatment outcome. Therefore, novel therapeutic strategies are
needed to improve prognosis. Recently, we showed that FLT3 is highly
expressed in MLL rearranged ALL (MLL). Here we demonstrate FLT3 expression
in infants with MLL (n = 41) to be significantly higher compared to both
infant (n = 8; P < .001) and noninfant patients with ALL (n = 23; P =
.001) carrying germline MLL genes. Furthermore, leukemic cells from
infants with MLL were significantly more sensitive to the Fms-like
tyrosine kinase 3 (FLT3) inhibitor PKC412 (N-benzoyl staurosporine) than
noninfant ALL cells, and at least as sensitive as internal tandem
duplication-positive (ITD+) AML cells. Surprisingly, activation loop
mutations only occurred in about 3% (1 of 36) of the cases and no
FLT3/ITDs were observed. However, measuring FLT3 phosphorylation in
infants with MLL expressing varying levels of wild-type FLT3 revealed that
high-level FLT3 expression is associated with ligand-independent FLT3
activation. This suggests that infant MLL cells displaying activated FLT3
as a result of overexpression can be targeted by FLT3 inhibitors such as
PKC412. However, at concentrations of PKC412 minimall
