2020
DOI: 10.3389/fonc.2020.612880
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FLT3 Mutations in Acute Myeloid Leukemia: Key Concepts and Emerging Controversies

Abstract: The FLT3 receptor is overexpressed on the majority of acute myeloid leukemia (AML) blasts. Mutations in FLT3 are the most common genetic alteration in AML, identified in approximately one third of newly diagnosed patients. FLT3 internal tandem duplication mutations (FLT3-ITD) are associated with increased relapse and inferior overall survival. Multiple small molecule inhibitors of FLT3 signaling have been identified, two of which (midostaurin and gilteritinib) are currently approved in the United States, and m… Show more

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Cited by 125 publications
(97 citation statements)
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References 161 publications
(210 reference statements)
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“…To investigate the underlying molecular mechanism whereby TIFAB enhances leukemogenesis, we performed RNA-sequencing (RNA-seq) using FACS-sorted control or TIFAB-transduced leukemic stem cells (Lin lo/- Sca1 − CD117 + CD16 + CD34 + ) from mice with full-blown leukemia. Compared to control LSCs, TIFAB LSCs showed downregulation of genes related to myeloid differentiation (Cd14, Cd163, Mpo, Elane, Csf1r) and cell cycle inhibition (Cdkn2a), whereas upregulated genes related to maintenance of the LSC signature ( Six1 , Msi2 , Flt3, and Hoxa gene families) ( Calvo et al., 2000 ; Chu et al., 2019 ; Collins and Hess, 2016 ; Ito et al., 2010 ; Kennedy and Smith, 2020 ) ( Figure 3 A). The upregulation of FLT3 also contributes to TIFAB's leukemia-enhancing impact, given that FLT3 is commonly mutated (approximately one-third of newly diagnosed AML) and associated with increased relapse and inferior overall survival ( Kennedy and Smith, 2020 ).…”
Section: Resultsmentioning
confidence: 99%
See 1 more Smart Citation
“…To investigate the underlying molecular mechanism whereby TIFAB enhances leukemogenesis, we performed RNA-sequencing (RNA-seq) using FACS-sorted control or TIFAB-transduced leukemic stem cells (Lin lo/- Sca1 − CD117 + CD16 + CD34 + ) from mice with full-blown leukemia. Compared to control LSCs, TIFAB LSCs showed downregulation of genes related to myeloid differentiation (Cd14, Cd163, Mpo, Elane, Csf1r) and cell cycle inhibition (Cdkn2a), whereas upregulated genes related to maintenance of the LSC signature ( Six1 , Msi2 , Flt3, and Hoxa gene families) ( Calvo et al., 2000 ; Chu et al., 2019 ; Collins and Hess, 2016 ; Ito et al., 2010 ; Kennedy and Smith, 2020 ) ( Figure 3 A). The upregulation of FLT3 also contributes to TIFAB's leukemia-enhancing impact, given that FLT3 is commonly mutated (approximately one-third of newly diagnosed AML) and associated with increased relapse and inferior overall survival ( Kennedy and Smith, 2020 ).…”
Section: Resultsmentioning
confidence: 99%
“…Compared to control LSCs, TIFAB LSCs showed downregulation of genes related to myeloid differentiation (Cd14, Cd163, Mpo, Elane, Csf1r) and cell cycle inhibition (Cdkn2a), whereas upregulated genes related to maintenance of the LSC signature ( Six1 , Msi2 , Flt3, and Hoxa gene families) ( Calvo et al., 2000 ; Chu et al., 2019 ; Collins and Hess, 2016 ; Ito et al., 2010 ; Kennedy and Smith, 2020 ) ( Figure 3 A). The upregulation of FLT3 also contributes to TIFAB's leukemia-enhancing impact, given that FLT3 is commonly mutated (approximately one-third of newly diagnosed AML) and associated with increased relapse and inferior overall survival ( Kennedy and Smith, 2020 ). The upregulation of Hoxa cluster genes was further validated by quantitative RT-PCR analysis ( Figure 3 B).…”
Section: Resultsmentioning
confidence: 99%
“…These increased ROS levels were shown to promote AML blast proliferation [165]. Activating mutations of the FLT3 receptor are detected in approximately one third of newly diagnosed AML cases, with ITD mutations being associated with an adverse prognosis [166]. The increased levels of endogenous ROS demonstrated in FLT3-ITD-mutated AML could be associated with the aggressiveness and poor prognosis of these AML cases [167].…”
Section: Mitochondrial Metabolismmentioning
confidence: 99%
“…Two well-defined activating mutations hold clinical relevance: the FLT3 Internal Tandem Duplicate (ITD) and FLT3 tyrosine kinase domain (TKD) point mutation. FLT3 ITD mutations are among the most common mutations in AML, comprising about 25% of cases, and point mutations in the FLT3 TKD (D835 or I836) make up 5–10% of cases [ 39 ]. While the exact prognostic significance of FLT3 TKD mutant AML remains unclear, because this class of disease as a whole portends poorer outcomes, the development of potent tyrosine kinase inhibitors quickly emerged as an area of medical necessity.…”
Section: Focus On Inhibiting Single-gene Mutationsmentioning
confidence: 99%