Subclinical Minute FLT3-ITD Clone Can be Detected in Clinically FLT3-ITD-Negative Acute Myeloid Leukemia
Shota YokoyamaMasahiro OnozawaShota YoshidaNaoki MiyashitaHiroyuki KimuraShogo TakahashiToshihiro MatsukawaShinichi FujisawaKosuke MikiDaisuke HidakaJunichi HashiguchiKentaro WakasaMakoto IbataYukari TakedaAkio ShigematsuKatsuya FujimotoYutaka TsutsumiAkio MoriToshimichi IshiharaYasutaka KakinokiTakeshi KondoTakanori Teshima
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Abstract ERBB2 amplification is a prognostic marker for aggressive tumors and a predictive marker for prolonged survival following treatment with HER2 inhibitors. We attempt to sub-group HER2+ tumors based on amplicon structures and co-amplified genes. We examined five HER2+ cell lines, three HER2+ xenographs and 57 HER2+ tumor tissues. ERBB2 amplification was analyzed using digital droplet PCR and low coverage whole genome sequencing. In some HER2+ tumors PPM1D , that encodes WIP1, is co-amplified. Cell lines were treated with HER2 and WIP1 inhibitors. We find that inverted duplication is the amplicon structure in the majority of HER2+ tumors. In patients suffering from an early stage disease the ERBB2 amplicon is composed of a single segment while in patients suffering from advanced cancer the amplicon is composed of several different segments. We find robust WIP1 inhibition in some HER2+ PPM1D amplified cell lines. Sub-grouping HER2+ tumors using low coverage whole genome sequencing identifies inverted duplications as the main amplicon structure and based on the number of segments, differentiates between local and advanced tumors. In addition, we found that we could determine if a tumor is a recurrent tumor or second primary tumor and identify co-amplified oncogenes that may serve as targets for therapy.
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FLT3/ITD acute myeloid leukemia is a poor prognosis disease driven by a constitutively activated receptor tyrosine kinase, making it an obvious target for drug development. The development of clinically effective FLT3 inhibitors has been slow, in part because many are multi-targeted inhibitors that are not selective or specific for FLT3. Quizartinib is the first small molecule FLT3 tyrosine kinase inhibitor expressly developed as a FLT3 inhibitor. It is potent, selective and has ideal pharmacokinetics in comparison to other compounds previously tested. This article summarizes its advantages and limitations, and details the insights into the biology of the disease that have been uncovered through the laboratory and clinical use of quizartinib.
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Abstract Mutations of the FLT3 receptor tyrosine kinase consisting of internal tandem duplications (ITD) have been detected in blasts from 20% to 30% of patients with acute myeloid leukemia (AML) and are associated with a poor prognosis. FLT3/ITD results in constitutive autophosphorylation of the receptor and factor-independent survival in leukemia cell lines. The C-28 methyl ester of the oleane triterpenoid (CDDO-Me) is a multifunctional molecule that induces apoptosis of human myeloid leukemia cells. Here, we report that CDDO-Me blocks targeting of NFκB to the nucleus by inhibiting IκB kinase β–mediated phosphorylation of IκBα. Moreover, CDDO-Me blocked constitutive activation of the signal transducer and activator of transcription 3. We report the potent and selective antiproliferative effects of CDDO-Me on FLT3/ITD-positive myeloid leukemia cell lines and primary AML cells. The present studies show that CDDO-Me treatment results in caspase-3–mediated induction of apoptosis of FLT3/ITD-expressing cells and its antiproliferative effects are synergistic with PKC412, a FLT3-tyrosine kinase inhibitor currently in clinical trials. Taken together, our studies indicate that CDDO-Me greatly enhanced the efficacy of the FLT3 inhibitor PKC412, suggesting that combining two separate pathway inhibitors might be a viable therapeutic strategy for AML associated with a FLT3/ITD mutation. Mol Cancer Res; 8(7); 986–93. ©2010 AACR.
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Acute myeloid leukemia has recently undergone a significant transition into identifying and successfully inhibiting driver mutations leading to disease. One of the most common mutations in acute myeloid leukemia involves the protein FMS-like tyrosine kinase 3 (FLT3), which leads to ligand-independent activation of intracellular signaling cascades leading to the survival and proliferation of the acute leukemia blast cell. Preclinical studies have demonstrated the presence of two dominant types of mutations of this protein: internal tandem duplication and tyrosine kinase domain mutations. Successful inhibition of this protein has proven to be challenging. While FLT3 has been shown to be successfully inhibited and shown to improve overall survival in the frontline therapy of acute myeloid leukemia in combination with cytarabine and anthracycline, relapsed and refractory (R/R) patients have not been shown to be a successful population until recently. A phase III trial (ADMIRAL trial) demonstrated significant overall survival benefit in patients receiving gilteritinib compared to patients receiving salvage chemotherapy. This review will provide an overview of the preclinical, clinical, and practical use of gilteritinib in the treatment of patients with relapsed and refractory acute myeloid leukemia with FLT3 mutation.
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The afforestation experiment of 21 poplar clones was conducted in Yiling District of Yichang City located in the western mountain areas of Hubei.The results showed that the five clones including clone 'Lushan',clone 'M81-18',clone '351',clone '375' and clone 'Zhonghan-17' were of excellent characteristics in growth and stable in the areas and not only suitable for intensive short-rotation plantation but also suitable for Short-rotation plantation.However,7 clones of 21 clones including clone 'Zhongjia-8',clone 'Zhongjia-5',clone 'Zhongjian-1',clone 'Zhongjian-3',clone 'Tianyan',clone 'Liaohe' and clone '108' were unsuitable for their lower survival rate and slow growth.The results provided a good basis for the selection of superior poplar clones in the western mountain areas of the Hubei.
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Constitutive activation of the fms-like tyrosine kinase 3 (FLT3) receptor by internal tandem duplication (ITD) of the juxtamembrane region has been described in patients with acute myeloid leukemia. FLT3/ITDs are present in about 20-30% of all acute myeloid leukemia cases. It has been shown that the mutation is correlated with worse prognosis. However, none of the previous studies investigated which FAB subtype is associated with higher percentage of FLT3/ITD, thus the reason for undertaking the current study.The prevalence and the potential prognostic impact of FLT3 mutations in 39 acute myeloid leukemia patients were analyzed by genomic polymerase chain reaction. Twelve samples with FLT3/ITDs and 27 acute myeloid leukemia samples without the mutations were compared with respect to clinical prognosis and FAB subtype. Results were correlated with cytogenetic data and the clinical response.FLT3/ITD mutations were found in 31% of patients. FLT3/ITD was associated with similar clinical characteristics and was more prevalent in patients with normal karyotype (83%). Interestingly, half of the FLT3/ITD aberrations were found in patients with FAB M1 (50%), and fewer were found in patients with FAB M2 (8%), M4 (8%), and M5 (8%). Although less frequent in patients with cytogenetic aberrations, FLT3/ITDs were found in 17% of patients with t(15;17). Although the study was powered to 80%, patients with FLT3/ITD mutation did not show shorter complete remission duration or a higher relapse rate.The data confirm that FLT3/ITD mutations represent a common alteration in adult acute myeloid leukemia, mainly with normal karyotype (83%) and de novo acute myeloid leukemia (75%), as compared to secondary acute myeloid leukemia (25%) (p<0.001). It also showed that half of the M1-FAB subtype is FLT3/ITD positive. Therefore, FLT3/ITD is a therapeutic target, and thus inhibition of FLT3 tyrosine kinase activity may provide a new approach in the treatment of leukemia carrying these mutations.
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The prognostics implications of patients with acute myeloid leukemia harboring non-canonical FLT3 is unknown. The use of tyrosine kinase inhibitors in this patient population has not been previously reported. We report successful targeted therapy against non-ITD, non-D835 driver FLT3 alterations in two patient case studies with acute myeloid leukemia.
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Fms-like tyrosine kinase 3 (FLT3) mutations have been found in about 30% of acute myeloid leukemia (AML) cases, and the most common form of FLT3 mutation is internal tandem duplication (ITD) in the juxtamembrane domain, which is associated with poor prognosis.
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