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https://www.readbyqxmd.com/read/28213513/runx1-cooperates-with-flt3-itd-to-induce-leukemia
#1
Kira Behrens, Katrin Maul, Nilgün Tekin, Neele Kriebitzsch, Daniela Indenbirken, Vladimir Prassolov, Ursula Müller, Hubert Serve, Jörg Cammenga, Carol Stocking
Acute myeloid leukemia (AML) is induced by the cooperative action of deregulated genes that perturb self-renewal, proliferation, and differentiation. Internal tandem duplications (ITDs) in the FLT3 receptor tyrosine kinase are common mutations in AML, confer poor prognosis, and stimulate myeloproliferation. AML patient samples with FLT3-ITD express high levels of RUNX1, a transcription factor with known tumor-suppressor function. In this study, to understand this paradox, we investigated the impact of RUNX1 and FLT3-ITD coexpression...
February 17, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28197208/molecular-mutations-and-their-cooccurrences-in-cytogenetically-normal-acute-myeloid-leukemia
#2
REVIEW
Mengning Wang, Chuanwei Yang, Le Zhang, Dale G Schaar
Adult acute myeloid leukemia (AML) clinically is a disparate disease that requires intensive treatments ranging from chemotherapy alone to allogeneic hematopoietic cell transplantation (allo-HCT). Historically, cytogenetic analysis has been a useful prognostic tool to classify patients into favorable, intermediate, and unfavorable prognostic risk groups. However, the intermediate-risk group, consisting predominantly of cytogenetically normal AML (CN-AML), itself exhibits diverse clinical outcomes and requires further characterization to allow for more optimal treatment decision-making...
2017: Stem Cells International
https://www.readbyqxmd.com/read/28194038/itd-mutation-in-flt3-tyrosine-kinase-promotes-warburg-effect-and-renders-therapeutic-sensitivity-to-glycolytic-inhibition
#3
H-Q Ju, G Zhan, A Huang, Y Sun, S Wen, J Yang, W-H Lu, R-H Xu, J Li, Y Li, G Garcia-Manero, P Huang, Y Hu
Internal tandem duplication (ITD) mutation in Fms-like tyrosine kinase 3 gene (FLT3/ITD) represents an unfavorable genetic change in acute myeloid leukemia (AML) and is associated with poor prognosis. Metabolic alterations have been involved in tumor progression and attracted interest as a target for therapeutic intervention. However, few studies analyzed the adaptations of cellular metabolism in the context of FLT3/ITD mutation. Here, we report that FLT3/ITD causes a significant increase in aerobic glycolysis through AKT-mediated upregulation of mitochondrial hexokinase (HK2), and renders the leukemia cells highly dependent on glycolysis and sensitive to pharmacological inhibition of glycolytic activity...
February 14, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28167452/tet2-exon-2-skipping-is-an-independent-favorable-prognostic-factor-for-cytogenetically-normal-acute-myelogenous-leukemia-aml-tet2-exon-2-skipping-in-aml
#4
Aminetou Mint Mohamed, Marie Balsat, Catherine Koering, Delphine Maucort-Boulch, Nicolas Boissel, Lea Payen-Gay, Meyling Cheok, Hussein Mortada, Didier Auboeuf, Christiane Pinatel, Mohamed El-Hamri, Isabelle Tigaud, Sandrine Hayette, Charles Dumontet, Emeline Cros, Pascale Flandrin-Gresta, Olivier Nibourel, Claude Preudhomme, Xavier Thomas, Franck-Emmanuel Nicolini, Françoise Solly, Denis Guyotat, Lydia Campos, Mauricette Michallet, Antony Ceraulo, Franck Mortreux, Eric Wattel
In AML, approximately one-third of expressed genes are abnormally spliced, including aberrant TET2 exon 2 expression. In a discovery cohort (n=99), TET2 exon 2 skipping (TET2E2S) was found positively associated with a significant reduction in the cumulative incidence of relapse (CIR). Age, cytogenetics, and TET2E2S were independent prognostic factors for disease-free survival (DFS), and favorable effects on outcomes predominated in cytogenetic normal (CN)-AML and younger patients. Using the same cutoff in a validation cohort of 86 CN-AML patients, TET2E2S(high) patients were found to be younger than TET2(low) patients without a difference in the rate of complete remission...
January 16, 2017: Leukemia Research
https://www.readbyqxmd.com/read/28164543/detection-the-frequency-and-characteristics-of-flt3-internal-tandem-duplication-mutations-by-capillary-electrophoresis-assay-and-next-generation-sequencing-in
#5
Liang Ma, Yongyue Cao, Yongwei Jiang, Xiao Cong, Shuang Lu, Jun Shen, Qian Liu, Chengwu Han, Yuliang Zhan, Yongtong Cao
BACKGROUND: FLT3-internal tandem duplication mutations (ITDs) are found in approximately 30% of patients with acute myeloid leukemia (AML) and are markers of poor prognosis. However, the characteristics of FLT3/ ITDs in Chinese AML patients have rarely been reported. The aim of this study was to analyze the frequency and characteristics of FLT3/ITDs in Chinese AML patients. METHODS: In the selected 152 cases of Chinese AML patients, capillary electrophoresis (CE) was used to analyze the frequency and characteristics of FLT3/ITDs...
October 1, 2016: Clinical Laboratory
https://www.readbyqxmd.com/read/28164537/flt3-gene-mutation-profile-and-prognosis-in-adult-acute-myeloid-leukemia
#6
Aileen Azari-Yam, Javad Tavakkoly-Bazzaz, Yousef Semnani, Elham Davoudi-Dehaghani, Robabeh Ghodssi-Ghassemabadi, Soodeh Kianfar, Ameneh Saadat, Mahboobeh Masoudifard, Marjan Yaghmaie, Kamran Alimoghaddam, Ardeshir Ghavamzadeh, Sirous Zeinali
BACKGROUND: Internal tandem duplication (ITD) of FMS-related tyrosine kinase 3 (FLT3) gene, which occurs in exons 14 and 15, is one of the most prevalent somatic mutations in adult acute myeloid leukemia (AML) and has biological, prognostic, and therapeutic implications. The prognostic importance of codon 835 tyrosine kinase domain (TKD) mutation (exon 20), which occurs relatively frequently in adult AML, is often debated. We aimed to study the FLT3 gene mutation profile and prognosis in 139 adult Iranian patients with newly diagnosed AML...
October 1, 2016: Clinical Laboratory
https://www.readbyqxmd.com/read/28163010/use-of-wilms-tumor-1-gene-expression-as-a-reliable-marker-for-prognosis-and-minimal-residual-disease-monitoring-in-acute-myeloid-leukemia-with-normal-karyotype-patients
#7
Irena Marjanovic, Teodora Karan-Djurasevic, Milena Ugrin, Marijana Virijevic, Ana Vidovic, Dragica Tomin, Nada Suvajdzic Vukovic, Sonja Pavlovic, Natasa Tosic
BACKGROUND: Acute myeloid leukemia with normal karyotype (AML-NK) represents the largest group of AML patients classified with an intermediate prognosis. A constant need exists to introduce new molecular markers for more precise risk stratification and for minimal residual disease (MRD) monitoring. PATIENTS AND METHODS: Quantitative assessment of Wilms tumor 1 (WT1) gene transcripts was performed using real-time polymerase chain reaction. The bone marrow samples were collected at the diagnosis from 104 AML-NK patients and from 34 of these patients during follow-up or disease relapse...
January 11, 2017: Clinical Lymphoma, Myeloma & Leukemia
https://www.readbyqxmd.com/read/28154969/what-is-the-best-daunorubicin-dose-and-schedule-for-acute-myeloid-leukemia-induction
#8
REVIEW
Priyanka Pophali, Mark Litzow
Daunorubicin dose intensification for induction in acute myeloid leukemia has been reported as an effective strategy in recent trials to improve patient outcomes without worsening treatment-related toxicity. Based on available evidence, 90 mg/m(2) of daunorubicin given for three consecutive days (cumulative dose 270 mg/m(2)) as a part of the "7 + 3" induction regimen along with cytarabine is the most effective dose to achieve a complete remission as well as improve survival in patients who can tolerate it...
January 2017: Current Treatment Options in Oncology
https://www.readbyqxmd.com/read/28138160/impact-of-salvage-regimens-on-response-and-overall-survival-in-acute-myeloid-leukemia-with-induction-failure
#9
M Wattad, D Weber, K Döhner, J Krauter, V I Gaidzik, P Paschka, M Heuser, F Thol, T Kindler, M Lübbert, H R Salih, A Kündgen, H-A Horst, P Brossart, K Götze, D Nachbaur, C-H Köhne, M Ringhoffer, G Wulf, G Held, H Salwender, A Benner, A Ganser, H Döhner, R F Schlenk
We evaluated the impact of salvage regimens and allogeneic hematopoietic cell transplantation (allo-HCT) in acute myeloid leukemia (AML) with induction failure. Between 1993 and 2009, 3324 patients with newly diagnosed AML were enrolled in 5 prospective treatment trials of the German-Austrian AML Study Group. After first induction therapy with idarubicin, cytarabine and etoposide (ICE), 845 patients had refractory disease. In addition, 180 patients, although responding to first induction, relapsed after second induction therapy...
February 10, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28125133/acute-wt1-positive-promyelocytic-leukemia-with-hypogranular-variant-morphology-bcr-3-isoform-of-pml-rar%C3%AE-and-flt3-itd-mutation-a-rare-case-report
#10
Xi Zhang, Cheng Yang, Xiangui Peng, Xinghua Chen, Yimei Feng
CONTEXT: Acute promyelocytic leukemia (APL) accounts for 8% to 10% of cases of acute myeloid leukemia (AML). Remission in cases of high-risk APL is still difficult to achieve, and relapses occur readily. CASE REPORT: Here, we describe a case of APL with high white blood cell counts in blood tests and hypogranular variant morphology in bone marrow, together with fms-like tyrosine kinase-3 with internal tandem duplication mutations (FLT3-ITD), and bcr-3 isoform of PML-RARα...
January 23, 2017: São Paulo Medical Journal, Revista Paulista de Medicina
https://www.readbyqxmd.com/read/28108543/disease-characteristics-and-prognostic-implications-of-cell-surface-flt3-receptor-cd135-expression-in-pediatric-acute-myeloid-leukemia-a-report-from-the-children-s-oncology-group
#11
Katherine Tarlock, Todd A Alonzo, Michael R Loken, Robert B Gerbing, Rhonda E Ries, Richard Aplenc, Lillian Sung, Susana Raimondi, Betsy A Hirsch, Samir B Kahwash, Amy McKenney, E Anders Kolb, Alan S Gamis, Soheil Meshinchi
PURPOSE: The FLT3 cell-surface receptor tyrosine kinase (CD135) is expressed in a majority of both acute lymphoid leukemia (ALL) and myeloid leukemia (AML). However, the prognostic significance of CD135 expression in AML remains unclear. We therefore evaluated the association between FLT3 surface expression and disease characteristics and outcomes in pediatric patients with AML. EXPERIMENTAL DESIGN: We analyzed FLT3 receptor expression on AML blasts by multi-dimensional flow cytometry and its association with disease characteristics, clinical outcomes, and FLT3 transcript level in 367 children with AML treated on the Children's Oncology Group trial AAML0531...
January 20, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28108507/flt3-and-jak2-mutations-in-acute-myeloid-leukemia-promote-inter-chromosomal-homologous-recombination-and-the-potential-for-copy-neutral-loss-of-heterozygosity-cn-loh
#12
Terry J Gaymes, Azim Mohamedali, Anthony Eiliazadeh, David Darling, Ghulam J Mufti
Acquired copy neutral loss-of-heterozygosity (CN-LOH) is a frequent occurrence in myeloid malignancies and is often associated with resistance to standard therapeutic modalities and poor survival. Here we show that constitutive signaling driven by mutated FLT3 and JAK2 confers inter-chromosomal homologous recombination (iHR), a precedent for CN-LOH. Using a targeted recombination assay, we determined significant iHR activity in internal tandem duplication FLT3 (FLT3-ITD) and JAK2V617F mutated cells. Sister chromatid exchanges, a surrogate measure of iHR, was significantly elevated in primary FLT3-ITD normal karyotype acute myeloid leukemia (NK-AML) compared to wild type FLT3 NK-AML...
January 20, 2017: Cancer Research
https://www.readbyqxmd.com/read/28106537/down-regulation-of-pseudogene-vimentin-2p-is-associated-with-poor-outcome-in-de-novo-acute-myeloid-leukemia
#13
Ling-Ling Zhai, Jiao Zhou, Jing Zhang, Xi Tang, Ling-Yu Zhou, Jia-Yu Yin, Minse-Evola Deniz Vanessa, Wen Peng, Jiang Lin, Zhao-Qun Deng
OBJECTIVES: This study was intended to investigate the expression status of Vimentin 2p (VIM 2p), a pseudogene of Vimentin, and further analyze its clinical significance in AML patients. METHODS: Real-time quantitative PCR (RQ-PCR) was employed to explore the expression status of VIM 2p in 128 patients with de novo AML and 36 healthy controls. RESULTS: The expression level of VIM 2p was significantly decreased compared with healthy controls (P< 0...
January 13, 2017: Cancer Biomarkers: Section A of Disease Markers
https://www.readbyqxmd.com/read/28102729/chronic-myelomonocytic-leukemia-with-double-mutations-in-dnmt3a-and-flt3-itd-treated-with-decitabine-and-sorafenib
#14
Jia Gu, Zhiqiong Wang, Min Xiao, Xia Mao, Li Zhu, Ying Wang, Wei Huang
Chronic myelomonocytic leukemia (CMML) is a heterogeneous neoplastic hematologic disorder with worse overall survival. Half of CMML have mutations, but case with concomitant mutations of DNA methyltransferase 3A (DNMT3A) and Internal tandem duplications of the juxtamembrane domain of FLT3 (FLT3-ITD) in CMML was not reported before. We reported a 51-year-old man who had CMML with concomitant mutations in DNMT3A and FLT3-ITD.The patient received decitabine and sorafenib combined treatment. In this report, we reviewed DNMT3A mutation and FLT3 mutation, and we reviewed treatment of decitabine and sorafenib...
January 19, 2017: Cancer Biology & Therapy
https://www.readbyqxmd.com/read/28100593/clinical-implications-of-dnmt3a-mutations-in-a-southeast-asian-cohort-of-acute-myeloid-leukaemia-patients
#15
Marcus Tan, Isaac K S Ng, Zhaojin Chen, Kenneth Ban, Christopher Ng, Lily Chiu, Elaine Seah, Mingxuan Lin, Bee Choo Tai, Benedict Yan, Chin Hin Ng, Wee-Joo Chng
AIMS: In recent years, genomic technologies have enabled the identification of mutations in acute myeloid leukaemia (AML). DNMT3A is a recurrently mutated epigenetic modifier gene in AML. To date, the prognostic significance of DNMT3A mutations has not been studied in a Southeast Asian AML population. We sought to investigate the clinical implications of DNMT3A mutations in a Southeast Asian cohort of AML patients. METHODS: DNMT3A mutations were identified using a targeted next-generation sequencing panel in 157 AML patients...
January 18, 2017: Journal of Clinical Pathology
https://www.readbyqxmd.com/read/28089879/clinical-outcome-of-autologous-hematopoietic-cell-transplantation-in-adult-patients-with-acute-myeloid-leukemia-who-may-benefit-from-autologous-hematopoietic-cell-transplantation
#16
Jae-Ho Yoon, Hee-Je Kim, Sung-Soo Park, Young-Woo Jeon, Sung-Eun Lee, Byung-Sik Cho, Ki-Seong Eom, Yoo-Jin Kim, Seok Lee, Chang-Ki Min, Seok-Goo Cho, Dong-Wook Kim, Jong-Wook Lee, Woo-Sung Min
The role of autologous hematopoietic cell transplantation (auto-HCT) for postremission therapy of acute myeloid leukemia is yet to be elucidated. We retrospectively analyzed 240 patients treated with auto-HCT in first remission. All patients were treated with standard induction chemotherapy, and CD34(+) stem cells were collected at each cycle of consolidation. Stem cells were infused after total body irradiation (1200 cGy), cytarabine (9 g/m(2)), and melphalan (100 mg/m(2)). Estimated 5-year overall survival, disease-free survival (DFS), cumulative incidence of relapse (CIR), and nonrelapse mortality were 58...
January 12, 2017: Biology of Blood and Marrow Transplantation
https://www.readbyqxmd.com/read/28088962/-efficacy-and-safety-of-sorafenib-as-monotherapy-to-flt3-itd-positive-acute-myeloid-leukemia
#17
J S Jia, H H Zhu, H X Fu, L Z Gong, J Kong, X J Huang, H Jiang
Objective: To explore the efficacy and safety of Sorafenib as monotherapy to FLT3 positive acute myeloid leukemia (AML). Methods: From April 2014 to December 2015, fourteen AML patients with FLT3 positive, 7 males and 7 females with a median age of 42 (range: 14-81) years old, were enrolled in this study. Of the 14 cases, 4 were de novo cases, 9 refractory cases and 1 relapsed case, including 78.6% patients with severe complications and 57.1% patients with KPS score less than 60 [the median KPS score was 45 (20-70) ]...
December 14, 2016: Zhonghua Xue Ye Xue za Zhi, Zhonghua Xueyexue Zazhi
https://www.readbyqxmd.com/read/28088961/-the-clinical-and-prognostic-significance-of-acute-myeloid-leukemia-with-flt3-itd
#18
D Lin, H Wei, Y Wang, C L Zhou, B C Liu, K Q Liu, B F Gong, S N Wei, G J Zhang, Y T Liu, X Y Gong, S W Qiu, Y C Mi, J X Wang
Objective: To investigate the clinical significance and prognosis factors of acute myeloid leukemia (AML) with FLT3 mutation-internal tandem duplication (FLT3-ITD) and provide more evidence for prognosis evaluation in AML with FLT3-ITD. Methods: The clinical characteristics and outcomes of 98 AML with FLT3-ITD were analyzed. Results: In patients with FLT3-ITD positive AML, the median of WBC and peripheral blood blast at initial diagnosis were 58.2 (0.3-461.8) ×10(9)/L and 42.2 (0-397.1) ×10(9)/L, respectively...
December 14, 2016: Zhonghua Xue Ye Xue za Zhi, Zhonghua Xueyexue Zazhi
https://www.readbyqxmd.com/read/28077790/flt3-activating-mutations-display-differential-sensitivity-to-multiple-tyrosine-kinase-inhibitors
#19
Bao Nguyen, Allen B Williams, David J Young, Hayley Ma, Li Li, Mark Levis, Patrick Brown, Donald Small
Fms-like tyrosine kinase-3 (FLT3) is a receptor tyrosine kinase that normally functions in hematopoietic cell survival, proliferation and differentiation. Constitutively activating mutations of FLT3 map predominately to the juxtamembrane domain (internal tandem duplications; ITD) or the activation loop (AL) of the kinase domain and are detected in about 1/3 of de novo acute myeloid leukemia (AML) patients. Small molecule tyrosine kinase inhibitors (TKI) effectively target FLT3/ITD mutations, but some activating mutations, particularly those on the AL, are relatively resistant to many FLT3 TKI...
January 6, 2017: Oncotarget
https://www.readbyqxmd.com/read/28077417/aid-is-a-key-regulator-of-myeloid-erythroid-differentiation-and-dna-methylation-in-hematopoietic-stem-progenitor-cells
#20
Hiroyoshi Kunimoto, Anna Sophia McKenney, Cem Meydan, Kaitlyn Shank, Abbas Nazir, Franck Rapaport, Benjamin Durham, Francine E Garrett-Bakelman, Elodie Pronier, Alan H Shih, Ari Melnick, Jayanta Chaudhuri, Ross L Levine
Recent studies have reported activation-induced cytidine deaminase (AID) and ten-eleven-translocation (TET) family members regulate active DNA demethylation. Genetic alterations of TET2 occur in myeloid malignancies and hematopoietic specific loss of Tet2 induces aberrant hematopoietic stem cell (HSC) self-renewal/differentiation, implicating TET2 as a master regulator of normal and malignant hematopoiesis. Despite the functional link between AID and TET in epigenetic gene regulation, the role of AID loss in hematopoiesis and myeloid transformation remains to be investigated...
January 11, 2017: Blood
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