Ligand-independent dimerization of FLT3 mutants

Stable Identifier
R-HSA-9695838
Type
Reaction [transition]
Species
Homo sapiens
Compartment
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Mutations in FLT3 are common in acute myeloid leukemia, with internal tandem duplications in the juxtamembrane or kinase domain occurring in 25% of FLT3-positive AMLs, and missense mutations in the kinase domain occurring in 7-10% of cases (reviewed in Klug et al, 2018; Daver et al, 2019; Staudt et al, 2018). Mutant receptors support ligand-independent dimerization and result in constitutive activation and signaling (Kiyoi et al, 1998; Yamamoto et al, 2001; Clark et al, 2004; Zheng et al, 2004; Stirewalt et al, 2004; Jiang et al, 2004; Brandts et al, 2005; Schittenhelm et al, 2006; Reindl et al, 2006; Frohling et al, 2007; Breteinbeucher et al, 2009; Huang et al, 2016; reviewed in Klug et al, 2018; Staudt et al, 2018; Daver et al, 2019).

Literature References
PubMed ID Title Journal Year
26891877 Leukemogenic potency of the novel FLT3-N676K mutant

Huang, K, Yang, M, Pan, Z, Heidel, FH, Scherr, M, Eder, M, Fischer, T, Büsche, G, Welte, K, von Neuhoff, N, Ganser, A, Li, Z

Ann. Hematol. 2016
18483393 Identification of a novel type of ITD mutations located in nonjuxtamembrane domains of the FLT3 tyrosine kinase receptor

Breitenbuecher, F, Schnittger, S, Grundler, R, Markova, B, Carius, B, Brecht, A, Duyster, J, Haferlach, T, Huber, C, Fischer, T

Blood 2009
16410449 Point mutations in the juxtamembrane domain of FLT3 define a new class of activating mutations in AML

Reindl, C, Bagrintseva, K, Vempati, S, Schnittger, S, Ellwart, JW, Wenig, K, Hopfner, KP, Hiddemann, W, Spiekermann, K

Blood 2006
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
12969963 FLT3 ligand causes autocrine signaling in acute myeloid leukemia cells

Zheng, R, Levis, M, Piloto, O, Brown, P, Baldwin, BR, Gorin, NC, Beran, M, Zhu, Z, Ludwig, D, Hicklin, D, Witte, L, Li, Y, Small, D

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
11290608 Activating mutation of D835 within the activation loop of FLT3 in human hematologic malignancies

Yamamoto, Y, Kiyoi, H, Nakano, Y, Suzuki, R, Kodera, Y, Miyawaki, S, Asou, N, Kuriyama, K, Yagasaki, F, Shimazaki, C, Akiyama, H, Saito, K, Nishimura, M, Motoji, T, Shinagawa, K, Takeshita, A, Saito, H, Ueda, R, Ohno, R, Naoe, T

Blood 2001
30332834 Targeting Oncogenic Signaling in Mutant FLT3 Acute Myeloid Leukemia: The Path to Least Resistance

Staudt, D, Murray, HC, McLachlan, T, Alvaro, F, Enjeti, AK, Verrills, NM, Dun, MD

Int J Mol Sci 2018
16266983 Constitutive activation of Akt by Flt3 internal tandem duplications is necessary for increased survival, proliferation, and myeloid transformation

Brandts, CH, Sargin, B, Rode, M, Biermann, C, Lindtner, B, Schwäble, J, Buerger, H, Müller-Tidow, C, Choudhary, C, McMahon, M, Berdel, WE, Serve, H

Cancer Res. 2005
15256420 Variable sensitivity of FLT3 activation loop mutations to the small molecule tyrosine kinase inhibitor MLN518

Clark, JJ, Cools, J, Curley, DP, Yu, JC, Lokker, NA, Giese, NA, Gilliland, DG

Blood 2004
18068628 Identification of driver and passenger mutations of FLT3 by high-throughput DNA sequence analysis and functional assessment of candidate alleles

Fröhling, S, Scholl, C, Levine, RL, Loriaux, M, Boggon, TJ, Bernard, OA, Berger, R, Döhner, H, Döhner, K, Ebert, BL, Teckie, S, Golub, TR, Jiang, J, Schittenhelm, MM, Lee, BH, Griffin, JD, Stone, RM, Heinrich, MC, Deininger, MW, Druker, BJ, Gilliland, DG

Cancer Cell 2007
30651634 Targeting FLT3 mutations in AML: review of current knowledge and evidence

Daver, N, Schlenk, RF, Russell, NH, Levis, MJ

Leukemia 2019
16990784 FLT3 K663Q is a novel AML-associated oncogenic kinase: Determination of biochemical properties and sensitivity to Sunitinib (SU11248)

Schittenhelm, MM, Yee, KW, Tyner, JW, McGreevey, L, Haley, AD, Town, A, Griffith, DJ, Bainbridge, T, Braziel, RM, O'Farrell, AM, Cherrington, JM, Heinrich, MC

Leukemia 2006
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
Participants
Participates
Functional status

Gain of function of FLT3 extracellular domain, kinase domain and juxtamembrane domain mutants [plasma membrane]

Status
Disease
Name Identifier Synonyms
cancer DOID:162 malignant tumor, malignant neoplasm, primary cancer
Authored
Reviewed
Created
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