This title appears in the Scientific Report : 2015 

Rare FLT3 deletion mutants may provide additional treatment options to patients with AML: an approach to individualized medicine
Chatain, N.
Perera, R. C. / Rossetti, G. / Rossa, J. / Carloni, P. / Schemionek, M. / Haferlach, T. / Brümmendorf, T. H. / Schnittger, S. / Koschmieder, S. (Corresponding author)
Computational Biomedicine; IAS-5
Computational Biomedicine; INM-9
Jülich Supercomputing Center; JSC
Leukemia, 29 (2015) 12, S. 2434 - 2438
Basingstoke Nature Publ. Group 2015
10.1038/leu.2015.131
Journal Article
(Dys-)function and Plasticity
Computational Science and Mathematical Methods
Please use the identifier: http://dx.doi.org/10.1038/leu.2015.131 in citations.
The receptor tyrosine kinase (RTK) FLT3 (Fms-like tyrosine kinase-3) is essential for the proliferation, differentiation and survival of hematopoietic cells.1, 2 Mutations in the gene for FLT3 have been described in acute myeloid leukemia (AML) as internal tandem duplications (ITD) localized in the juxtamembrane (JM) domain and FLT3 tyrosine kinase domain (TKD) mutations amounting to 2–30% and 7–10% of patients, respectively. In patients with AML, FLT3-ITD confers an unfavorable prognosis.3 In AML, recently discovered FLT3 mutations involve point mutations as well as short deletions in the JM domain, highlighting the importance for a deeper understanding and further studies of these aberrations.4, 5 The FLT3 JM domain (Supplementary Figure 1a) is indeed the critical regulator region of receptor autoinhibition.6 Kiyoi et al.7 had shown constitutive activation of the FLT3 receptor by deletion of a stretch of amino acids in the JM domain, generally duplicated in FLT3-ITD.In this study, during diagnostic screening for ITD and TKD mutations, we have identified and functionally characterized deletion mutations of FLT3 in the diagnostic work-up of over 6843 AML patients. Deletions were detected in seven patients (0.1%) with newly diagnosed or relapsed AML. All deletions detected by gene scan were in the range of 3–18 base pairs (Supplementary Table 1 and Figure 1a). Subsequent sequencing revealed that all but one of these deletions, which was situated in the transmembrane domain, were in the JM domain, and were simple deletions (n=5) or indels (n=2). In three cases out of seven, the mutations resulted in a premature stop codon. As loss of the wild-type (WT) allele in FLT3-ITD knock-in mice led to a more severe phenotype,8 we analyzed whether the FLT3 mutations were biallelic. However, we could not detect ITD or TKD mutations on the other allele of these patients. Remission samples of patient Id 2–7 confirmed the somatic character of the mutations. We analyzed the transforming potential of such deletions and performed computational modeling to predict the structural effect of two deletions (Id 5: p.Glu598_Tyr599del—delEY; Id 6: p.Phe590_Asp593delinsLeuTyr—delIns).