FLT3 inhibition in t(4;11)+ adult acute lymphoid leukaemia.
The present study was designed to investigate, in t(4;11)+ adult lymphoid leukaemia (ALL) blast cells, the pathogenetic role of the FLT3 protein, its level of mRNA and protein expression, the degree of constitutive phosphorylation, the possible presence of mutations of the sequence, the capacity of signal transduction and the potential therapeutic role of specific inhibitors. We evaluated nine adult ALL patients carrying this translocation. The increased FLT3 mRNA levels, determined by oligonucleotide microarray analysis, was in agreement with the increased protein expression evaluated by Western blot. The protein was constitutively phosphorylated in all cases analysed. Polymerase chain reaction detected no internal tandem duplication or point mutations. The signal transduction apparatus, after stimulation with the specific ligand, was preserved. We then investigated the effect of specific FLT3 inhibition on signal transduction and survival. The PKC412 inhibitor specifically inhibited ligand-induced phosphorylation; the same inhibitor reduced the survival of leukaemic cells when compared with untreated cells. These data indicate that the FLT3 protein might play a role in this subgroup of ALL with a particularly poor prognosis. Specific inhibition of the kinase receptor must be hypothesised as an innovative therapeutic tool for t(4;11)+ ALL patients.
Torelli
Giovanni F
GF
Division of Haematology, Department of Cellular Biotechnologies and Haematology, University of Rome La Sapienza, Rome, Italy.
Guarini
Anna
A
Porzia
Alessandra
A
Chiaretti
Sabina
S
Tatarelli
Caterina
C
Diverio
Daniela
D
Maggio
Roberta
R
Vitale
Antonella
A
Ritz
Jerome
J
Foa
Robin
R
D000328:Adult; D015153:Blotting, Western; D016022:Case-Control Studies; D002880:Chromosomes, Human, Pair 11; D002894:Chromosomes, Human, Pair 4; D018076:DNA, Complementary / Q000032:analysis; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism / Q000494:pharmacology; D020411:Oligonucleotide Array Sequence Analysis; D010766:Phosphorylation; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000378:metabolism; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D011518:Proto-Oncogene Proteins / Q000032:analysis / Q000235:genetics* / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis; D020794:Receptor Protein-Tyrosine Kinases / Q000032:analysis / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction; D019311:Staurosporine / Q000031:analogs & derivatives / Q000494:pharmacology; D014178:Translocation, Genetic; D051941:fms-Like Tyrosine Kinase 3
D018076:DNA, Complementary; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; C084881:flt3 ligand protein; C497970:FLT3 protein, human; D020794:Receptor Protein-Tyrosine Kinases; D051941:fms-Like Tyrosine Kinase 3; D011493:Protein Kinase C; D019311:Staurosporine; C059539:midostaurin