Mutations in the Receptor Tyrosine Kinase Pathway Are Associated with Clinical Outcome in Patients with Acute Myeloblastic Leukemia Harboring t(8;21)(q22;q22).

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3000-3000
Author(s):  
Tomoko Nanri ◽  
Naofumi Matsuno ◽  
Toshiro Kawakita ◽  
Hitoshi Suzushima ◽  
Fumio Kawano ◽  
...  
Keyword(s):  
Clinical Outcome ◽  
Tyrosine Kinase ◽  
Receptor Tyrosine Kinase ◽  
Disease Free Survival ◽  
Kinase Domain ◽  
Acute Myeloblastic Leukemia ◽  
Tyrosine Kinase Domain ◽  
Juxtamembrane Domain ◽  
Ras Gene ◽  
Hematopoietic Stem

Abstract AML1-MTG8 generated by t(8;21)(q22;q22) contributes to leukemic transformation but additional events are required for full leukemogenesis. We examined whether mutations in the receptor tyrosine kinase (RTK) pathway could be the genetic events that cause acute myeloblastic leukemia (AML) harboring t(8;21). Mutations in the second tyrosine kinase domain, juxtamembrane domain and exon 8 of the C-KIT gene were observed in 7, 1 and 3 of 37 AML patients with t(8;21), respectively. Three patients showed an internal tandem duplication in the juxtamembrane domain of the FLT3 gene. One patient had a mutation in the K-Ras gene at codon 12. As the occurrence of these mutations was mutually exclusive, a total of 15 (41%) patients showed mutations in the RTK pathway. These results suggest that AML1-MTG8 predisposes cells to the acquisition of activating mutations in the RTK pathway as an additional event leading to the development of AML. Ten of 15 patients with mutations in the RTK pathway relapsed, compared with only 3 of 19 patients lacking such mutations (p=0.0042). Furthermore, the 6-year disease-free survival (DFS) in patients with mutations was 12% compared to 55% in those without mutations (p=0.0344). When patients who underwent allogeneic hematopoietic stem cell transplantation (HSCT) were censored at the date of the HSCT, patients with mutations had a 6-year DFS of 0% versus 60% for the patients without mutations (p=0.0096) These observations indicate that RTK mutations are associated with the clinical outcome in t(8;21) AML.

scholarly journals 3′UTRs Regulate Mouse Ntrk2 mRNA Distribution in Cortical Neurons

2020 ◽  
Vol 70 (11) ◽  
pp. 1858-1870
Author(s):  
Shangqin Chen ◽  
Jinjin Zhu ◽  
Peijun Li ◽  
Zhaonan Xia ◽  
Mengjing Tu ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Receptor Tyrosine Kinase ◽  
Cortical Neurons ◽  
Kinase Domain ◽  
Tyrosine Kinase Domain ◽  
Mrna Levels ◽  
Tyrosine Kinase 2 ◽  
Mrna Transcripts ◽  
Cultured Cortical Neurons ◽  
Apical Dendrites

Abstract There are two major isoforms of NTRK2 (neurotrophic receptor tyrosine kinase 2, or TrkB), full-length isoform with tyrosine kinase (TK) domain intact (+) and spliced isoform without tyrosine kinase domain (TK(−)). Within each isoform, there exist subtypes with minor modifications of the protein sequences. In human, the NTRK2 mRNA transcripts encoding TK(+) have same 3′UTRs, while the transcripts encoding subtypes of NTRK2 TK(−) have two completely different 3′UTRs. In mouse, the mRNA transcripts encoding same NTRK2 protein sequence for either TK(+) or TK(−) have long or short 3′UTRs, respectively. The physiological functions of these different 3′UTRs are still unknown. Pilocarpine stimulation increased Ntrk2 mRNA levels in soma, while the increase in synaptosome was smaller. FISH results further showed that mouse Ntrk2 transcripts with different 3′UTRs were distributed differently in cultured cortical neurons. The transcripts with long 3′UTR were distributed more in apical dendrites compared with transcripts with short 3′UTR. Our results provide evidence of non-coding 3′UTR function in regulating mRNA distribution in neurons.

scholarly journals Structure of the FGF Receptor Tyrosine Kinase Domain Reveals a Novel Autoinhibitory Mechanism

Cell ◽  
1996 ◽  
Vol 86 (4) ◽  
pp. 577-587 ◽  
Author(s):  
Moosa Mohammadi ◽  
Joseph Schlessinger ◽  
Stevan R Hubbard
Keyword(s):  
Tyrosine Kinase ◽  
Receptor Tyrosine Kinase ◽  
Kinase Domain ◽  
Tyrosine Kinase Domain ◽  
Fgf Receptor

scholarly journals Antibodies to insulin receptor tyrosine kinase stimulate its activity towards exogenous substrates without inducing receptor autophosphorylation

1989 ◽  
Vol 260 (3) ◽  
pp. 749-756 ◽  
Author(s):  
V Baron ◽  
N Gautier ◽  
N Rochet ◽  
R Ballotti ◽  
B Rossi ◽  
...  
Keyword(s):  
Growth Factor ◽  
Tyrosine Kinase ◽  
Insulin Receptor ◽  
Receptor Tyrosine Kinase ◽  
Kinase Activity ◽  
Kinase Domain ◽  
Tyrosine Kinase Domain ◽  
Insulin Receptor Tyrosine Kinase ◽  
Substrate Phosphorylation ◽  
Exogenous Substrates

Anti-peptide antibodies directed against a highly-conserved sequence of the insulin receptor tyrosine kinase domain have been used to study the relationship between this specific region and kinase activation. Antibodies have been prepared by the injection into a rabbit of a synthetic peptide (P2) corresponding to residues 1110-1125 of the proreceptor. The peptide exhibits 88-95% sequence similarity with the corresponding sequence in the v-ros protein and in receptors for epidermal growth factor and for insulin-like growth factor 1. Two antibodies with different specificities could be separated from total antiserum obtained after immunization with P2. One antibody [anti-(P-Tyr)] cross-reacted with phosphotyrosine and immunoprecipitated solely autophosphorylated receptors. This antibody was shown to increase or decrease the receptor tyrosine kinase activity depending on its concentration. In all circumstances receptor autophosphorylation and substrate phosphorylation were modulated in a parallel fashion. The second antibody (anti-P2) failed to immunoprecipitate the insulin receptor, but was found to interact with both the peptide and the receptor by e.l.i.s.a. assay. Using a tyrosine co-polymer we found that anti-P2 activated the insulin receptor kinase leading to substrate phosphorylation at a level similar to that observed with insulin. This effect was additive to the hormonal effect. In contrast, receptor autophosphorylation was not modified by the anti-peptide. The differential effect of this anti-peptide further supports the idea that receptor autophosphorylation and kinase activity towards exogenous substrates might be independently regulated. Finally, our data suggest that conformational changes in the receptor tyrosine kinase domain may be sufficient for activation of its enzymic activity.

scholarly journals Infection of Nippostrongylus brasiliensis induces normal increase of basophils in mast cell-deficient Ws/Ws rats with a small deletion at the kinase domain of c-kit

Blood ◽  
1993 ◽  
Vol 81 (10) ◽  
pp. 2521-2529 ◽  
Author(s):  
T Kasugai ◽  
M Okada ◽  
M Morimoto ◽  
N Arizono ◽  
K Maeyama ◽  
...  
Keyword(s):  
Mast Cells ◽  
Tyrosine Kinase ◽  
Kinase Domain ◽  
Tissue Type ◽  
Tyrosine Kinase Domain ◽  
Nippostrongylus Brasiliensis ◽  
Hematopoietic Stem ◽  
Small Deletion ◽  
Nude Rats ◽  
Kit Receptor

All basophils, mucosal-type mast cells (MMC) and connective tissue-type mast cells (CTMC) are derived from the multipotential hematopoietic stem cell. Mutations at the c-kit locus resulted in deficiency of MMC and CTMC in both mice and rats. To investigate the role of the c-kit receptor tyrosine kinase for production of basophils, we used white spotting/white spotting (Ws/Ws) mutant rats that have a small deletion at the tyrosine kinase domain of the c-kit gene. When Ws/Ws, nude athymic, and normal (+/+) rats were infected with Nippostrongylus brasiliensis (NB), the number of basophils increased greater than 50- fold in the peripheral blood of Ws/Ws and +/+ rats but did not increase in that of nude rats. Blood histamine concentration increased significantly in Ws/Ws and +/+ rats but did not increase in nude rats. Immature basophils increased greater than 10-fold in the bone marrow of Ws/Ws and +/+ rats but did not increase in that of nude rats. Mature and immature basophils that developed after the NB infection were identified by electron microscopy. The present result confirms that T- cell-derived cytokines are indispensable for the augmented production of basophils and suggests that stimulation via the c-kit receptor may not be necessary for the augmented production.

FLT3 ITD and FLT3 Tyrosine Kinase Domain Mutants Induce Different Phenotypes in a Murine Bone Marrow Transplant Model.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3371-3371
Author(s):  
Rebekka Grundler ◽  
Cornelius Miething ◽  
Christian Thiede ◽  
Christian Peschel ◽  
Justus Duyster
Keyword(s):  
Bone Marrow ◽  
Clinical Outcome ◽  
Tyrosine Kinase ◽  
Lymph Nodes ◽  
Point Mutations ◽  
Marrow Transplant ◽  
Kinase Domain ◽  
Tyrosine Kinase Domain ◽  
Myeloproliferative Disease ◽  
Transplant Model

Abstract Activating mutations of FLT3 are frequent in patients with acute myeloid leukemia (AML). Two distinct types of FLT3 mutations are most common: Internal tandem duplication (ITD) of the juxtamembrane domain-coding sequence in approximately 30% of patients with AML and point mutations within the second tyrosine kinase domain (TKD) in about 7% of AML patients. Patients carrying the FLT3 ITD mutation seem to have a significantly worse prognosis, whereas the impact of TKD mutations on clinical outcome has not yet been determined. Recently, point mutations within the activation loop of FLT3 were also found in a significant percentage of infant and childhood acute lymhoblastic leukemia (ALL). Previous studies demonstrate that mice receiving transplants of bone marrow retrovirally infected with FLT3 ITD develop a myeloproliferative disease. The effect of FLT3 TKD mutations in vivo has not yet been investigated. To examine the transforming properties of FLT3 TKD mutants in primary hematopoietic cells, we used a bone marrow transplant model (BMT). Therefore we transduced bone marrow with retrovirus expressing either FLT3 D835Y or FLT3 I836M+R and transplanted it to lethally irradiated syngeneic recipient mice. As control we also transplanted mice with FLT3 WT and ITD infected bone marrow, respectively. We found that mice transplanted with FLT3 ITD developed a myeloproliferative disorder in mice, as previously described. In contrast, mice transplanted with FLT3 TKD mutants developed a lymphoid disease with distinct hematologic manifestation. Most recipients of FLT3 TKD transduced bone marrow developed T lymphoma syndrome, characterized by massive enlargement of thymus and lymph nodes. Some mice developed a B lymphoid leukemia with splenomegaly and enlarged lymph nodes. Interestingly, the disease latency of 53 to 183 days (median 102 days) of FLT3 TKD mutants contrasted with FLT3 ITD mice, which succumbed myeloproliferative disease within 53 to 70 days (median 58 days). The lymphoid manifestation and longer latency of FLT3 TKD in a murine BMT model together with the absent influence of FLT3 TKD mutations on clinical outcome of AML patients suggest differences in cell signaling between FLT3 TKD mutants and FLT3 ITD. The TKD mutants seem to require lymphoid cell context for full malignant transformation, whereas FLT3 ITDs transform myeloid cells.

Imatinib Mesylate for Refractory Acute Myeloblastic Leukemia Harboring inv(16) and C-KIT Exon 8 Mutation.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4405-4405
Author(s):  
Naofumi Matsuno ◽  
Tomoko Nanri ◽  
Toshiro Kawakita ◽  
Hiroaki Mitsuya ◽  
Norio Asou
Keyword(s):  
Tyrosine Kinase ◽  
Imatinib Mesylate ◽  
Kinase Inhibitors ◽  
Kinase Domain ◽  
Acute Myeloblastic Leukemia ◽  
Tyrosine Kinase Domain ◽  
High Dose ◽  
Term Survival ◽  
Kit Gene

Abstract While approximately 50% of acute myeloblastic leukemia (AML) patients carrying favorable karyotypes show long-term survival, treatment outcome is not universally favorable in such patients. Recently, mutations in the C-KIT and FLT3 genes were frequently found in patients with inv(16) AML. Of 15 patients we examined, 2 had the FLT3-D835 mutations, 1 had a mutation in the second tyrosine kinase domain, 1 in the juxtamembrane domain, and 1 in the exon 8 of the C-KIT gene. These mutations are potential therapeutic targets for specific tyrosine kinase inhibitors. In this study, we present a case of inv(16) AML harboring C-KIT exon 8 mutation that was successfully treated with imatinib mesylate. After treatment with low-dose cytarabine, aclarubicin and granulocyte colony-stimulating factor (CAG) plus vincristine and prednisone (VP), a 58-year-old man with AML M4Eo showed second relapse with left inguinal lymph nodes involvement. The patient was treated with high-dose cytarabine and mitoxantrone only unsuccessfully. However, the following treatment with 400 mg of imatinib mesylate for 2 weeks in combination with CAG plus VP brought about complete hematological remission. This treatment was well tolerated, and no severe adverse events occurred. This observation suggests that imatinib mesylate can be an alternative treatment modality for AML with the mutation in exon 8 of the C-KIT gene, although further studies are required to confirm the efficacy of this approach for refractory AML.

Favourable Prognosis Associated with FLT3 Tyrosine Kinase Domain Mutations in AML in Contrast to the Adverse Outcome Associated with Internal Tandem Duplications.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 334-334 ◽  
Author(s):  
Adam Mead ◽  
David Linch ◽  
Robert Hills ◽  
Keith Wheatley ◽  
Alan Burnett ◽  
...  
Keyword(s):  
Overall Survival ◽  
Tyrosine Kinase ◽  
Relapse Rate ◽  
Poor Prognosis ◽  
Disease Free Survival ◽  
Kinase Domain ◽  
Small Sample ◽  
Tyrosine Kinase Receptor ◽  
Tyrosine Kinase Domain ◽  
Tandem Duplications

Abstract It is widely accepted that internal tandem duplications (ITDs) of the juxtamembrane domain of FLT3 occur in about one quarter of cases of acute myeloid leukaemia (AML) in young adults and predict for early relapse from complete remission (CR). Constitutive activation of FLT3 can also arise from mutations in the tyrosine kinase domain (TKD) but there is controversy as to the clinical significance of this class of mutation. This is partly due to the small sample size of some studies and the inclusion of elderly patients who have a poor prognosis regardless of their FLT3 status. To definitively resolve this issue we have screened for TKD mutations in AML blast cells from 1339 young adult patients included in the UK MRC AML 10 and 12 trials using a sensitive denaturing HPLC technique (Transgenomic WAVE®). Mutant samples were confirmed by sequencing or specific restriction digest. 161 of 1339 (12%) patients had a TKD mutation which is a higher frequency than previously reported both because of the sensitivity of the technique and the detection of mutations outside the EcoRV digest site. 91 patients (6.8%) were deemed to have high level mutant arbitrarily defined as ≥ 20% of all FLT3 alleles and 70 (5.2%) had a low level mutant. 79 of the 161 (49%) mutants were Asp835Tyr. 8 mutants occurred outside the EcoRV digest site and 3 novel mutations were characterised. 372 (28%) patients in this cohort had an ITD. There was a negative correlation between the presence of an ITD and a TKD mutation with only 2.5% having evidence of both mutations. Furthermore, high levels of both class of mutation in the same patient were not seen so that it is possible that both mutations never arise in the same cell. The demographics of patients with a TKD mutation differed from those with a FLT3 ITD in that the presence of TKD mutations were not correlated with FAB type and were infrequent in patients with secondary AML. Both types of mutation were more frequent in patients with a high white count but were infrequent in patients with adverse cytogenetics. The presence of TKD mutations did not impact on CR rate, the incidence of resistant disease or the induction death rate. In contrast to FLT3 ITDs, TKD mutations were associated with a reduced relapse rate (odds ratio [OR] 0.77, 95% confidence intervals [CI] 0.59–0.99, P.04), improved disease free survival (OR 0.75, CI 0.60–0.93, P.008) and increased overall survival (OR 0.79, CI 0.64–0.97, P.02). In patients with wild type FLT3 the actuarial relapse rate at 5 years was 46%, compared to 57% with an ITD (excluding rare double mutants) and 34% in those with a TKD mutation. The overall survival at 5 years was 44%, 35% and 55% respectively. In multivariate analysis, the presence of a TKD mutation still had an effect on the relapse rate (OR 0.82, CI 0.67–1.01, P.05) and overall survival (OR 0.83, CI 0.70–0.98, P.03). These data suggest that different classes of activating mutation of the same tyrosine kinase receptor can be associated with markedly different clinical outcomes. FLT3 ITDs are associated with a poor prognosis and FLT3 TKD mutations with a relatively good prognosis. This unexpected genotype-phenotype relationship has not previously been described with oncogenic mutations and is significant to the understanding of the pathophysiology of chemoresistance as well as prognostic stratification.

Infection of Nippostrongylus brasiliensis induces normal increase of basophils in mast cell-deficient Ws/Ws rats with a small deletion at the kinase domain of c-kit

Blood ◽  
1993 ◽  
Vol 81 (10) ◽  
pp. 2521-2529 ◽  
Author(s):  
T Kasugai ◽  
M Okada ◽  
M Morimoto ◽  
N Arizono ◽  
K Maeyama ◽  
...  
Keyword(s):  
Mast Cells ◽  
Tyrosine Kinase ◽  
Kinase Domain ◽  
Tissue Type ◽  
Tyrosine Kinase Domain ◽  
Nippostrongylus Brasiliensis ◽  
Hematopoietic Stem ◽  
Small Deletion ◽  
Nude Rats ◽  
Kit Receptor

Abstract All basophils, mucosal-type mast cells (MMC) and connective tissue-type mast cells (CTMC) are derived from the multipotential hematopoietic stem cell. Mutations at the c-kit locus resulted in deficiency of MMC and CTMC in both mice and rats. To investigate the role of the c-kit receptor tyrosine kinase for production of basophils, we used white spotting/white spotting (Ws/Ws) mutant rats that have a small deletion at the tyrosine kinase domain of the c-kit gene. When Ws/Ws, nude athymic, and normal (+/+) rats were infected with Nippostrongylus brasiliensis (NB), the number of basophils increased greater than 50- fold in the peripheral blood of Ws/Ws and +/+ rats but did not increase in that of nude rats. Blood histamine concentration increased significantly in Ws/Ws and +/+ rats but did not increase in nude rats. Immature basophils increased greater than 10-fold in the bone marrow of Ws/Ws and +/+ rats but did not increase in that of nude rats. Mature and immature basophils that developed after the NB infection were identified by electron microscopy. The present result confirms that T- cell-derived cytokines are indispensable for the augmented production of basophils and suggests that stimulation via the c-kit receptor may not be necessary for the augmented production.

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