Targeting FLT3 in primary MLL-gene-rearranged infant acute lymphoblastic leukemia.
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 minimally required to fully inhibit FLT3 phosphorylation, the cytotoxic effects were only fractional. Thus, PKC412-induced apoptosis in infant MLL cells is unlikely to be a consequence of FLT3 inhibition alone but may involve inhibition of multiple other kinases by this drug.
Stam
Ronald W
RW
Erasmus Medical Center/Sophia Children's Hospital, Pediatric Oncology/Hematology, Rotterdam, The Netherlands.
den Boer
Monique L
ML
Schneider
Pauline
P
Nollau
Peter
P
Horstmann
Martin
M
Beverloo
H Berna
HB
van der Voort
Ella
E
Valsecchi
Maria G
MG
de Lorenzo
Paola
P
Sallan
Stephen E
SE
Armstrong
Scott A
SA
Pieters
Rob
R
D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D001665:Binding Sites; D045744:Cell Line, Tumor; D004247:DNA / Q000737:chemistry / Q000378:metabolism; D004252:DNA Mutational Analysis; D017931:DNA Primers / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance; D004791:Enzyme Inhibitors / Q000494:pharmacology; D020440:Gene Duplication; D015321:Gene Rearrangement; D006801:Humans; D047468:Immunoprecipitation; D017404:In Situ Hybridization, Fluorescence; D007223:Infant; D007231:Infant, Newborn; D008024:Ligands; D009154:Mutation; D010766:Phosphorylation; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics*; D011379:Prognosis; D012313:RNA / Q000737:chemistry / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017422:Sequence Analysis, DNA; D019311:Staurosporine / Q000031:analogs & derivatives / Q000494:pharmacology; D013778:Tetrazolium Salts / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology
D000970:Antineoplastic Agents; D017931:DNA Primers; D004791:Enzyme Inhibitors; D008024:Ligands; D013778:Tetrazolium Salts; D013844:Thiazoles; D012313:RNA; D004247:DNA; C022616:thiazolyl blue; D019311:Staurosporine; C059539:midostaurin