Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2012 Apr 15;485(7397):260-3.
doi: 10.1038/nature11016.

Validation of ITD mutations in FLT3 as a therapeutic _target in human acute myeloid leukaemia

Catherine C Smith  1 , Qi Wang, Chen-Shan Chin, Sara Salerno, Lauren E Damon, Mark J Levis, Alexander E Perl, Kevin J Travers, Susana Wang, Jeremy P Hunt, Patrick P Zarrinkar, Eric E Schadt, Andrew Kasarskis, John Kuriyan, Neil P Shah
Affiliations

Validation of ITD mutations in FLT3 as a therapeutic _target in human acute myeloid leukaemia

Catherine C Smith et al. Nature. .

Abstract

Effective _targeted cancer therapeutic development depends upon distinguishing disease-associated 'driver' mutations, which have causative roles in malignancy pathogenesis, from 'passenger' mutations, which are dispensable for cancer initiation and maintenance. Translational studies of clinically active _targeted therapeutics can definitively discriminate driver from passenger lesions and provide valuable insights into human cancer biology. Activating internal tandem duplication (ITD) mutations in FLT3 (FLT3-ITD) are detected in approximately 20% of acute myeloid leukaemia (AML) patients and are associated with a poor prognosis. Abundant scientific and clinical evidence, including the lack of convincing clinical activity of early FLT3 inhibitors, suggests that FLT3-ITD probably represents a passenger lesion. Here we report point mutations at three residues within the kinase domain of FLT3-ITD that confer substantial in vitro resistance to AC220 (quizartinib), an active investigational inhibitor of FLT3, KIT, PDGFRA, PDGFRB and RET; evolution of AC220-resistant substitutions at two of these amino acid positions was observed in eight of eight FLT3-ITD-positive AML patients with acquired resistance to AC220. Our findings demonstrate that FLT3-ITD can represent a driver lesion and valid therapeutic _target in human AML. AC220-resistant FLT3 kinase domain mutants represent high-value _targets for future FLT3 inhibitor development efforts.

PubMed Disclaimer

Figures

Figure 1
Figure 1. Mutation screen of FLT3-ITD reveals secondary kinase domain mutations that cause varying degrees of resistance to AC220
a, Numbers of independent AC220-resistant Ba/F3 FLT3-ITD subpopulations with amino acid substitution at the indicated residue obtained from a saturation mutagenesis assay (n = 97 clones). b, Normalized cell viability of Ba/F3 populations stably expressing FLT3-ITD mutant isoforms after 48 h in various concentrations of AC220 (error bars represent standard deviations of triplicates from the same experiment). c, Western blot analysis using anti-phospho-FLT3 (pFLT3) or anti-FLT3 antibody performed on lysates from IL-3-independent Ba/F3 populations expressing the FLT3-ITD mutant isoforms indicated. Cells were exposed to AC220 at the indicated concentrations for 90 min.
Figure 2
Figure 2. Modelling of FLT3–AC220 interactions
a, Docking model of the AC220-bound FLT3 kinase domain: AC220 (blue); activation loop (orange) and DFG motif (green); amino acid residues that confer AC220 resistance when mutated (F691, D835 and Y842) and that interact with AC220 (F691, C694 and F830) in sticks. b, Surface and stick presentation of AC220 and AC220-interacting residues on FLT3: the carbonyl oxygen of C694 interacts with one of the AC220 amide groups; F691 forms a π–π stacking interaction with AC220; F830 interacts with AC220 through a perpendicular aromatic–aromatic interaction. c, Structure of the activation loop: residues D835,Y842 and interacting residues on FLT3 depicted in sticks.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Thiede C, et al. Analysis of FLT3-activating mutations in 979 patients with acute myelogenous leukemia: association with FAB subtypes and identification of subgroups with poor prognosis. Blood. 2002;99:4326–4335. - PubMed
    1. Lee BH, et al. FLT3 internal tandem duplication mutations induce myeloproliferative or lymphoid disease in a transgenic mouse model. Oncogene. 2005;24:7882–7892. - PubMed
    1. Shih LY, et al. Acquisition of FLT3 or N-ras mutations is frequently associated with progression of myelodysplastic syndrome to acute myeloid leukemia. Leukemia. 2004;18:466–475. - PubMed
    1. Knapper S, et al. A phase 2 trial of the FLT3 inhibitor lestaurtinib (CEP701) as first-line treatment for older patients with acute myeloid leukemia not considered fit for intensive chemotherapy. Blood. 2006;108:3262–3270. - PubMed
    1. Fischer T, et al. Phase IIB trial of oral Midostaurin (PKC412), the FMS-like tyrosine kinase 3 receptor (FLT3) and multi-_targeted kinase inhibitor, in patients with acute myeloid leukemia and high-risk myelodysplastic syndrome with either wild-type or mutated FLT3. J. Clin. Oncol. 2010;28:4339–4345. - PMC - PubMed

Publication types

MeSH terms

  NODES
Association 1
INTERN 2
twitter 2