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https://www.readbyqxmd.com/read/30544932/therapeutic-vulnerabilities-in-flt3-mutant-aml-unmasked-by-palbociclib
#1
Iris Z Uras, Barbara Maurer, Sofie Nebenfuehr, Markus Zojer, Peter Valent, Veronika Sexl
While significant progress has been made in the treatment of acute myeloid leukemia (AML), not all patients can be cured. Mutated in about 1/3 of de novo AML, the FLT3 receptor tyrosine kinase is an attractive target for drug development, activating mutations of the FLT3 map to the juxtamembrane domain (internal tandem duplications, ITD) or the tyrosine kinase domain (TKD), most frequently at codon D835. While small molecule tyrosine kinase inhibitors (TKI) effectively target ITD mutant forms, those on the TKD are not responsive...
December 11, 2018: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/30541869/high-throughput-identification-of-flt3-wild-type-and-mutant-kinase-substrate-preferences-and-application-to-design-of-sensitive-in-vitro-kinase-assay-substrates
#2
Minervo Perez, John Blankenhorn, Kevin Jason Murray, Laurie L Parker
Acute myeloid leukemia (AML) is an aggressive disease that is characterized by abnormal increase of immature myeloblasts in blood and bone marrow. The FLT3 receptor tyrosine kinase plays an integral role in haematopoiesis, and one third of AML diagnoses exhibit gain-of-function mutations in FLT3, with the juxtamembrane domain internal tandem duplication (ITD) and the kinase domain D835Y variants observed most frequently. Few FLT3 substrates or phosphorylation sites are known, which limits insight into FLT3's substrate preferences and makes assay design particularly challenging...
December 12, 2018: Molecular & Cellular Proteomics: MCP
https://www.readbyqxmd.com/read/30514174/discontinuation-of-sorafenib-can-lead-to-the-emergence-of-flt3-itd-positive-acute-myeloid-leukemia
#3
Seiji Kakiuchi, Kimikazu Yakushijin, Rina Sakai, Koji Kawaguchi, Ako Higashime, Keiji Kurata, Hiroya Ichikawa, Shigeki Nagao, Junpei Rikitake, Naomi Kiyota, Hiroshi Matsuoka, Hironobu Minami
A 69-year-old woman who had been diagnosed with unresectable papillary thyroid cancer was referred to our hospital. We initially treated her with sorafenib, but she subsequently developed erythema multiforme, which was suspected to be a drug rush due to sorafenib; therefore, sorafenib was discontinued. At the time of discontinuation, immature blast cells were detected in her peripheral blood. Approximately two weeks later, her skin rash improved substantially, but the proportion of blasts in the peripheral blood increased...
December 4, 2018: Journal of Oncology Pharmacy Practice
https://www.readbyqxmd.com/read/30513526/igf2bp2-overexpression-indicates-poor-survival-in-patients-with-acute-myelocytic-leukemia
#4
Xin He, Wenlu Li, Xiaogong Liang, Xuan Zhu, Lei Zhang, Yu Huang, Teng Yu, Shu Li, Zhigang Chen
BACKGROUND/AIMS: IGF2BP2 has been reported to serve as an oncogene in various solid cancers. However, the role of IGF2BP2 in acute myelocytic leukemia (AML) is still unknown. METHODS: Public databases Gene Omnibus was used to evaluate the expression of IGF2BP2 in AML patients and healthy controls. In addition, primary cells from these two populations were prepared by Ficoll density centrifugation. Rt-qPCR and western blot were used to detect IGF2BP2 expression in the primary cells from these two populations...
December 4, 2018: Cellular Physiology and Biochemistry
https://www.readbyqxmd.com/read/30510164/midostaurin-reduces-regulatory-t-cells-markers-in-acute-myeloid-leukemia
#5
Lucas Gutierrez, Miran Jang, Tian Zhang, Mojtaba Akhtari, Houda Alachkar
Acute myeloid leukemia (AML) is a heterogeneous hematological malignancy in which the only curative approach is allogeneic stem cell transplant (Allo-HSCT). The recognition and elimination of leukemic clones by donor T-cells contribute significantly to Allo-HSCT success. FLT3-ITD, a common mutation in AML, is associated with poor prognosis. Recently, midostaurin became the first FDA approved FLT3-inhibitor for pre-transplant patients with FLT3-ITD in combination with standard therapy. In addition to their multikinase activity which may affect T-cell signaling, FLT3-inhibitors induce apoptosis of malignant cells which may also enhance antigen presentation to activate T-cells...
December 3, 2018: Scientific Reports
https://www.readbyqxmd.com/read/30508668/discovery-of-a-highly-selective-flt3-inhibitor-with-specific-proliferation-inhibition-against-aml-cells-harboring-flt3-itd-mutation
#6
Hao Heng, Yanle Zhi, Haoliang Yuan, Zhijie Wang, Hongmei Li, Shuxian Wang, Jieyi Tian, Haichun Liu, Yadong Chen, Tao Lu, Ting Ran, Shuai Lu
FLT3 is often over-expressed in AML, and FLT3 mutants, especially FLT-ITD, are closely related to the poor prognosis in AML patients. Thus, FLT3 has become an attractive target for AML therapy. A series of FLT3 inhibitors have been evaluated in various clinical trials, one of which was approved for AML. However, current FLT3 inhibitors still faced the challenges of kinase selectivity and drug resistance due to concurrent FLT3-ITD-TKD mutations. In this work, a new FLT3 inhibitor (compound 1) with simple structure was discovered through virtually screening an in-house molecule database which contains numerous compounds with kinase-inhibition activity...
November 27, 2018: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/30503388/flt3-itd-and-cebpa-mutations-predict-prognosis-in-acute-myeloid-leukemia-irrespective-of-hematopoietic-stem-cell-transplantation
#7
Hong Wang, Tian-Tian Chu, Shi-Yu Han, Jia-Qian Qi, Ya-Qiong Tang, Hui-Ying Qiu, Cheng-Cheng Fu, Xiao-Wen Tang, Chang-Geng Ruan, De-Pei Wu, Yue Han
Cytogenetic and genetic changes have prognostic significance in acute myeloid leukemia (AML). In our study, we compared the cytogenetic changes and gene mutations (NPM1, CEBPA, DNMT3A, FLT3-ITD, FLT3-TKD and C-KIT) with clinical outcome in 1132 AML patients enrolled at our center over 10 years. A total of 977 patients provided gene mutation data: there were subsets of patients who exhibited mutations in NPM1 (17.9%), CEBPA (16.4%), FLT3-ITD (18.5%), FLT3-TKD (3.9%), DNMT3A (8.6%), and C-KIT (8.8%). A total of 557 patients (49...
November 29, 2018: Biology of Blood and Marrow Transplantation
https://www.readbyqxmd.com/read/30501709/-efficacy-of-decitabine-combined-with-pre-excitation-chemotherapy-in-the-treatment-of-middle-aged-and-elderly-mds-transformed-acute-myeloid-leukemia
#8
Zhang-Kun Li, Ying-Chang Lai, Kun Li, Ji-Xiang He, Yi-Rong Jiang, Shu-Yang Liu
OBJECTIVE: To investigate the efficacy of domestic decitabine (D) combined with pre-excitation chemotherapy consisted of Ara-c, THP and G-CSF(CTG) in treatment of middle-aged and elderly patients with MDS-transformed AML and prognosis-related factors. METHODS: Seventy-six patients with MDS-transformed AML treated in our hospital from June 2013 to June 2015 were selected according to treatment regimens, 76 patients were divided into 2 groups: CTG group(36 cases) and D+CTG group(40 cases)...
December 2018: Zhongguo Shi Yan Xue Ye Xue za Zhi
https://www.readbyqxmd.com/read/30472492/inhibition-of-the-stat5-pim-kinase-axis-enhances-cytotoxic-effects-of-proteasome-inhibitors-on-flt3-itd-positive-aml-cells-by-cooperatively-inhibiting-the-mtorc1-4ebp1-s6k-mcl-1-pathway
#9
Ayako Nogami, Keigo Okada, Shinya Ishida, Hiroki Akiyama, Yoshihiro Umezawa, Osamu Miura
FLT3-ITD and FLT3-TKD are the most frequent tyrosine kinase mutations in acute myeloid leukemia (AML), with the former conferring a poor prognosis. We have recently revealed that FLT3-ITD confers resistance to the PI3K/AKT pathway inhibitors by protecting the mTORC1/4EBP1/Mcl-1 pathway through Pim kinases induced by STAT5 activation in AML. The proteasome inhibitor bortezomib has recently been reported as a promising agent for treatment of AML. Here, we show that the proteasome inhibitor bortezomib as well as carfilzomib induces apoptosis through the intrinsic pathway more conspicuously in cells transformed by FLT3-TKD than FLT3-ITD...
November 22, 2018: Translational Oncology
https://www.readbyqxmd.com/read/30472087/high-parp-1-expression-predicts-poor-survival-in-acute-myeloid-leukemia-and-parp-1-inhibitor-and-saha-bendamustine-hybrid-inhibitor-combination-treatment-synergistically-enhances-anti-tumor-effects
#10
Xia Li, Chenying Li, Jingrui Jin, Jinghan Wang, Jiansong Huang, Zhixin Ma, Xin Huang, Xiao He, Yile Zhou, Yu Xu, Mengxia Yu, Shujuan Huang, Xiao Yan, Fenglin Li, Jiajia Pan, Yungui Wang, Yongping Yu, Jie Jin
BACKGROUND: PARP-1 plays a critical role in DNA damage repair and contributes to progression of cancer. To explore the role of PARP-1 in acute myeloid leukemia (AML), we analyzed the expression of PARP-1 in AML and its relation to the clinical prognosis. Then, we investigated the efficacy and mechanism of PARP inhibitor BMN673 (Talazoparib) combined with NL101, a novel SAHA-bendamustine hybrid in vitro and in vivo. METHODS: The expression of PARP-1 in 339 cytogenetically normal AML (CN-AML) cases was evaluated using RT-PCR...
November 21, 2018: EBioMedicine
https://www.readbyqxmd.com/read/30455361/-npm1-mutated-aml-can-relapse-with-wild-type-npm1-persistent-clonal-hematopoiesis-can-drive-relapse
#11
Alexander Höllein, Manja Meggendorfer, Frank Dicker, Sabine Jeromin, Niroshan Nadarajah, Wolfgang Kern, Claudia Haferlach, Torsten Haferlach
Acute myeloid leukemia (AML) with NPM1 mutation ( NPM1 mut ) defines a World Health Organization entity. Absence of minimal residual disease (MRD) following induction chemotherapy is associated with an excellent prognosis. Data are conflicting on NPM1 mut AML relapsing with wild-type NPM1 (NPM1 wt ). We analyzed 104 paired samples of NPM1 mut AML patients with relapse and identified 14/104 that relapsed with NPM1 wt AML. Blood counts at diagnosis differed significantly between patients with NPM1 mut and NPM1 wt relapse (median white blood cell count, 30 vs 3 × 109 /L, P = ...
November 27, 2018: Blood Advances
https://www.readbyqxmd.com/read/30450744/cd123-expression-levels-in-846-acute-leukemia-patients-based-on-standardized-immunophenotyping
#12
Anne E Bras, Valerie de Haas, Arthur van Stigt, Mojca Jongen-Lavrencic, H Berna Beverloo, Jeroen G Te Marvelde, C Michel Zwaan, Jacques J M van Dongen, Jeanette H W Leusen, Vincent H J van der Velden
BACKGROUND: While it is known that CD123 is normally strongly expressed on plasmacytoid dendritic cells and completely absent on nucleated red blood cells, detailed information regarding CD123 expression in acute leukemia is scarce and, if available, hard to compare due to different methodologies. METHODS: CD123 expression was evaluated using standardized EuroFlow immunophenotyping in 139 pediatric AML, 316 adult AML, 193 pediatric BCP-ALL, 69 adult BCP-ALL, 101 pediatric T-ALL, and 28 adult T-ALL patients...
November 18, 2018: Cytometry. Part B, Clinical Cytometry
https://www.readbyqxmd.com/read/30450160/knock-in-of-the-wt1-r394w-mutation-causes-mds-and-cooperates-with-flt3-itd-to-drive-aggressive-myeloid-neoplasms-in-mice
#13
Colleen E Annesley, Cara Rabik, Amy S Duffield, Rachel E Rau, Daniel Magoon, Li Li, Vicki Huff, Donald Small, David M Loeb, Patrick Brown
Wilms tumor 1 (WT1) is a zinc finger transcriptional regulator, and has been implicated as both a tumor suppressor and oncogene in various malignancies. Mutations in the DNA-binding domain of the WT1 gene are described in 10-15% of normal-karyotype AML (NK-AML) in pediatric and adult patients. Similar WT1 mutations have been reported in adult patients with myelodysplastic syndrome (MDS). WT1 mutations have been independently associated with treatment failure and poor prognosis in NK-AML. Internal tandem duplication (ITD) mutations of FMS-like tyrosine kinase 3 ( FLT3 ) commonly co-occur with WT1 -mutant AML, suggesting a cooperative role in leukemogenesis...
October 19, 2018: Oncotarget
https://www.readbyqxmd.com/read/30441973/detection-of-flt3-mutations-in-patients-from-eastern-slovakia
#14
Dubayová Katarína, Kožlejová Zuzana, Vašková Judita, Čakanová Gladys, Kiktavá Mária, Guman Tomáš, Sabo Ján, Karabinos Anton
BACKGROUND: The study investigated FLT3 gene mutations in patients from eastern Slovakia using a simple molecular method. PATIENTS AND METHODS: We analyzed 141 patients with primary acute myeloid leukemia (AML) and 8 patients with AML that developed from myelodysplastic syndrome (MDS) who were aged 19-81 years. DNA isolated from peripheral blood and/or bone marrow was analyzed by PCR. FLT3 internal tandem duplication (FLT3-ITD) was detected by amplification of exons 14 and 15...
2018: Klinická Onkologie: Casopis Ceské a Slovenské Onkologické Spolecnosti
https://www.readbyqxmd.com/read/30423915/recent-studies-on-ponatinib-in-cancers-other-than-chronic-myeloid-leukemia
#15
REVIEW
Francesca Musumeci, Chiara Greco, Giancarlo Grossi, Alessio Molinari, Silvia Schenone
Ponatinib is a third line drug for the treatment of chronic myeloid leukemia patients, especially those that develop the gatekeeper mutation T315I, which is resistant to the first and the second line drugs imatinib, nilotinib, dasatinib and bosutinib. The compound was first identified as a pan Bcr-Abl and Src kinase inhibitor. Further studies have indicated that it is a multitargeted inhibitor that is active on FGFRs, RET, AKT, ERK1/2, KIT, MEKK2 and other kinases. For this reason, the compound has been evaluated on several cancers in which these kinases play important roles, including thyroid, breast, ovary and lung cancer, neuroblastoma, rhabdoid tumours and in myeloproliferative disorders...
November 9, 2018: Cancers
https://www.readbyqxmd.com/read/30417521/pattern-associated-leukemia-immunophenotypes-and-measurable-disease-detection-in-acute-myeloid-leukemia-or-myelodysplastic-syndrome-with-mutated-npm1
#16
Yi Zhou, Andres Moon, Eric Hoyle, Jonathan R Fromm, Xueyan Chen, Lori Soma, Stephen J Salipante, Brent L Wood, David Wu
BACKGROUND: The presence of measurable residual disease after therapy is a significant risk factor of relapse in patients with acute myeloid leukemia (AML). By detecting cells with leukemia-associated immunophenotype (LAIP), multiparameter flow cytometry (MFC) can detect residual leukemia at a level significantly lower than that detected by morphology. However, changes in LAIPs during or after therapy may pose a challenge to MRD testing. AML with mutated NPM1 represents the largest subtype of AML sharing a common leukemogenic mechanism and similar LAIPs...
November 12, 2018: Cytometry. Part B, Clinical Cytometry
https://www.readbyqxmd.com/read/30410361/clinical-use-of-flt3-inhibitors-in-acute-myeloid-leukemia
#17
REVIEW
Grerk Sutamtewagul, Carlos E Vigil
Acute myeloid leukemia (AML) is a highly heterogeneous disease. Mutation with internal tandem duplication of fms-like tyrosine kinase-3 ( FLT3 -ITD) is one of the two most common driver mutations and the presence of FLT3 -ITD delivers poor prognosis. A number of ongoing clinical efforts are focused on FLT3 inhibitor use to improve the outcomes of this otherwise difficult leukemia. Midostaurin has been shown to improve outcomes in FLT3 -mutated AML in the frontline setting. Several FLT3 inhibitors, especially second-generation agents, have shown clinically meaningful activity in relapsed or refractory AML and in patients not amenable to intensive therapy...
2018: OncoTargets and Therapy
https://www.readbyqxmd.com/read/30407095/long-term-effect-of-all-trans-retinoic-acid-and-arsenic-trioxide-sequential-maintenance-in-patients-with-acute-promyelocytic-leukemia
#18
Shandong Tao, Chunling Wang, Yue Chen, Yuan Deng, Lixiao Song, Yuyue Shi, Lanlan Ling, Banghe Ding, Zhengmei He, Liang Yu
The specific prognostic factors and the long-term effects of different treatment options in APL remain unclear. In this retrospective study, 70 APL patients were treated with ATRA + DNR/DA or ATRA + ATO regimens for induction therapy and DA or ATRA + ATO for consolidation and maintenance therapy. The prognostic factors and treatment effects on outcome were analyzed. Results showed that the 5-year OS in low-intermediate risk and high risk groups were 95.63% and 100%, and the 5-year RFS were 95.34% and 100%, respectively, the early mortality rate was 4...
November 8, 2018: Leukemia & Lymphoma
https://www.readbyqxmd.com/read/30405611/incubation-of-immune-cell-grafts-with-max-16h5-igg1-anti-human-cd4-antibody-prolonged-survival-after-hematopoietic-stem-cell-transplantation-in-a-mouse-model-for-fms-like-tyrosine-kinase-3-positive-acute-myeloid-leukemia
#19
Nadja Hilger, Claudia Mueller, Lilly Stahl, Anne M Mueller, Bianca Zoennchen, Sarah Dluczek, Christoph Halbich, Claudia Wickenhauser, Dennis Gerloff, Alexander A Wurm, Gerhard Behre, Anna Kretschmer, Stephan Fricke
Despite the constant development of innovative therapeutic options for hematological malignancies, the gold-standard therapy regimen for curative treatment often includes allogeneic hematopoietic stem cell transplantation (HSCT). The graft-vs.-leukemia effect (GVL) is one of the main therapeutic goals that arises from HSCT. On the other hand, graft-vs.-host disease (GVHD) is still one of the main and most serious complications following allogeneic HSCT. In acute myeloid leukemia (AML), HSCT together with high-dose chemotherapy is used as a treatment option...
2018: Frontiers in Immunology
https://www.readbyqxmd.com/read/30389660/prognostic-models-turn-the-heat-it-up-on-flt3itd-mutated-aml
#20
Paolo Gallipoli, Brian Jp Huntly
The presence of internal tandem duplications (ITDs) in the FLT3 receptor tyrosine kinase gene have long been known to confer a poor prognosis to acute myeloid leukemia (AML) patients. Now, specific structural features of the ITD are also suggested to alter patient outcome, including sensitivity to targeted therapies, prompting their evaluation in therapeutic algorithms.
November 2, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
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