Targeting FLT3 in primary MLL-gene-rearranged infant acute lymphoblastic leukemia - PubMed (original) (raw)
. 2005 Oct 1;106(7):2484-90.
doi: 10.1182/blood-2004-09-3667. Epub 2005 Jun 14.
Monique L den Boer, Pauline Schneider, Peter Nollau, Martin Horstmann, H Berna Beverloo, Ella van der Voort, Maria G Valsecchi, Paola de Lorenzo, Stephen E Sallan, Scott A Armstrong, Rob Pieters
Affiliations
- PMID: 15956279
- DOI: 10.1182/blood-2004-09-3667
Free article
Targeting FLT3 in primary MLL-gene-rearranged infant acute lymphoblastic leukemia
Ronald W Stam et al. Blood. 2005.
Free article
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.
Similar articles
- Inhibition of FLT3 in MLL. Validation of a therapeutic target identified by gene expression based classification.
Armstrong SA, Kung AL, Mabon ME, Silverman LB, Stam RW, Den Boer ML, Pieters R, Kersey JH, Sallan SE, Fletcher JA, Golub TR, Griffin JD, Korsmeyer SJ. Armstrong SA, et al. Cancer Cell. 2003 Feb;3(2):173-83. doi: 10.1016/s1535-6108(03)00003-5. Cancer Cell. 2003. PMID: 12620411 - FLT3 is implicated in cytarabine transport by human equilibrative nucleoside transporter 1 in pediatric acute leukemia.
Català A, Pastor-Anglada M, Caviedes-Cárdenas L, Malatesta R, Rives S, Vega-García N, Camós M, Fernández-Calotti P. Català A, et al. Oncotarget. 2016 Aug 2;7(31):49786-49799. doi: 10.18632/oncotarget.10448. Oncotarget. 2016. PMID: 27391351 Free PMC article. - Targeting PRMT1-mediated FLT3 methylation disrupts maintenance of MLL-rearranged acute lymphoblastic leukemia.
Zhu Y, He X, Lin YC, Dong H, Zhang L, Chen X, Wang Z, Shen Y, Li M, Wang H, Sun J, Nguyen LX, Zhang H, Jiang W, Yang Y, Chen J, Müschen M, Chen CW, Konopleva MY, Sun W, Jin J, Carlesso N, Marcucci G, Luo Y, Li L. Zhu Y, et al. Blood. 2019 Oct 10;134(15):1257-1268. doi: 10.1182/blood.2019002457. Blood. 2019. PMID: 31395602 Free PMC article. - MLL-Rearranged Acute Lymphoblastic Leukemia.
El Chaer F, Keng M, Ballen KK. El Chaer F, et al. Curr Hematol Malig Rep. 2020 Apr;15(2):83-89. doi: 10.1007/s11899-020-00582-5. Curr Hematol Malig Rep. 2020. PMID: 32350732 Review. - Midostaurin/PKC412 for the treatment of newly diagnosed FLT3 mutation-positive acute myeloid leukemia.
Luskin MR, DeAngelo DJ. Luskin MR, et al. Expert Rev Hematol. 2017 Dec;10(12):1033-1045. doi: 10.1080/17474086.2017.1397510. Epub 2017 Oct 30. Expert Rev Hematol. 2017. PMID: 29069942 Review.
Cited by
- Therapeutic opportunities and targets in childhood leukemia.
Ford AM, Martínez-Ramírez A. Ford AM, et al. Clin Transl Oncol. 2006 Aug;8(8):560-5. doi: 10.1007/s12094-006-0061-5. Clin Transl Oncol. 2006. PMID: 16952844 Review. - High-risk childhood acute lymphoblastic leukemia.
Bhojwani D, Howard SC, Pui CH. Bhojwani D, et al. Clin Lymphoma Myeloma. 2009;9 Suppl 3(Suppl 3):S222-30. doi: 10.3816/CLM.2009.s.016. Clin Lymphoma Myeloma. 2009. PMID: 19778845 Free PMC article. Review. - Novel targeted drug therapies for the treatment of childhood acute leukemia.
Brown P, Hunger SP, Smith FO, Carroll WL, Reaman GH. Brown P, et al. Expert Rev Hematol. 2009 Apr 1;2(9):145. doi: 10.1586/ehm.09.1. Expert Rev Hematol. 2009. PMID: 20126514 Free PMC article. - Irinotecan Induces Disease Remission in Xenograft Mouse Models of Pediatric _MLL_-Rearranged Acute Lymphoblastic Leukemia.
Kerstjens M, Garrido Castro P, Pinhanços SS, Schneider P, Wander P, Pieters R, Stam RW. Kerstjens M, et al. Biomedicines. 2021 Jun 23;9(7):711. doi: 10.3390/biomedicines9070711. Biomedicines. 2021. PMID: 34201500 Free PMC article. - MLL-Rearranged Leukemias-An Update on Science and Clinical Approaches.
Winters AC, Bernt KM. Winters AC, et al. Front Pediatr. 2017 Feb 9;5:4. doi: 10.3389/fped.2017.00004. eCollection 2017. Front Pediatr. 2017. PMID: 28232907 Free PMC article. Review.
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Other Literature Sources
Miscellaneous