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Flt3-itd

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https://www.readbyqxmd.com/read/28937371/npm1-and-flt3-mutations-in-acute-myeloid-leukemia-with-normal-karyotype-indian-perspective
#1
Sudha Sazawal, Neha Singh, Sonal Jain, Sunita Chhikara, Rekha Chaubey, Jina Bhattacharyya, Kandarpa Kr Saikia, Manoranjan Mahapatra, Renu Saxena
BACKGROUND: FLT3-ITD and NPM1 mutations are considered to be the major determinants of the patient response to therapy and outcome. The primary aim of this study was to establish the correlation between these molecular mutations and the clinico-hematologic parameters as well as the prognostic outcome of the Indian acute myeloid leukemia (AML) patients. MATERIALS AND METHODS: This prospective study involved newly diagnosed nonpromyelocytic AML patients who had undergone complete diagnostic workup, including immunophenotyping, conventional cytogenetics and molecular analysis for NPM1 and FLT3-ITD mutation by reverse transcriptase polymerase chain reaction at presentation...
July 2017: Indian Journal of Pathology & Microbiology
https://www.readbyqxmd.com/read/28933735/clinical-outcomes-and-co-occurring-mutations-in-patients-with-runx1-mutated-acute-myeloid-leukemia
#2
Maliha Khan, Jorge Cortes, Tapan Kadia, Kiran Naqvi, Mark Brandt, Sherry Pierce, Keyur P Patel, Gautam Borthakur, Farhad Ravandi, Marina Konopleva, Steven Kornblau, Hagop Kantarjian, Kapil Bhalla, Courtney D DiNardo
(1) Runt-related transcription factor 1 (RUNX1) mutations in acute myeloid leukemia (AML) are often associated with worse prognosis. We assessed co-occurring mutations, response to therapy, and clinical outcomes in patients with and without mutant RUNX1 (mRUNX1); (2) We analyzed 328 AML patients, including 177 patients younger than 65 years who received intensive chemotherapy and 151 patients >65 years who received hypomethylating agents. RUNX1 and co-existing mutations were identified using next-generation sequencing; (3) RUNX1 mutations were identified in 5...
July 26, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28927163/frequency-and-clinicopathologic-features-of-runx1-mutations-in-patients-with-acute-myeloid-leukemia-not-otherwise-specified
#3
Eunkyoung You, Young-Uk Cho, Seongsoo Jang, Eul-Ju Seo, Jung-Hee Lee, Je-Hwan Lee, Kyoo-Hyung Lee, Kyung-Nam Koh, Ho Joon Im, Jong Jin Seo, Young-Mi Park, Jong-Keuk Lee, Chan-Jeoung Park
Objectives: To evaluate the frequency and clinicopathologic characteristics of RUNX1 mutations, focusing on patients with acute myeloid leukemia not otherwise specified (AML NOS). Methods: Diagnostic samples from 219 patients with AML NOS were analyzed for RUNX1 mutations using standard polymerase chain reaction and direct sequencing. Results: Thirty-one RUNX1 mutations were detected in 33 (15.1%) patients. Mutations clustered in the Runt homology (61...
July 1, 2017: American Journal of Clinical Pathology
https://www.readbyqxmd.com/read/28923853/adaptation-to-tki-treatment-reactivates-erk-signaling-in-tyrosine-kinase-driven-leukemias-and-other-malignancies
#4
Joshua K Bruner, Hayley S Ma, Li Li, Alice Can Ran Qin, Michelle A Rudek, Richard J Jones, Mark J Levis, Keith W Pratz, Christine A Pratilas, Donald Small
FLT3 tyrosine kinase inhibitors (TKI) have been tested extensively to limited benefit in acute myeloid leukemia. We hypothesized that FLT3/ITD leukemia cells exhibit mechanisms of intrinsic signaling adaptation to TKI treatment that are associated with an incomplete response. Here we identified reactivation of ERK signaling within hours following treatment of FLT3/ITD AML cells with selective inhibitors of FLT3. When these cells were treated with inhibitors of both FLT3 and MEK in combination, ERK reactivation was abrogated and anti-leukemia effects were more pronounced compared to either drug alone...
September 18, 2017: Cancer Research
https://www.readbyqxmd.com/read/28914261/rsk2-is-a-new-pim2-target-with-pro-survival-functions-in-flt3-itd-positive-acute-myeloid-leukemia
#5
M-A Hospital, A Jacquel, F Mazed, E Saland, C Larrue, J Mondesir, R Birsen, A S Green, M Lambert, P Sujobert, E-F Gautier, V Salnot, M Le Gall, J Decroocq, L Poulain, N Jacque, M Fontenay, O Kosmider, C Récher, P Auberger, P Mayeux, D Bouscary, J-E Sarry, J Tamburini
Acute myeloid leukemia (AML) with the FLT3 internal tandem duplication (FLT3-ITD AML) accounts for 20-30% of AML cases. This subtype usually responds poorly to conventional therapies, and might become resistant to FLT3 tyrosine kinase inhibitors (TKIs) due to molecular bypass mechanisms. New therapeutic strategies focusing on resistance mechanisms are therefore urgently needed. Pim kinases are FLT3-ITD oncogenic targets that have been implicated in FLT3 TKI resistance. However, their precise biological function downstream of FLT3-ITD requires further investigation...
September 15, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28895560/tyrosine-kinase-inhibition-increases-the-cell-surface-localization-of-flt3-itd-and-enhances-flt3-directed-immunotherapy-of-acute-myeloid-leukemia
#6
K Reiter, H Polzer, C Krupka, A Maiser, B Vick, M Rothenberg-Thurley, K H Metzeler, D Dörfel, H R Salih, G Jung, E Nößner, I Jeremias, W Hiddemann, H Leonhardt, K Spiekermann, M Subklewe, P A Greif
The fms-related tyrosine kinase 3 (FLT3) receptor has been extensively studied over the past two decades with regard to oncogenic alterations that do not only serve as prognostic markers but also as therapeutic targets in acute myeloid leukemia (AML). Internal tandem duplications (ITDs) became of special interest in this setting as they are associated with unfavorable prognosis. Because of sequence-dependent protein conformational changes FLT3-ITD tends to autophosphorylate and displays a constitutive intracellular localization...
August 14, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28894287/prognostic-significance-of-high-gfi1-expression-in-aml-of-normal-karyotype-and-its-association-with-a-flt3-itd-signature
#7
Giacomo Volpe, David S Walton, David E Grainger, Carl Ward, Pierre Cauchy, Daniel Blakemore, Daniel J L Coleman, Peter N Cockerill, Paloma Garcia, Jon Frampton
Growth Factor Independence 1 (GFI1) is a transcriptional repressor that plays a critical role during both myeloid and lymphoid haematopoietic lineage commitment. Several studies have demonstrated the involvement of GFI1 in haematological malignancies and have suggested that low expression of GFI1 is a negative indicator of disease progression for both myelodysplastic syndromes (MDS) and acute myeloid leukaemia (AML). In this study, we have stratified AML patients into those defined as having a normal karyotype (CN-AML)...
September 11, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28893624/cd8-t-cells-expressing-both-pd-1-and-tigit-but-not-cd226-are-dysfunctional-in-acute-myeloid-leukemia-aml-patients
#8
Mengjie Wang, Jin Bu, Maohua Zhou, Jessica Sido, Yu Lin, Guanfang Liu, Qiwen Lin, Xiuzhang Xu, Jianmei W Leavenworth, Erxia Shen
Acute myeloid leukemia (AML) is one of the most common types of leukemia among adults with an overall poor prognosis and very limited treatment management. Immune checkpoint blockade of PD-1 alone or combined with other immune checkpoint blockade has gained impressive results in murine AML models by improving anti-leukemia CD8(+)T cell function, which has greatly promoted the strategy to utilize combined immune checkpoint inhibitors to treat AML patients. However, the expression profiles of these inhibitory receptors in T cells from AML patients have not been clearly defined...
September 8, 2017: Clinical Immunology: the Official Journal of the Clinical Immunology Society
https://www.readbyqxmd.com/read/28884855/overexpression-of-mir-216b-prognostic-and-predictive-value-in-acute-myeloid-leukemia
#9
Ting-Juan Zhang, De-Hong Wu, Jing-Dong Zhou, Xi-Xi Li, Wei Zhang, Hong Guo, Ji-Chun Ma, Zhao-Qun Deng, Jiang Lin, Jun Qian
Accumulating studies have shown that miR-216b acted as a tumor suppressor and was down-regulated in solid tumors. However, little studies revealed the role or clinical implication of miR-216b in blood cancers. Herein, we reported miR-216b expression and its clinical significance in patients with acute myeloid leukemia (AML). In the current study, we analyzed bone marrow (BM) miR-216b expression in 115 de novo AML patients examined by real-time quantitative PCR. Notably, BM miR-216b expression was significantly up-regulated in AML patients, and could serve as a potential biomarker distinguishing AML from controls...
September 8, 2017: Journal of Cellular Physiology
https://www.readbyqxmd.com/read/28883284/pediatric-acute-myeloid-leukemia-with-genetic-alterations
#10
Akira Shimada
Annually, it is estimated that approximately 150-200 children aged 0-16 years are diagnosed with acute myeloid leukemia (AML). In Japan, clinical studies with ANLL91, AML99, CCLSG-AML9805, and JPLSG-AML05 protocols were performed historically, and the risk stratification with a combination of chemotherapy and hematopoietic stem cell transplantation resulted in the improvement of clinical outcomes. Regarding the onset of pediatric AML at the molecular level, mutations in FLT3-ITD or KIT (Class I mutation) showed a poor prognosis, but the ratio of mutations in Class III-V genes was smaller than that in adult AML...
2017: [Rinshō Ketsueki] the Japanese Journal of Clinical Hematology
https://www.readbyqxmd.com/read/28881711/characterization-of-midostaurin-as-a-dual-inhibitor-of-flt3-and-syk-and-potentiation-of-flt3-inhibition-against-flt3-itd-driven-leukemia-harboring-activated-syk-kinase
#11
Ellen L Weisberg, Alexandre Puissant, Richard Stone, Martin Sattler, Sara J Buhrlage, Jing Yang, Paul W Manley, Chengcheng Meng, Michael Buonopane, John F Daley, Suzan Lazo, Renee Wright, David M Weinstock, Amanda L Christie, Kimberly Stegmaier, James D Griffin
Oncogenic FLT3 kinase is a clinically validated target in acute myeloid leukemia (AML), and both multi-targeted and selective FLT3 inhibitors have been developed. Spleen tyrosine kinase (SYK) has been shown to be activated and increased in FLT3-ITD-positive AML patients, and has further been shown to be critical for transformation and maintenance of the leukemic clone in these patients. Further, over-expression of constitutively activated SYK causes resistance to highly selective FLT3 tyrosine kinase inhibitors (TKI)...
August 8, 2017: Oncotarget
https://www.readbyqxmd.com/read/28876197/the-impact-of-flt3-mutations-on-treatment-response-and-survival-in-chinese-de%C3%A2-novo-aml-patients
#12
Qiao-Cheng Qiu, Chao Wang, Xie-Bing Bao, Jing Yang, Hong-Jie Shen, Zi-Xuan Ding, Hong Liu, Jun He, Hong Yao, Su-Ning Chen, Zheng Li, Sheng-Li Xue, Song-Bai Liu
OBJECTIVE: Two distinct forms of FMS-like tyrosine kinase 3 (FLT3) mutations, internal tandem duplication (ITD) in the juxtamembrane domain and point mutation within the activation loop of the tyrosine kinase domain (TKD), have been identified in considerable number of patients with AML. This study was aimed to analyze the impacts of these mutations on clinical outcomes, and assess the efficacy of different therapeutic regimens (allo-HSCT, sorafenib, or conventional chemotherapy) for AML patients with FLT3 mutations after the standard induction therapy...
September 6, 2017: Hematology (Amsterdam, Netherlands)
https://www.readbyqxmd.com/read/28857842/relapsed-refractory-acute-myeloid-leukemia-any-progress
#13
Richard F Schlenk, Carsten Müller-Tidow, Axel Benner, Meinhard Kieser
PURPOSE OF REVIEW: Aim of this review was to focus on prognostic and predictive factors, standard and new treatment approaches, and on statistical considerations for future clinical trials in patients with relapsed/refractory acute myeloid leukemia (r/r-AML). RECENT FINDINGS: New prognostic molecular markers were identified in r/r-AML, FLT3-ITD, mutated IDH1, and biallelic CEBPA mutations. Intensive combination chemotherapy including gemtuzumab ozogamicin emerged as an effective salvage therapy in refractory AML...
August 28, 2017: Current Opinion in Oncology
https://www.readbyqxmd.com/read/28841206/overexpression-of-sox4-correlates-with-poor-prognosis-of-acute-myeloid-leukemia-and-is-leukemogenic-in-zebrafish
#14
J-W Lu, M-S Hsieh, H-A Hou, C-Y Chen, H-F Tien, L-I Lin
The SOX4 transcription factor is a key regulator of embryonic development, cell-fate decision, cellular differentiation and oncogenesis. Abnormal expression of SOX4 is related to malignant tumor transformation and cancer metastasis. However, no reports are available regarding the clinical significance of SOX4 in acute myeloid leukemia (AML) and the role of SOX4 in leukemogenesis. In the current study, we found that AML patients with low bone marrow (BM) SOX4 expression had higher remission rates and longer overall survival than those with high SOX4 expression, regardless of age, white blood cell count at diagnosis, karyotype profile and NPM1/FLT3-ITD status...
August 25, 2017: Blood Cancer Journal
https://www.readbyqxmd.com/read/28835438/molecular-synergy-underlies-the-co-occurrence-patterns-and-phenotype-of-npm1-mutant-acute-myeloid-leukemia
#15
Oliver M Dovey, Jonathan L Cooper, Annalisa Mupo, Carolyn S Grove, Claire Lynn, Nathalie Conte, Robert M Andrews, Suruchi Pacharne, Konstantinos Tzelepis, M S Vijayabaskar, Paul Green, Roland Rad, Mark Arends, Penny Wright, Kosuke Yusa, Allan Bradley, Ignacio Varela, George S Vassiliou
NPM1 mutations define the commonest subgroup of acute myeloid leukemia (AML) and frequently co-occur with FLT3 internal tandem duplications (ITD) or, less commonly, NRAS or KRAS mutations. Co-occurrence of mutant NPM1 with FLT3-ITD carries a significantly worse prognosis than NPM1-RAS combinations. To understand the molecular basis of these observations we compare the effects of the two combinations on hematopoiesis and leukemogenesis in knock-in mice. Early effects of these mutations on hematopoiesis show that compound Npm1(cA/+);Nras(G12D/+) or Npm1(cA);Flt3(ITD) share a number of features: Hox gene over-expression, enhanced self-renewal, expansion of hematopoietic progenitors and myeloid differentiation bias...
August 23, 2017: Blood
https://www.readbyqxmd.com/read/28825709/ascorbate-regulates-haematopoietic-stem-cell-function-and-leukaemogenesis
#16
Michalis Agathocleous, Corbin E Meacham, Rebecca J Burgess, Elena Piskounova, Zhiyu Zhao, Genevieve M Crane, Brianna L Cowin, Emily Bruner, Malea M Murphy, Weina Chen, Gerald J Spangrude, Zeping Hu, Ralph J DeBerardinis, Sean J Morrison
Stem cell fate can be influenced by metabolite levels in culture but it is unknown whether physiological variations in metabolite levels in normal tissues regulate stem cell function in vivo. We developed a metabolomics method for analysis of rare cell populations isolated directly from tissues and used it to compare haematopoietic stem cells (HSCs) to restricted haematopoietic progenitors. Each haematopoietic cell type had a distinct metabolic signature. Human and mouse HSCs had unusually high levels of ascorbate, which declined with differentiation...
August 21, 2017: Nature
https://www.readbyqxmd.com/read/28810326/-the-analysis-of-prognosis-associated-factors-in-adults-with-acute-promyelocytic-leukemia
#17
R J Ma, Z M Zhu, X L Yuan, L Jiang, S W Yang, J Yang, J M Guo, J Shi, P C Lei, L Zhang, B J Shang, K Sun, Y P Zhai, W Li, Y Zhang
Objective: To explore the prognostic value of CD34, CD2, CD56 expressions and FLT3-ITD mutation in adults with acute promyelocytic leukemia (APL) . Methods: The immuno-phenotypic and molecular characteristics of 137 adult patients with APL (from January 2010 to March 2016, in Henan Provincial People's Hospital) were investigated. And the relationships between CD34, CD2, CD56 expressions, FLT3-ITD mutation and the outcomes of high WBC counts at onset, complete remission (CR) rate, early mortality, relapse rate (RR) , overall survival (OS) , disease free survival (DFS) were explored...
July 14, 2017: Zhonghua Xue Ye Xue za Zhi, Zhonghua Xueyexue Zazhi
https://www.readbyqxmd.com/read/28810324/-minimal-residual-disease-level-predicts-outcomes-in-the-non-favorable-risk-patients-with-acute-myeloid-leukemia
#18
X Ren, T Zhao, J Wang, H H Zhu, H Jiang, J S Jia, S M Yang, B Jiang, D B Wang, X J Huang, Q Jiang
Objective: To explore impact of minimal residual leukemia (MRD) on outcomes in the non-favorable risk adults with de novo acute myeloid leukemia (AML) . Methods: From January 2008 to February 2016, data of consecutive newly-diagnosed non-favorable risk adults with AML (non-APL) according to SWOG criteria who achieved morphologic leukemia-free state (MLFS) and received continuous chemotherapy were assessed retrospectively. Results: 292 AML patients were enrolled, 150 (51.4%) were male. Median age was 46 years (range, 18-65 years) ...
July 14, 2017: Zhonghua Xue Ye Xue za Zhi, Zhonghua Xueyexue Zazhi
https://www.readbyqxmd.com/read/28793301/high-expression-of-ahsp-epb42-gypc-and-hemgn-predicts-favorable-prognosis-in-flt3-itd-negative-acute-myeloid-leukemia
#19
Gang-Zhi Zhu, Yong-Long Yang, Yan-Jiao Zhang, Wei Liu, Mu-Peng Li, Wen-Jing Zeng, Xie-Lan Zhao, Xiao-Ping Chen
BACKGROUND/AIMS: Acute myeloid leukemia (AML) is a heterogeneous clonal disease and patients with AML who harbor an FMS-like tyrosine kinase 3 (FLT3) mutation present several dilemmas for the clinician. This study aims to identify novel targets for explaining the dilemmas. METHODS: We analyzed four microarray gene expression profiles to investigate changes in whole genome expression associated with FLT3-ITD mutation. RESULTS: We identified 22 differentially expressed genes which are commonly expressed among all four profiles...
August 9, 2017: Cellular Physiology and Biochemistry
https://www.readbyqxmd.com/read/28767575/dnmt3a-mutations-in-chinese-childhood-acute-myeloid-leukemia
#20
Weijing Li, Lei Cui, Chao Gao, Shuguang Liu, Xiaoxi Zhao, Ruidong Zhang, Huyong Zheng, Minyuan Wu, Zhigang Li
BACKGROUND: DNA methyltransferase 3A (DNMT3A) mutations have been found in approximately 20% of adult acute myeloid leukemia (AML) patients and in 0% to 1.4% of children with AML, and the hotspots of mutations are mainly located in the catalytic methyltransferase domain, hereinto, mutation R882 accounts for 60%. Although the negative effect of DNMT3A on treatment outcome is well known, the prognostic significance of other DNMT3A mutations in AML is still unclear. Here, we tried to determine the incidence and prognostic significance of DNMT3A mutations in a large cohort in Chinese childhood AML...
August 2017: Medicine (Baltimore)
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