scholarly journals Emerging FMS-like tyrosine kinase 3 inhibitors for the treatment of acute myelogenous leukemia

2011 ◽  
Vol 16 (3) ◽  
pp. 407-423 ◽  
Author(s):  
Hillary Prescott ◽  
Hagop Kantarjian ◽  
Jorge Cortes ◽  
Farhad Ravandi
Keyword(s):  
Tyrosine Kinase ◽  
Acute Myelogenous Leukemia ◽  
Myelogenous Leukemia ◽  
Acute Myelogenous

scholarly journals FLT3-ITD transduces autonomous growth signals during its biosynthetic trafficking in acute myelogenous leukemia cells

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Kouhei Yamawaki ◽  
Isamu Shiina ◽  
Takatsugu Murata ◽  
Satoru Tateyama ◽  
Yutarou Maekawa ◽  
...  
Keyword(s):  
Golgi Apparatus ◽  
Tyrosine Kinase ◽  
Acute Myelogenous Leukemia ◽  
Kinase Inhibitors ◽  
Active Form ◽  
Myelogenous Leukemia ◽  
Perinuclear Region ◽  
Oncogenic Signaling ◽  
Trafficking Inhibitor ◽  
Acute Myelogenous

AbstractFMS-like tyrosine kinase 3 (FLT3) in hematopoietic cells binds to its ligand at the plasma membrane (PM), then transduces growth signals. FLT3 gene alterations that lead the kinase to assume its permanently active form, such as internal tandem duplication (ITD) and D835Y substitution, are found in 30–40% of acute myelogenous leukemia (AML) patients. Thus, drugs for molecular targeting of FLT3 mutants have been developed for the treatment of AML. Several groups have reported that compared with wild-type FLT3 (FLT3-wt), FLT3 mutants are retained in organelles, resulting in low levels of PM localization of the receptor. However, the precise subcellular localization of mutant FLT3 remains unclear, and the relationship between oncogenic signaling and the mislocalization is not completely understood. In this study, we show that in cell lines established from leukemia patients, endogenous FLT3-ITD but not FLT3-wt clearly accumulates in the perinuclear region. Our co-immunofluorescence assays demonstrate that Golgi markers are co-localized with the perinuclear region, indicating that FLT3-ITD mainly localizes to the Golgi region in AML cells. FLT3-ITD biosynthetically traffics to the Golgi apparatus and remains there in a manner dependent on its tyrosine kinase activity. Tyrosine kinase inhibitors, such as quizartinib (AC220) and midostaurin (PKC412), markedly decrease FLT3-ITD retention and increase PM levels of the mutant. FLT3-ITD activates downstream in the endoplasmic reticulum (ER) and the Golgi apparatus during its biosynthetic trafficking. Results of our trafficking inhibitor treatment assays show that FLT3-ITD in the ER activates STAT5, whereas that in the Golgi can cause the activation of AKT and ERK. We provide evidence that FLT3-ITD signals from the early secretory compartments before reaching the PM in AML cells.

Nucleophosmin gene mutations are predictors of favorable prognosis in acute myelogenous leukemia with a normal karyotype

Blood ◽  
2005 ◽  
Vol 106 (12) ◽  
pp. 3733-3739 ◽  
Author(s):  
Susanne Schnittger ◽  
Claudia Schoch ◽  
Wolfgang Kern ◽  
Cristina Mecucci ◽  
Claudia Tschulik ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Acute Myelogenous Leukemia ◽  
Gene Mutations ◽  
Normal Karyotype ◽  
Kinase Domain ◽  
Myelogenous Leukemia ◽  
Tyrosine Kinase Domain ◽  
Double Positive ◽  
Acute Myelogenous ◽  
Cebpa Mutations

Nucleophosmin (NPM1) exon-12 gene mutations are the hallmark of a large acute myelogenous leukemia (AML) subgroup with normal karyotype, but their prognostic value in this AML subset has not yet been determined. We screened 401 AML patients with normal karyotype treated within the German AML Cooperative Group Protocol 99 (AMLCG99) study for NPM1 mutations. Results were related with partial tandem duplications within the MLL gene (MLL-PTD), Fms-like tyrosine kinase 3–length mutations (FLT3-LM), the tyrosine kinase domain of FLT3 (FLT3-TKD), NRAS, KIT, and CEBPA mutations and with clinical characteristics and outcome. NPM1 mutations were detected in 212 (52.9%) of 401 patients. Fourteen mutations, including 8 new variants, were identified. NPM1-mutated cases associated frequently with FLT3 mutations but rarely with other mutations. The NPM1-mutated group had a higher complete remission (CR) rate (70.5% vs 54.7%, P = .003), a trend to a longer overall survival (OS; median 1012 vs 549 days, P = .076), and significantly longer event-free survival (EFS; median 428 vs 336 days; P = .012). The favorable impact of NPM1 mutations on OS and EFS clearly emerged in the large group (264 [66.8%] of 395 cases) of normal-karyotype AML without FLT3-LM. This positive effect was lost in the presence of a concomitant FLT3-LM, since survival of the NPM1+/FLT3-LM+ double positive was similar to NPM1–/FLT3-LM+ cases. In conclusion, this study demonstrates that NPM1+/FLT3-LM– mutations are an independent predictor for a favorable outcome in AML with normal karyotype.

Analysis of FLT3-activating mutations in 979 patients with acute myelogenous leukemia: association with FAB subtypes and identification of subgroups with poor prognosis

Blood ◽  
2002 ◽  
Vol 99 (12) ◽  
pp. 4326-4335 ◽  
Author(s):  
Christian Thiede ◽  
Christine Steudel ◽  
Brigitte Mohr ◽  
Markus Schaich ◽  
Ulrike Schäkel ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Acute Myelogenous Leukemia ◽  
Point Mutations ◽  
Disease Free Survival ◽  
Myelogenous Leukemia ◽  
Tyrosine Kinase Domain ◽  
Prognostic Impact ◽  
Constitutive Activation ◽  
Juxtamembrane Region ◽  
Acute Myelogenous

Constitutive activation of the FLT3 receptor tyrosine kinase, either by internal tandem duplication (ITD) of the juxtamembrane region or by point mutations in the second tyrosine kinase domain (TKD), has been described in patients with acute myelogenous leukemia (AML). We analyzed the prevalence and the potential prognostic impact of FLT3 mutations in 979 AML patients. Results were correlated with cytogenetic data and the clinical response. FLT3-ITD mutations were found in 20.4% and FLT3-TKD mutations in 7.7% of the patients. Each mutation was associated with similar clinical characteristics and was more prevalent in patients with normal karyotype. Significantly more FLT3 aberrations were found in patients with FAB M5, and fewer were found in patients with FAB M2 and M6. Although less frequent in patients with cytogenetic aberrations, FLT3-ITDs were found in 13 of 42 patients with t(15;17) and in 9 of 10 patients with t(6;9). The prevalence of the ITD allele on the DNA level was heterogeneous, ranging from faint mutant bands in some patients to predominant mutant bands in others. Based on quantitative analysis, the mutant–wild-type (wt) ratio ranged from 0.03 to 32.56 (median, 0.78). Patients with a high mutant/wt ratio (ie, greater than 0.78) had significantly shorter overall and disease-free survival, whereas survival in patients with ratios below 0.78 did not differ from those without FLT3 aberrations. Multivariate analysis confirmed a high mutant/wt ratio to be a strong independent prognostic factor. Taken together, these data confirm that FLT mutations represent a common alteration in adult AML. Constitutive activation may be associated with monocytoid differentiation. A high mutant/wt ratio in ITD-positive patients appears to have a major impact on the prognostic relevance.

scholarly journals FLT3-ITD transduces autonomous growth signals during its biosynthetic trafficking in acute myelogenous leukemia cells.

2021 ◽  
Author(s):  
Kouhei Yamawaki ◽  
Isamu Shiina ◽  
Takatsugu Murata ◽  
Satoru Tateyama ◽  
Yutarou Maekawa ◽  
...  
Keyword(s):  
Golgi Apparatus ◽  
Tyrosine Kinase ◽  
Acute Myelogenous Leukemia ◽  
Kinase Inhibitor ◽  
Active Form ◽  
Myelogenous Leukemia ◽  
Perinuclear Region ◽  
Oncogenic Signaling ◽  
Trafficking Inhibitor ◽  
Acute Myelogenous

Abstract FMS-like tyrosine kinase 3 (FLT3) in hematopoietic cells binds to its ligand at the plasma membrane (PM), then transduces growth signals. FLT3 gene alterations that lead the kinase to assume its permanently active form, such as internal tandem duplication (ITD) and D835Y substitution, are found in 30~40% of acute myelogenous leukemia (AML) patients. Thus, the drugs for molecular targeting of FLT3 mutants have been developed for the treatment of AML. Several groups have reported that compared with wild-type FLT3 (FLT3-wt), FLT3 mutants are retained in organelles, resulting in low levels of PM localization of the receptor. However, the precise subcellular localization of mutant FLT3 remains unclear, and the relationship between oncogenic signaling and the mislocalization is not completely understood. In this study, we show that in cell lines established from AML patients, endogenous FLT3-ITD but not FLT3-wt clearly accumulates in the perinuclear region. Our co-immunofluorescence assays demonstrate that Golgi markers are co-localized with the perinuclear region, indicating that FLT3-ITD mainly localizes to the Golgi region in AML cells. FLT3-ITD biosynthetically traffics to the Golgi apparatus and remains there in a manner dependent on its tyrosine kinase activity. A tyrosine kinase inhibitor midostaurin (PKC412) markedly decreases in FLT3-ITD retention and increases in the PM levels of the mutant. FLT3-ITD activates downstream in the endoplasmic reticulum (ER) and the Golgi apparatus during its biosynthetic trafficking. Results of our trafficking inhibitor treatment assays show that FLT3-ITD in the ER activates STAT5, whereas that in the Golgi can cause the activation of AKT and ERK. We provide evidence that FLT3-ITD signals from the early secretory compartments before reaching the PM in AML cells.

Sign in / Sign up

Export Citation Format

Share Document