No Evidence for Constitutively Activated FLT3 in Juvenile Myelo-Monocytic Leukemia.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4915-4915
Author(s):  
Andrica C.H. de Vries ◽  
Ronald W. Stam ◽  
Pauline Schneider ◽  
Charlotte M. Niemeyer ◽  
Elisabeth R. van Wering ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Kinase Inhibitors ◽  
Kinase Domain ◽  
Leukemic Cells ◽  
Tyrosine Kinase Domain ◽  
Mrna Levels ◽  
Monocytic Leukemia ◽  
Real Time Quantitative Pcr ◽  
Flt3 Inhibitor ◽  
Flt3 Mutations

Abstract Activating FLT3 mutations have been identified as prognostic factors in multiple myeloid malignancies. Recent studies have demonstrated that ligand-independent activation of FLT3 can also result from overexpression of wild-type FLT3. In addition, ligand-dependent activation has been observed in leukemic cells co-expressing FLT3 ligand (FLT3L), resulting in autocrine FLT3 signaling which is independent of FLT3 mutations. In Juvenile Myelo-Monocytic Leukemia (JMML), FLT3 internal tandem duplications (FLT3/ITDs) mutations affecting the tyrosine kinase domain (TKD) are rare. However, no data are yet available on the frequency of expression levels of FLT3 and FLT3L in JMML. If activated FLT3 occurs in JMML, one could imagine that these patients might benefit from treatment with small molecule FLT3 inhibitors, especially as to date the curative treatment of JMML is limited to allogeneous bone marrow transplantation. In 36 JMML patients FLT3 and FLT3L mRNA levels were assessed using real-time quantitative PCR (Taqman). Furthermore these samples were screened for the presence of activating FLT3/ITDs and FLT3/TKD mutations. MTT assays were performed to assess the response of JMML cells to the known FLT3 inhibitor PKC412 (Novartis). FLT3 appeared to be expressed only at basal levels and FLT3L expression was very low. In none of the 36 JMML samples FLT3/ITDs or TDK mutations were found, consistent with the observation that PKC412 was not cytotoxic in JMML samples (n=12), in contrast to leukemic cells of children with ALL which carried an activated FLT3. These data suggest that constitutively activated FLT3 does not occur in JMML. Therefore targeting FLT3 by tyrosine kinase inhibitors like PKC412 is unlikely to be effective in JMML.

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 Gilteritinib is a clinically active FLT3 inhibitor with broad activity against FLT3 kinase domain mutations

2020 ◽  
Vol 4 (3) ◽  
pp. 514-524 ◽  
Author(s):  
Theodore C. Tarver ◽  
Jason E. Hill ◽  
Leena Rahmat ◽  
Alexander E. Perl ◽  
Erkut Bahceci ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Kinase Inhibitor ◽  
Kinase Domain ◽  
Tyrosine Kinase Domain ◽  
Flt3 Mutations ◽  
Tki Resistance ◽  
Sequencing Studies ◽  
Moderate Resistance ◽  
Vitro Analysis

Abstract Gilteritinib is the first FMS-like tyrosine kinase 3 (FLT3) tyrosine kinase inhibitor (TKI) approved as monotherapy in acute myeloid leukemia with FLT3 internal tandem duplication and D835/I836 tyrosine kinase domain (TKD) mutations. Sequencing studies in patients have uncovered less common, noncanonical (NC) mutations in FLT3 and have implicated secondary TKD mutations in FLT3 TKI resistance. We report that gilteritinib is active against FLT3 NC and TKI resistance-causing mutations in vitro. A mutagenesis screen identified FLT3 F691L, Y693C/N, and G697S as mutations that confer moderate resistance to gilteritinib in vitro. Analysis of patients treated with gilteritinib revealed that 2/9 patients with preexisting NC FLT3 mutations responded and that secondary TKD mutations are acquired in a minority (5/31) of patients treated with gilteritinib. Four of 5 patients developed F691L mutations (all treated at <200 mg). These studies suggest that gilteritinib has broad activity against FLT3 mutations and limited vulnerability to resistance-causing FLT3 TKD mutations, particularly when used at higher doses.

scholarly journals Treatment with FLT3 inhibitor in patients withFLT3-mutated acute myeloid leukemia is associated with development of secondaryFLT3-tyrosine kinase domain mutations

Cancer ◽  
2014 ◽  
Vol 120 (14) ◽  
pp. 2142-2149 ◽  
Author(s):  
Yesid Alvarado ◽  
Hagop M. Kantarjian ◽  
Rajyalakshmi Luthra ◽  
Farhad Ravandi ◽  
Gautam Borthakur ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Myeloid Leukemia ◽  
Kinase Domain ◽  
Tyrosine Kinase Domain ◽  
Flt3 Inhibitor ◽  
Kinase Domain Mutations ◽  
Acute Myeloid

Expanding the search for significant EGFR mutations in NSCLC outside of the tyrosine kinase domain (TKD) with next-generation sequencing (NGS).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e20506-e20506
Author(s):  
Matthew K Stein ◽  
Lindsay Kaye Morris ◽  
Jennifer Sullivan ◽  
Moon Jung Fenton ◽  
Ari M. Vanderwalde ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
In Silico ◽  
Kinase Inhibitors ◽  
Stage Iv ◽  
In Silico Analysis ◽  
Large Cell ◽  
Kinase Domain ◽  
Egfr Mutations ◽  
Tyrosine Kinase Domain ◽  
Carboxy Terminal

e20506 Background: While conventional organization of EGFR mutations in NSCLC includes classic lesions sensitive to tyrosine kinase inhibitors (TKI) and variants localized to TKD in exons 18-21, NGS raises the prospect of identifying clinically relevant variants in extra-TKD regulatory regions. Methods: Patients (pts) with lung cancer who received tumor profiling with NGS from 2013-2015 via Caris were identified. EGFR mutations were arranged based upon their known distribution relative to the TKD. In silico analysis was performed with PolyPhen-2 (Harvard) to predict nsSNPs’ pathogenicity. Results: 259 pts (248 NSCLC, 11 SC) had median age 65 years (26-85); 50% female; 64% white, 34% black; 73% with ≥20 pack-years (py), 12% non-smokers; 53% of samples were metastases. 65% NSCLC were adenocarcinoma (A), 21% squamous (S), 8% large-cell; 87% stage IV, 12% III. 44 EGFR variants were seen in 40 pts (15%; 39 NSCLC, 1 SC). While 32 pts had TKD lesions demonstrable through standard testing, 8 had extra-TKD mutations (8/44), of which 5 were extracellular domain (ECD), 1 juxtamembrane (JM) and 2 carboxy terminal (CT). Aside from pathogenic ECD mutation G598V, 5/7 extra-TKD nsSNPs were predicted-damaging (pnsSNP) with in silico (Table 1). 7/7 extra-TKD nsSNP+ pts smoked (6/7 ≥20 py) and all 6 NSCLC pts were stage IV; 50% A, 17% S; 83% male. The pt with JM R675Q had erlotinib, 150 mg daily, added following progression of stage IV NSCLC on carboplatin and paclitaxel and had a partial response for 4 months. No other pt received EGFR-directed therapy. Conclusions: 2% NSCLC cases in our cohort had EGFR pnsSNPs located outside of the TKD, representing >18% of all EGFR mutations. Extra-TKD variants should be characterized collaboratively to determine TKI sensitivity and additional therapeutic targets. [Table: see text]

New insights into the mechanisms of hematopoietic cell transformation by activated receptor tyrosine kinases

Blood ◽  
2010 ◽  
Vol 116 (14) ◽  
pp. 2429-2437 ◽  
Author(s):  
Federica Toffalini ◽  
Jean-Baptiste Demoulin
Keyword(s):  
Growth Factor ◽  
Tyrosine Kinase ◽  
Tyrosine Kinases ◽  
Kinase Inhibitors ◽  
Cell Transformation ◽  
Chromosomal Rearrangements ◽  
Point Mutations ◽  
Large Cell ◽  
Kinase Domain ◽  
Leukemic Cells

Abstract A large number of alterations in genes encoding receptor tyrosine kinase (RTK), namely FLT3, c-KIT, platelet-derived growth factor (PDGF) receptors, fibroblast growth factor (FGF) receptors, and the anaplastic large cell lymphoma kinase (ALK), have been found in hematopoietic malignancies. They have drawn much attention after the development of tyrosine kinase inhibitors. RTK gene alterations include point mutations and gene fusions that result from chromosomal rearrangements. In both cases, they activate the kinase domain in the absence of ligand, producing a permanent signal for cell proliferation. Recently, this simple model has been refined. First, by contrast to wild-type RTK, many mutated RTK do not seem to signal from the plasma membrane, but from various locations inside the cell. Second, their signal transduction properties are altered: the pathways that are crucial for cell transformation, such as signal transducer and activator of transcription (STAT) factors, do not necessarily contribute to the physiologic functions of these receptors. Finally, different mechanisms prevent the termination of the signal, which normally occurs through receptor ubiquitination and degradation. Several mutations inactivating CBL, a key RTK E3 ubiquitin ligase, have been recently described. In this review, we discuss the possible links among RTK trafficking, signaling, and degradation in leukemic cells.

scholarly journals SRC is a signaling mediator in FLT3-ITD– but not in FLT3-TKD–positive AML

Blood ◽  
2012 ◽  
Vol 119 (17) ◽  
pp. 4026-4033 ◽  
Author(s):  
Hannes Leischner ◽  
Corinna Albers ◽  
Rebekka Grundler ◽  
Elena Razumovskaya ◽  
Karsten Spiekermann ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Point Mutations ◽  
Kinase Domain ◽  
Sh2 Domain ◽  
Src Family Kinases ◽  
Tyrosine Kinase Domain ◽  
Molecular Abnormalities ◽  
Flt3 Mutations ◽  
Worse Prognosis ◽  
Tandem Duplications

Abstract Mutations of Fms-like tyrosine kinase 3 (FLT3) are among the most frequently detected molecular abnormalities in AML patients. Internal tandem duplications (ITDs) are found in approximately 25% and point mutations within the second tyrosine kinase domain (TKD) in approximately 7% of AML patients. Patients carrying the FLT3-ITD but not the FLT3-TKD mutation have a significantly worse prognosis. Therefore, both FLT3 mutations seem to exert different biologic functions. FLT3-ITD but not FLT3-TKD has been shown to induce robust activation of the STAT5 signaling pathway. In the present study, we investigated the mechanisms leading to differential STAT5 activation and show that FLT3-ITD but not FLT3-TKD uses SRC to activate STAT5. Coimmunoprecipitation and pull-down experiments revealed an exclusive interaction between SRC but not other Src family kinases and FLT3-ITD, which is mediated by the SRC SH2 domain. We identified tyrosines 589 and 591 of FLT3-ITD to be essential for SRC binding and subsequent STAT5 activation. Using site-specific Abs, we found that both residues were significantly more strongly phosphorylated in FLT3-ITD compared with FLT3-TKD. SRC inhibition and knock-down blocked STAT5 activation and proliferation induced by FLT3-ITD but not by FLT3-TKD. We conclude that SRC might be a therapeutic target in FLT3-ITD+ AML.

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.

Activating FLT3 Mutations in CD4+/CD8− Pediatric T-Cell Acute Lymphoblastic Leukemias.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1465-1465
Author(s):  
Pieter Van Vlierberghe ◽  
Jules P.P. Meijerink ◽  
Ronald W. Stam ◽  
Wendy van der Smissen ◽  
Elisabeth R. van Wering ◽  
...  
Keyword(s):  
T Cell ◽  
Tyrosine Kinase ◽  
Point Mutations ◽  
Kinase Domain ◽  
Tyrosine Kinase Domain ◽  
Activating Mutations ◽  
Activated State ◽  
Flt3 Mutations ◽  
Genetic Aberration ◽  
High Level

Abstract Activating mutations in the FMS-like tyrosine kinase 3 gene (FLT3) are the most common genetic aberration in acute myeloid leukemia (AML). Internal tandem duplications (ITD) in the juxtamembrane (JM) domain, or point mutations (PM) in the activation loop of the tyrosine kinase domain lead to a constitutive activated state of the FLT3 tyrosine kinase. Recently, FLT3 mutations were identified in a cohort of 69 adult T-ALL patients, showing that this genetic abnormality is not only restricted to myeloid leukemias. To validate the incidence of FLT3 mutations in pediatric T-ALL and investigate its relation to outcome and other clinical and immunophenotypical parameters, we screened 72 diagnostic pediatric T-ALL samples. FLT3/ITD mutations were identified in 2/72 pediatric T-ALLs (2.7%), whereas 0/72 showed point mutations in the kinase domain. Immunophenotypic analysis revealed a similar profile for both FLT3 mutated patient samples, i.e. TdT+, CD2+, CD5+, CD7+, CD4+/CD8−, cytoplasmic CD3+, surface CD3− and CD10−. Although representing early T-cell differentiation stages for both patient samples, these cases seem to have a more advanced immunophenotype compared to the FLT3 mutated adult T-ALL cases, previously described (CD34+, CD4−/CD8−). Both FLT3 mutated patients showed high level LYL1 and LMO2 expression. In addition, both pediatric samples contained a HOX11L2 translocation, which was not present in the FLT3 mutated adult T-ALL cases. The first FLT3 mutated patient suffered a relapse 13 months after initial diagnosis, whereas the other is still in continued complete remission for 61+ months. Interestingly, the relapse material showed no FLT3/ITD mutation, indicating that the FLT3 mutated T-ALL subclone seems to be effectively eradicated by current chemotherapy. These data suggest that the application of FLT3 inhibitors for FLT3-mutated T-ALLs, as recently suggested in literature, may not further improve treatment outcome in pediatric T-ALL.

FLT3 Mutations at Diagnosis and Relapse in Acute Myeloid Leukemia: Cytogenetic and Pathologic Correlations, Including Cuplike Blast Morphology

2010 ◽  
Vol 134 (8) ◽  
pp. 1143-1151 ◽  
Author(s):  
Stanley R. McCormick ◽  
Matthew J. McCormick ◽  
Patricia S. Grutkoski ◽  
Gregory S. Ducker ◽  
Nilanjana Banerji ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Myeloid Leukemia ◽  
Kinase Domain ◽  
World Health ◽  
Tyrosine Kinase Domain ◽  
Mutation Status ◽  
Flt3 Mutation ◽  
Flt3 Mutations ◽  
Health Organization ◽  
Acute Myeloid

Abstract Context.—Acquired mutations in the fms-like tyrosine kinase 3 gene (FLT3) adversely impact relapse risk after chemotherapy in patients with acute myeloid leukemia (AML). The FLT3 mutation status may differ at diagnosis and relapse, suggesting a potential role in chemoresistance, yet few reports have addressed the cytogenetic and pathologic correlates of FLT3 mutations in relapsed AML. Objectives.—To determine FLT3 mutations at diagnosis and relapse in a cohort of adult patients with chemoresistant AML and to correlate mutation status with multiple variables. Design.—We retrospectively determined FLT3 internal tandem duplication (FLT3/ITD) and FLT3 tyrosine kinase domain mutations in 50 diagnosis/relapse pairs. We correlated FLT3 status with karyotype, World Health Organization 2008 subtype, white blood cell count, biopsy cellularity, blast percentage, and the presence of invaginated (“cuplike”) blast nuclei. Results.—In 11 of 50 patients (22%) the FLT3 mutation status differed at relapse and diagnosis, with a trend toward gain of FLT3/ITD (n  =  7) and loss of FLT3 tyrosine kinase domain (n  =  5) mutations. FLT3-mutated AMLs correlated with the World Health Organization 2008 subtype, AML, not otherwise specified, hyperproliferative features at diagnosis and relapse, and cytogenetic evolution. FLT3-wild type AMLs correlated with the subtype AML with myelodysplasia-related changes and frequently had adverse presentation karyotypes. Cuplike blast morphology was associated with FLT3/ITD+ status and with high mutation levels. Four of 7 patients with relapse-only FLT3/ITD mutations exhibited cuplike blasts at relapse after being noncuplike at diagnosis. Conclusions.—In addition to well-known correlates in pretreatment specimens, FLT3 mutation status has pathologic and cytogenetic significance at relapse. A shift to cuplike blast morphology at relapse may herald emergence of a previously undetected FLT3/ITD mutation.

Sign in / Sign up

Export Citation Format

Share Document