Signaling by FLT3 ITD and TKD mutants

Stable Identifier
R-HSA-9703648
Type
Pathway
Species
Homo sapiens
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FLT3 is subject to internal tandem duplications (ITDs) of lengths varying from 3 to 1236 base pairs (Nakao et al, 1996; Kiyoi et al 1997, Meshinchi et al, 2008; reviewed in Kazi and Roonstrand, 2019). These ITDs are generally found in the juxtamembrane domain, or more rarely, the first tyrosine kinase domain (TKD) and disrupt the autoinhibitory loop of the receptor, constitutively activating it (Kiyoi et al, 2002; Griffith et al, 2004; reviewed in Lagunas-Rangel and Chavez-Valencia, 2017; Kazi and Roonstrand, 2019). FLT3 ITDs are found in ~25% of acute myeloid leukemias (AMLs) and represent the most frequent mutation of this cancer (reviewed in Kazi and Roonstrand, 2019, Klug et al, 2018)
At lower frequency, FLT3 is subject to activating point mutations (~7% of AML cases). These mutations tend to cluster in the TKD, with mutation of the activation loop residue D835 and the gatekeeper F691 residue the most common sites (Griffin et al, 2001; Jiang et al, 2004; reviewed in Kazi and Roonstrand, 2019).
FLT3 ITD and TKD mutants support cellular transformation through activation of downstream signaling pathways such as the MAP kinase, PI3K/AKT and STAT5 cascades. There is some debate about the extent to which the pathways activated by the ITD and TKD mutants are distinct, with some evidence that STAT5 signaling, in particular, is more characteristic of FLT3 ITD activation (Hayakawa et al, 2000; Choudhary et al, 2005; Grundler et al, 2005; Choudhary et al, 2007; Yoshimoto et al, 2009; Leischner et al, 2012; Janke et al, 2014; Marhall et al, 2018; reviewed in Chan, 2011; Kazi and Roonstrand, 2019).

Literature References
PubMed ID Title Journal Year
24608088 Activating FLT3 mutants show distinct gain-of-function phenotypes in vitro and a characteristic signaling pathway profile associated with prognosis in acute myeloid leukemia

Janke, H, Pastore, F, Schumacher, D, Herold, T, Hopfner, KP, Schneider, S, Berdel, WE, Büchner, T, Woermann, BJ, Subklewe, M, Bohlander, SK, Hiddemann, W, Spiekermann, K, Polzer, H

2014
19808698 FLT3-ITD up-regulates MCL-1 to promote survival of stem cells in acute myeloid leukemia via FLT3-ITD-specific STAT5 activation

Yoshimoto, G, Miyamoto, T, Jabbarzadeh-Tabrizi, S, Iino, T, Rocnik, JL, Kikushige, Y, Mori, Y, Shima, T, Iwasaki, H, Takenaka, K, Nagafuji, K, Mizuno, S, Niiro, H, Gilliland, GD, Akashi, K

2009
29372308 Internal tandem duplication mutations in the tyrosine kinase domain of FLT3 display a higher oncogenic potential than the activation loop D835Y mutation

Marhäll, A, Heidel, F, Fischer, T, Rönnstrand, L

2018
15718420 FLT3-ITD and tyrosine kinase domain mutants induce 2 distinct phenotypes in a murine bone marrow transplantation model

Grundler, R, Miething, C, Thiede, C, Peschel, C, Duyster, J

2005
31066629 FMS-like Tyrosine Kinase 3/FLT3: From Basic Science to Clinical Implications

Kazi, JU, Rönnstrand, L

Physiol. Rev. 2019
17356133 Activation mechanisms of STAT5 by oncogenic Flt3-ITD

Choudhary, C, Brandts, C, Schwäble, J, Tickenbrock, L, Sargin, B, Ueker, A, Böhmer, FD, Berdel, WE, Müller-Tidow, C, Serve, H

Blood 2007
10698507 Tandem-duplicated Flt3 constitutively activates STAT5 and MAP kinase and introduces autonomous cell growth in IL-3-dependent cell lines

Hayakawa, F, Towatari, M, Kiyoi, H, Tanimoto, M, Kitamura, T, Saito, H, Naoe, T

Oncogene 2000
28470536 FLT3-ITD and its current role in acute myeloid leukaemia

Lagunas-Rangel, FA, Chávez-Valencia, V

2017
21359601 Differential signaling of Flt3 activating mutations in acute myeloid leukemia: a working model

Chan, PM

2011
15769897 AML-associated Flt3 kinase domain mutations show signal transduction differences compared with Flt3 ITD mutations

Choudhary, C, Schwäble, J, Brandts, C, Tickenbrock, L, Sargin, B, Kindler, T, Fischer, T, Berdel, WE, Müller-Tidow, C, Serve, H

2005
15178581 Identifying and characterizing a novel activating mutation of the FLT3 tyrosine kinase in AML

Jiang, J, Paez, JG, Lee, JC, Bo, R, Stone, RM, Deangelo, DJ, Galinsky, I, Wolpin, BM, Jonasova, A, Herman, P, Fox, EA, Boggon, TJ, Eck, MJ, Weisberg, E, Griffin, JD, Gilliland, DG, Meyerson, M, Sellers, WR

Blood 2004
14984498 Novel FLT3 point mutations within exon 14 found in patients with acute myeloid leukaemia

Stirewalt, DL, Meshinchi, S, Kussick, SJ, Sheets, KM, Pogosova-Agadjanyan, E, Willman, CL, Radich, JP

Br. J. Haematol. 2004
11290575 Point mutations in the FLT3 gene in AML

Griffin, JD

2001
8946930 Internal tandem duplication of the flt3 gene found in acute myeloid leukemia

Nakao, M, Yokota, S, Iwai, T, Kaneko, H, Horiike, S, Kashima, K, Sonoda, Y, Fujimoto, T, Misawa, S

1996
9737679 Internal tandem duplication of the FLT3 gene is a novel modality of elongation mutation which causes constitutive activation of the product

Kiyoi, H, Towatari, M, Yokota, S, Hamaguchi, M, Ohno, R, Saito, H, Naoe, T

Leukemia 1998
29964125 Structural and clinical consequences of activation loop mutations in class III receptor tyrosine kinases

Klug, LR, Kent, JD, Heinrich, MC

Pharmacol. Ther. 2018
22411868 SRC is a signaling mediator in FLT3-ITD- but not in FLT3-TKD-positive AML

Leischner, H, Albers, C, Grundler, R, Razumovskaya, E, Spiekermann, K, Bohlander, S, Rönnstrand, L, Götze, K, Peschel, C, Duyster, J

Blood 2012
14759363 The structural basis for autoinhibition of FLT3 by the juxtamembrane domain

Griffith, J, Black, J, Faerman, C, Swenson, L, Wynn, M, Lu, F, Lippke, J, Saxena, K

2004
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cancer 162 malignant tumor, malignant neoplasm, primary cancer
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