Fms-related tyrosine kinase 3 (FLT3) is a
gene that encodes for a tyrosine kinase that activates pathways in
hematopoietic cells (Gene
2013) important in cellular proliferation. The FLT3 protein has an extracellular
domain consisting of five immunoglobulin-like domains, a transmembrane domain, a
juxtamembrane domain, and two tyrosine kinase domains (Leung, Man, and
FLT3 is frequently mutated in acute myeloid leukemia, myelodysplastic syndromes, other
hematologic malignancies, and colorectal cancer (COSMIC).
Mutations in MDS are skewed towards the
highest risk disease (refractory anemia with excess blasts).
Suggested Citation: Wheeler, S., A. Seegmiller, C. Vnencak-Jones, S. Strickland,
A. Kim. 2016. FLT3. My Cancer Genome https://www.padiracinnovation.org/content/disease/acute-myeloid-leukemia/flt3/?tab=0
(Updated June 17).
Last Updated: June 17, 2016
FLT3 in Acute Myeloid Leukemia
FLT3 mutations are observed in 24.3% of AML (COSMIC).
Of these, most are internal tandem duplications. FLT3 internal tandem duplication (ITD) occurs
when sequences of less than ten to several hundred bases in length are repeated within the
juxtamembrane domain (Fathi
and Chen 2011; Kottaridis
et al. 2001). All duplications are “in frame,” with the number of
nucleotides added as a multiple of three. Corresponding new amino acids are inserted into the
protein, but the coding frame of the protein remains unchanged. In addition to internal tandem
duplications, point mutations have also been observed in the tyrosine kinase domain (TKD) of the
FLT3 protein in 5-7% of AML patients. FLT3 ITD and FLT3 TKD mutations lead to aberrant
activation of FLT3 signaling, leading to proliferation of tumor cells (Leung, Man, and Kwong
2013). FLT3 mutations fall into class I of the “two-hit” theory of
leukemogenesis (Naoe and
Suggested Citation: Wheeler, S., A. Seegmiller, C. Vnencak-Jones. 2013. FLT3 in
Acute Myeloid Leukemia. My Cancer Genome https://www.padiracinnovation.org/content/disease/acute-myeloid-leukemia/flt3/
(Updated September 9).
Last Updated: September 9, 2013
FLT3 c. 2504A>C (D835A) Mutation in Acute Myeloid Leukemia
|Location of mutation
||Exon 20 (Ensembl); kinase
|Frequency of FLT3 mutations in AML
|Frequency of FLT3 D835A mutations
in FLT3-mutated AML
||< 1% (COSMIC)
|Implications for Targeted Therapeutics
|Response to FLT3 inhibitors (Midostaurin)
||Confers increased sensitivitya
|Response to MEK inhibitors
||Unknown at this time
|Response to JAK2 inhibitors
||Unknown at this time
|Response to sorafenib
||Unknown at this timeb
The D835A mutation results in an amino acid substitution at position 835 in
FLT3, from an aspartic acid (D) to an alanine (A). The prognostic impact of FLT3 kinase domain point mutations is unknown at this time (Martelli et al.
2013). FLT3 mutations combined with t(8;21), inv(16), or t(16;16) may be associated
with favorable prognosis (Allen et al. 2013; Jourdan et al.
a Patients with FLT3 mutation
(ITD and TKD) positive AML treated with midostaurin had increased survival (74.7 months)
compared to patients treated with placebo (26 months) (Stone et
a Data suggest that sorafenib is not efficacious in FLT3 tyrosine kinase domain–mutated AML (Man et al. 2012;
Smith and Shah
2013; Smith et al. 2012a).
||Study Type / Phase
||Line of Treatment
||# Patients in Study
et al. 2015
||1st or greater
||ITD or TKD Mutation
NOTE: PFS = progression-free survival; OS = overall survival; TTD = time to death; TTP = time
Figure 1. Schematic of FLT3. Domains encoded by various exons are shown.
NOTE: JM = juxtamembrane domain; TKD1 = tyrosine kinase
domain 1; TKD2 = tyrosine kinase domain 2;
TM = transmembrane domain.
Suggested Citation: Wheeler, S., A. Seegmiller, C. Vnencak-Jones. 2017. FLT3 c.
2504A>C (D835A) Mutation in Acute Myeloid
Leukemia. My Cancer Genome https://www.padiracinnovation.org/content/disease/acute-myeloid-leukemia/flt3/281/
(Updated May 31).
Last Updated: May 31, 2017
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