|
|
Blood, 1 October 2005, Vol. 106, No. 7, pp. 2484-2490.
Prepublished online as a Blood First Edition Paper on June 14, 2005; DOI 10.1182/blood-2004-09-3667.
 Previous Article | Table of Contents | Next Article 
NEOPLASIA
Targeting FLT3 in primary MLL-gene–rearranged infant acute lymphoblastic leukemia
Ronald W. Stam,
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, and
Rob Pieters
From the Erasmus Medical Center (MC)/Sophia Children's Hospital, Department of Pediatric Oncology/Hematology, Rotterdam, The Netherlands; Institute for Clinical Chemistry, University Hospital Hamburg-Eppendorf and Clinic for Pediatric Hematology and Oncology, University Hospital Hamburg-Eppendorf, Hamburg, Germany; Erasmus MC, Department of Clinical Genetics, Rotterdam, The Netherlands; Department of Clinical Medicine, Prevention and Biotechnologies, Section of Medical Statistics, University of Milano-Bicocca, Monza, Italy; Departments of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA; Harvard Medical School, Boston, MA; Division of Pediatric Hematology/Oncology, Children's Hospital, Boston, MA.
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. (Blood. 2005;106: 2484-2490)
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
This article has been cited by other articles:
|
|
|
|
 
B. W. Robinson, N.-K. V. Cheung, C. P. Kolaris, S. C. Jhanwar, J. K. Choi, N. Osheroff, and C. A. Felix
Prospective tracing of MLL-FRYL clone with low MEIS1 expression from emergence during neuroblastoma treatment to diagnosis of myelodysplastic syndrome
Blood,
April 1, 2008;
111(7):
3802 - 3812.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. C.H. de Vries, R. W. Stam, P. Schneider, C. M. Niemeyer, E. R. van Wering, O. A. Haas, C. P. Kratz, M. L. den Boer, R. Pieters, and M. M. van den Heuvel-Eibrink
Role of mutation independent constitutive activation of FLT3 in juvenile myelomonocytic leukemia
Haematologica,
November 1, 2007;
92(11):
1557 - 1560.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. W. Stam, M. L. den Boer, P. Schneider, M. Meier, H. B. Beverloo, and R. Pieters
D-HPLC analysis of the entire FLT3 gene in MLL rearranged and hyperdiploid acute lymphoblastic leukemia
Haematologica,
November 1, 2007;
92(11):
1565 - 1568.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. W. Stam, P. Schneider, P. de Lorenzo, M. G. Valsecchi, M. L. den Boer, and R. Pieters
Prognostic significance of high-level FLT3 expression in MLL-rearranged infant acute lymphoblastic leukemia
Blood,
October 1, 2007;
110(7):
2774 - 2775.
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. Van Vlierberghe, J. P. P. Meijerink, R. W. Stam, W. van der Smissen, E. R. van Wering, H. B. Beverloo, and R. Pieters
Activating FLT3 mutations in CD4+/CD8- pediatric T-cell acute lymphoblastic leukemias
Blood,
December 15, 2005;
106(13):
4414 - 4415.
[Full Text]
[PDF]
|
|
|
| |
