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Jensen, Christopher E.; Montgomery, Nathan D.; Galeotti, Jonathan; Foster, Matthew C.; Zeidner, Joshua F.
Journal of cellular and molecular medicine, December 2022, Letnik: 26, Številka: 24Journal Article
FMS-like tyrosine kinase 3 (FLT3) is a receptor tyrosine kinase involved in regulation of haematopoietic stem cell and progenitor cell proliferation and differentiation. 1 Activating mutations in FLT3 are found in 25%–35% of adults with acute myeloid leukaemia (AML), most commonly in-frame internal tandem duplications (ITD) within the intracellular juxtamembrane domain (JMD). 2 This domain, consisting of residues 572–603, serves an autoinhibitory function, in part by preventing the activation loop from unfolding into its active conformation. 3 FLT3-ITD mutations cause a gain-of-function phenotype with increased proliferation and protection from apoptosis 4 and are associated with worse clinical outcomes. 5 Most other activating FLT3 mutations are found in the tyrosine kinase domain (TKD), 2 though rare activating JMD deletions have also been described. 6,7 We identified three patients with rare FLT3 JMD missense mutations (Table 1). PATIENT 1 A 74-year-old woman with prior breast cancer managed with lumpectomy, chemotherapy, radiation and endocrine therapy developed erythematous, lower-extremity-predominant skin lesions 4 years after treatment. Reindl and colleagues developed models of V579A, V592A, F594L, and F590G/Y591D FLT3 variants via site-directed mutagenesis in BaF3 cells, a murine interleukin-3 (IL-3) dependent haematopoietic cell line. 12 Affected cells exhibited increased IL-3-independent growth, growth in response to FLT3 ligand, resistance to apoptosis upon IL-3 withdrawal and FLT3 autophosphorylation compared with FLT3-wildtype controls.
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JCR | SNIP | JCR | SNIP | JCR | SNIP | JCR | SNIP |
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Vir: Osebne bibliografije
in: SICRIS
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