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Blood, 15 November 2006, Vol. 108, No. 10, pp. 3504-3513.
Prepublished online as a Blood First Edition Paper on July 13, 2006; DOI 10.1182/blood-2006-05-021691.
 Previous Article | Next Article 
Submitted May 9, 2006
Accepted June 28, 2006
Newly identified c-kit receptor tyrosine kinase ITD in
childhood AML induces ligand independent growth and is
responsive to a synergistic effect of imatinib and
rapamycin
Selim Corbacioglu*, Mehtap Kilic, Mike-Andrew Westhoff, Dirk Reinhardt, Simone Fulda, and Klaus-Michael Debatin
University of Ulm, Department of Pediatrics, Ulm, Germany
Children's Hospital, Hannover Medical School, Department of Pediatric Hematology & Oncology, Germany
* Corresponding author; email: selim.corbacioglu{at}uniklinik-ulm.de.
Activating mutations of c-kit lead to ligand independent
growth. Internal tandem duplications (ITD) of exon 11
which encodes the juxtamembrane domain (JMD) are
constitutively activating mutations found in 7% of
gastrointestinal stromal tumors (GIST) but have not been
described in childhood AML. DNA and cDNA from 60 children
with AML were screened by PCR for mutations of the JMD. A
complex ITD (kit cITD) involving exon 11 and exon 12 was
identified with a relative frequency of 7% (4/60). The
human kit cITD were inserted into the murine c kit
backbone and expressed in Ba/F3 cells. KIT cITD induced
factor-independent growth, apoptosis resistance and
exhibited constitutive autophosphorylation. KIT cITD
constitutively activated the PI3K/AKT pathway and
phosphorylated STAT1, STAT3, STAT5 and SHP-2. Imatinib
(IM) or rapamycin (Rap) led to complete inhibition of
growth with IC50 values at nanomolar levels. IM and Rap
synergistically inhibited growth and surmounted KIT cITD
induced apoptosis resistance. IM but not LY294002
inhibited phosphorylation of STAT3 and STAT5 suggesting
aberrant crosstalk between PI3K and STAT activating
pathways. The findings presented may have immediate
therapeutic impact for a subgroup of childhood AML
expressing c-kit mutations.
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