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Targeting FLT3 in primary MLL-gene-rearranged infant acute lymphoblastic leukemia
Ronald W Stam1, Monique L den Boer, Pauline Schneider
1Erasmus Medical Center/Sophia Children's Hospital, Pediatric Oncology/Hematology, Rotterdam, The Netherlands.
Abstract:
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.
Insights
Infant acute lymphoblastic leukemia (ALL) with MLL gene rearrangements shows high FLT3 expression. FLT3 inhibitors like PKC412 show promise, though additional kinase inhibition may be involved in their efficacy.
Area of Science:
- Pediatric Oncology
- Molecular Biology
- Hematology
Background:
- Infant acute lymphoblastic leukemia (ALL) with MLL gene rearrangements presents poor prognosis and drug resistance.
- FLT3 (Fms-like tyrosine kinase 3) is a potential therapeutic target in MLL-rearranged ALL.
Purpose of the Study:
- To investigate FLT3 expression levels in infant MLL-rearranged ALL.
- To assess the sensitivity of infant MLL-rearranged ALL cells to the FLT3 inhibitor PKC412.
- To explore the mechanism of FLT3 activation and drug response in this patient group.
Main Methods:
- Quantified FLT3 expression in infant MLL-rearranged ALL cells via comparative analysis.
- Assessed cellular sensitivity to the FLT3 inhibitor PKC412.
- Analyzed FLT3 phosphorylation and mutations (including ITDs) in leukemic cells.
Main Results:
- Significantly higher FLT3 expression was observed in infant MLL-rearranged ALL compared to other ALL groups.
- Infant MLL-ALL cells demonstrated greater sensitivity to PKC412 than non-infant ALL cells.
- Ligand-independent FLT3 activation was linked to high FLT3 expression, despite rare mutations.
Conclusions:
- High FLT3 expression in infant MLL-rearranged ALL suggests potential for FLT3 inhibitor therapy.
- PKC412 exhibits cytotoxic effects beyond FLT3 inhibition, potentially involving other kinases.
- Targeting FLT3 in infant MLL-ALL warrants further investigation, considering multi-kinase inhibitory activity.
