|
|
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 | Next Article 
Submitted September 27, 2004
Accepted May 25, 2005
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
Department of Pediatric Oncology / Hematology, Erasmus MC / Sophia Children's Hospital, Rotterdam, The Netherlands
University Hospital Hamburg-Eppendorf, Institute for Clinical Chemistry, Hamburg, Germany
University Hospital Hamburg-Eppendorf, Clinic for Pediatric Hematology and Oncology, Hamburg, Germany
Department of Clinical Genetics, Erasmus MC, 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, Harvard Medical School, Boston, Massachusetts, USA; Division of Pediatric Hematology/Oncology, Children's Hospital, Boston, Massachusetts, USA
* Corresponding author; email: m.l.denboer{at}erasmusmc.nl.
Acute lymphoblastic leukemia (ALL) in infants is characterized by rearrangements of the 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 infant MLL patients (n=41) to be significantly higher compared to both infant (n=8) (p< 0.001) and non-infant ALL patients (n=23) (p=0.001) carrying germ line MLL genes. Furthermore, leukemic cells from infant MLL patients were significantly more sensitive to the FLT3 inhibitor PKC412 than non-infant ALL cells, and at least as sensitive as ITD positive AML cells (MTT-assay). Surprisingly, activation loop mutations only occurred in ~3% (1/36) of the cases and no FLT3/ITDs were observed. However, measuring FLT3 phosphorylation in infant MLL patients 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 like PKC412. However, at concentrations of PKC412 minimally required to fully inhibit FLT3 phosphorylation, the cytotoxic effects were only fractional. Thus, PK412 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.
 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]
|
|
|
| |
