• What is FLT3?
  • FLT3 in Acute Myeloid Leukemia
  • FLT3 c.2506_2507delATinsCA (I836H)
  • Clinical Trials

FLT3

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 Kwong 2013).

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).

Related Pathways

Contributors: Scott Wheeler, Ph.D. (through June 2014), Adam Seegmiller, M.D., Ph.D., Cindy L. Vnencak-Jones, Ph.D., Stephen A. Strickland, M.D., MSCI, Annette S. Kim, M.D., Ph.D.

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 Kiyoi 2013).​

Contributors: Scott Wheeler, Ph.D. (through June 2014), Adam Seegmiller, M.D., Ph.D., Cindy L. Vnencak-Jones, Ph.D.

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.2506_2507delATinsCA (I836H) Mutation in Acute Myeloid Leukemia

Properties
Location of mutation Exon 20 (Ensembl); kinase domain (UniProt)
Frequency of FLT3 mutations in AML 24.3% (COSMIC)
Frequency of FLT3 I836H 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 I836H mutation results in an amino acid substitution at position 836 in FLT3, from an isoleucine (I) to a histidine (H). 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. 2013).

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 al. 2015). 

b 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).

 

Reference Study Type / Phase Line of Treatment Mutation Status Treatment Agent # Patients in Study Response Rate PFS OS
Stone et al. 2015 Phase 3 1st or greater ITD or TKD Mutation midostaurin 360     74.7
placebo 357     26

NOTE: PFS = progression-free survival; OS = overall survival; TTD = time to death; TTP = time to progression.

FLT3 I836H


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.

Contributors: Scott Wheeler, Ph.D. (through June 2014), Adam Seegmiller, M.D., Ph.D., Cindy L. Vnencak-Jones, Ph.D.

Suggested Citation: Wheeler, S., A. Seegmiller, C. Vnencak-Jones. 2017. FLT3 c.2506_2507delATinsCA (I836H) Mutation in Acute Myeloid Leukemia. My Cancer Genome https://www.padiracinnovation.org/content/disease/acute-myeloid-leukemia/flt3/287/ (Updated May 31).

Last Updated: May 31, 2017

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