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Acute myeloid leukemia

Shinya Ishida, Hiroki Akiyama, Yoshihiro Umezawa, Keigo Okada, Ayako Nogami, Gaku Oshikawa, Toshikage Nagao, Osamu Miura
The activated JAK2-V617F mutant is very frequently found in myeloproliferative neoplasms (MPNs), and its inhibitor ruxolitinib has been in clinical use, albeit with limited efficacies. Here, we examine the signaling mechanisms from JAK2-V617F and responses to ruxolitinib in JAK2-V617F-positive leukemic cell lines, including PVTL-2, newly established from a patient with post-MPN secondary acute myeloid leukemia, and the widely used model cell line HEL. We have found that ruxolitinib downregulated the mTORC1/S6K/4EBP1 pathway at least partly through inhibition of the STAT5/Pim-2 pathway with concomitant downregulation of c-Myc, MCL-1, and BCL-xL as well as induction of autophagy in these cells...
June 1, 2018: Oncotarget
Claire Calmettes, Frederic Gabriel, Elodie Blanchard, Vincent Servant, Stéphane Bouchet, Nathanael Kabore, Edouard Forcade, Camille Leroyer, Audrey Bidet, Valérie Latrabe, Thibaut Leguay, Stephane Vigouroux, Reza Tabrizi, Dominique Breilh, Isabelle Accoceberry, Manuel Tunon de Lara, Arnaud Pigneux, Noel Milpied, Pierre-Yves Dumas
Posaconazole prophylaxis has demonstrated efficacy in the prevention of invasive aspergillosis during prolonged neutropenia following acute myeloid leukemia induction chemotherapy. Antifungal treatment decreases serum galactomannan enzyme immunoassay diagnostic accuracy that could delay the diagnosis and treatment. We retrospectively studied patients with acute myeloid leukemia who underwent intensive chemotherapy and antifungal prophylaxis by posaconazole oral suspension. Clinical, radiological, microbiological features and treatment response of patients with invasive aspergillosis that occurred despite posaconazole prophylaxis were analyzed...
June 1, 2018: Oncotarget
Jatinder K Lamba, Xueyuan Cao, Susana C Raimondi, Roya Rafiee, James R Downing, Shi Lei, Tanja Gruber, Raul C Ribeiro, Jeffrey E Rubnitz, Stanley B Pounds
Acute myeloid leukemia (AML) may be an epigenetically-driven malignancy because it harbors fewer genomic mutations than other cancers. In recent studies of AML in adults, DNA methylation patterns associate with clinical risk groups and prognosis. However, thorough evaluations of methylation in pediatric AML have not been done. Therefore, we performed an integrated analysis (IA) of the methylome and transcriptome with clinical outcome in 151 pediatric patients from the multi-center AML02 clinical trial discovery cohort...
June 1, 2018: Oncotarget
Evan C Chen, Amir T Fathi, Andrew M Brunner
Despite increasing understanding of the pathobiology of acute myeloid leukemia (AML), outcomes remain dismal particularly for patients over the age of 60 years, a population enriched for therapy-related AML (tAML) and secondary AML (sAML). For decades, the standard of care for AML has been the combination of cytarabine and daunorubicin, typically delivered in combination as "7 + 3" induction. In 2017, a liposomal-encapsulated combination of daunorubicin and cytarabine (CPX-351, Vyxeos) was approved by the US Food and Drug Administration (FDA) for use in the treatment of newly diagnosed tAML or AML with myelodysplasia-related changes (AML-MRCs)...
2018: OncoTargets and Therapy
Holly Koblish, Yun-Long Li, Niu Shin, Leslie Hall, Qian Wang, Kathy Wang, Maryanne Covington, Cindy Marando, Kevin Bowman, Jason Boer, Krista Burke, Richard Wynn, Alex Margulis, Gary W Reuther, Que T Lambert, Valerie Dostalik Roman, Ke Zhang, Hao Feng, Chu-Biao Xue, Sharon Diamond, Greg Hollis, Swamy Yeleswaram, Wenqing Yao, Reid Huber, Kris Vaddi, Peggy Scherle
The Proviral Integration site of Moloney murine leukemia virus (PIM) serine/threonine protein kinases are overexpressed in many hematologic and solid tumor malignancies and play central roles in intracellular signaling networks important in tumorigenesis, including the Janus kinase-signal transducer and activator of transcription (JAK/STAT) and phosphatidylinositol 3-kinase (PI3K)/AKT pathways. The three PIM kinase isozymes (PIM1, PIM2, and PIM3) share similar downstream substrates with other key oncogenic kinases and have differing but mutually compensatory functions across tumors...
2018: PloS One
Frédéric Baron, Marian Stevens-Kroef, Michal Kicinski, Giovanna Meloni, Petra Muus, Jean-Pierre Marie, Constantijn J M Halkes, Xavier Thomas, Radovan Vrhovac, Giorgina Specchia, Francois Lefrere, Simona Sica, Marco Mancini, Adriano Venditti, Anne Hagemeijer, Heiko Becker, Joop H Jansen, Sergio Amadori, Theo de Witte, Roelof Willemze, Stefan Suciu
The presence of cytogenetic clonal heterogeneity has been associated with poor prognosis in patients with acute myeloid leukemia (AML). Here, we reassessed this association. The study cohort consisted of all patients with an abnormal karyotype randomized in the EORTC/GIMEMA AML-10 and AML-12 trials. Abnormal karyotypes were classified as no subclones present (cytogenetic abnormality in a single clone), defined subclones present (presence of one to three subclones), and composite karyotypes (CP) (clonal heterogeneity not allowing enumeration of individual subclones)...
June 20, 2018: Annals of Hematology
Claudia Gebhard, Dagmar Glatz, Lucia Schwarzfischer, Julia Wimmer, Sebastian Stasik, Margit Nuetzel, Daniel Heudobler, Reinhard Andreesen, Gerhard Ehninger, Christian Thiede, Michael Rehli
Malignant transformation is frequently associated with disease-specific epigenetic alterations, but the underlying mechanisms and pathophysiological consequences remain poorly understood. Here, we used global comparative DNA methylation profiling at CG-rich regions of 27 acute myeloid leukemia (AML) samples to select a subset of aberrantly methylated CG-rich regions (~400 regions, ~15,000 CpGs) for quantitative DNA methylation profiling in a large cohort of AML patients (n = 196) using MALDI-TOF analysis of bisulfite-treated DNA...
June 20, 2018: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Sharon Wu, Yang Du, John Beckford, Houda Alachkar
BACKGROUND: Vimentin (VIM) is a type III intermediate filament that maintains cell integrity, and is involved in cell migration, motility and adhesion. When overexpressed in solid cancers, vimentin drives epithelial to mesenchymal transition (EMT) and ultimately, metastasis. The effects of its overexpression in AML are unclear. METHODS: In this study, we analyzed the TCGA data of 173 AML patients for which complete clinical and expression data were available. In this analysis, we assessed the association between VIM mRNA expression and patient's clinical and molecular characteristics including clinical outcome...
June 20, 2018: Journal of Translational Medicine
Ashley Leak Bryant, Sarah W Drier, Sejin Lee, Antonia V Bennett
The purpose of this systematic literature review was to identify clinical trials of MDS and AML that included patient-reported outcome (PRO) instruments, and to summarize the symptom and other health related quality of life (HRQOL) concepts most frequently assessed and the PRO instruments that were used. Sixteen manuscripts describing 14 distinct trials met all criteria (i.e., phase 2 or 3 clinical trial for MDS or AML which included PRO assessment) and were published between 1996-2017. In trials evaluating anemia, PRO scores showed significant improvement in relevant domains (e...
June 7, 2018: Leukemia Research
Ye Jee Shim, Jae Min Lee, Heung Sik Kim, Nani Jung, Young Tak Lim, Eu Jeen Yang, Jeong Ok Hah, Young-Ho Lee, Hee Won Chueh, Jae Young Lim, Eun Sil Park, Jeong A Park, Ji Kyoung Park, Sang Kyu Park
We compared transplant outcomes between donor types and stem cell sources for childhood acute myeloid leukemia (AML). The medical records of children with AML in the Yeungnam region of Korea from January 2000 to June 2017 were reviewed. In all, 76 children with AML (male-to-female ratio = 46:30) received allogenic hematopoietic stem cell transplantation (allo-HSCT). In total, 29 patients received HSCT from either a matched-related donor or a mismatched-related donor, 32 patients received an unrelated donor, and 15 patients received umbilical cord blood...
June 19, 2018: Pediatric Transplantation
Guoju Hong, Vincent Kuek, Jiaxi Shi, Lin Zhou, Xiaorui Han, Wei He, Jennifer Tickner, Heng Qiu, Qiushi Wei, Jiake Xu
Epidermal growth factor-like domain-containing protein 7 (EGFL7), a member of the epidermal growth factor (EGF)-like protein family, is a potent angiogenic factor expressed in many different cell types. EGFL7 plays a vital role in controlling vascular angiogenesis during embryogenesis, organogenesis, and maintaining skeletal homeostasis. It regulates cellular functions by mediating the main signaling pathways (Notch, integrin) and EGF receptor cascades. Accumulating evidence suggests that Egfl7 plays a crucial role in cancer biology by modulating tumor angiogenesis, metastasis, and invasion...
June 19, 2018: Journal of Cellular Physiology
Min Wang, Chen Zhang, Tian Tian, Teng Zhang, Ruiqing Wang, Fengjiao Han, Chaoqin Zhong, Mingqiang Hua, Daoxin Ma
Acute myeloid leukemia (AML) harbors an immune suppression environment, featured by increased regulatory T cells (Tregs). The expression of tumor necrosis factor receptor-2 (TNFR2) on Tregs could be used to identify the maximally suppressive Treg population, and TNF-α furtherly promoted the expansion and function of Tregs via TNFR2 in mice. However, the role of TNF-α has not been determined in AML patients. In view of high levels of TNF-α and Tregs in AML patients, we hypothesized that the increased frequency of Tregs may rely on TNF-α-TNFR2 pathway...
2018: Frontiers in Immunology
Isabelle Laverdière, Meaghan Boileau, Andrea L Neumann, Héloïse Frison, Amanda Mitchell, Stanley W K Ng, Jean C Y Wang, Mark D Minden, Kolja Eppert
Therapy for acute myeloid leukemia (AML) involves intense cytotoxic treatment and yet approximately 70% of AML are refractory to initial therapy or eventually relapse. This is at least partially driven by the chemo-resistant nature of the leukemic stem cells (LSCs) that sustain the disease, and therefore novel anti-LSC therapies could decrease relapses and improve survival. We performed in silico analysis of highly prognostic human AML LSC gene expression signatures using existing datasets of drug-gene interactions to identify compounds predicted to target LSC gene programs...
June 6, 2018: Blood Cancer Journal
Tomoo Osumi, Shin-Ichi Tsujimoto, Moe Tamura, Meri Uchiyama, Kazuhiko Nakabayashi, Kohji Okamura, Masanori Yoshida, Daisuke Tomizawa, Akihiro Watanabe, Hiroyuki Takahashi, Tsukasa Hori, Shohei Yamamoto, Kazuko Hamamoto, Masahiro Migita, Hiroko Ogata-Kawata, Toru Uchiyama, Hiroe Kizawa, Hitomi Ueno-Yokohata, Ryota Shirai, Masafumi Seki, Kentaro Ohki, Junko Takita, Takeshi Inukai, Seishi Ogawa, Toshio Kitamura, Kimikazu Matsumoto, Kenichiro Hata, Nobutaka KIyokawa, Susumu Goyama, Motohiro Kato
Translocations of retinoic acid receptor-α (RARA), typically PML-RARA, are a genetic hallmark of acute promyelocytic leukemia (APL). However, because a small fraction of APL lack translocations of RARA, we focused here on APL cases without RARA translocation to elucidate the molecular etiology of RARA-negative APL. We performed whole-genome sequencing, PCR, and FISH for five APL cases without RARA translocations. Four of five RARA-negative APL cases had translocations involving retinoic acid receptor-β (RARB) translocations, and TBL1XR1-RARB was identified as an in-frame fusion in three cases; one case had an RARB rearrangement detected by FISH, although the partner gene could not be identified...
June 19, 2018: Cancer Research
Justin Taylor, Dean Pavlick, Akihide Yoshimi, Christina Marcelus, Stephen S Chung, Jaclyn F Hechtman, Ryma Benayed, Emiliano Cocco, Benjamin H Durham, Lillian Bitner, Daichi Inoue, Young Rock Chung, Kerry Mullaney, Justin M Watts, Eli L Diamond, Lee A Albacker, Tariq I Mughal, Kevin Ebata, Brian B Tuch, Nora Ku, Maurizio Scaltriti, Mikhail Roshal, Maria Arcila, Siraj Ali, David M Hyman, Jae H Park, Omar Abdel-Wahab
Rearrangements involving the neurotrophic receptor kinase genes (NTRK1, NTRK2, and NTRK3; hereafter referred to as TRK) produce oncogenic fusions in a wide variety of cancers in adults and children. Although TRK fusions occur in <1% of all solid tumors, inhibition of TRK results in profound therapeutic responses resulting in breakthrough FDA-approval of the TRK inhibitor larotrectinib for adult and pediatric solid tumor patients regardless of histology. In contrast to solid tumors, the frequency of TRK fusions and clinical effects of targeting TRK in hematologic malignancies is unknown...
June 19, 2018: Journal of Clinical Investigation
J Li, C-K Sun
OBJECTIVE: Growing evidence has demonstrated that the dysregulation of long non-coding RNAs (lncRNAs) may act as an important role in human tumorigenesis. Our present study aimed to explore the expression pattern and prognostic value of a newly discovered lncRNA small nucleolar RNA host gene 5 (SNHG5) in acute myeloid leukemia (AML). PATIENTS AND METHODS: The expression of SNHG5 was determined using Real-time reverse transcription-polymerase chain reaction (qRT-PCR) in bone marrow and plasma obtained from AML patients and healthy controls...
June 2018: European Review for Medical and Pharmacological Sciences
Xiao-Hui Zhang, Lin Yang, Xiao-Jun Liu, Ying Zhan, Yu-Xia Pan, Xing-Zhe Wang, Jian-Min Luo
Suppressor of cytokine signaling‑1 (SOCS1) is a widely recognized tumor suppressor gene. Silencing of SOCS1 expression as a result of promoter methylation is associated with occurrence and development of solid tumors such as liver, cervical and pancreatic cancer. However, the association between SOCS1 gene methylation and acute myeloid leukemia (AML) has not been well explored. In the present study, we examined whether gene expression and methylation status of SOCS1 was altered in AML, and whether this was related to disease occurrence and development...
June 19, 2018: Oncology Reports
Rosalie M Sterner, Kimberly N Kremer, Amel Dudakovic, Jennifer J Westendorf, Andre J van Wijnen, Karen E Hedin
The bone marrow microenvironment harbors and protects leukemic cells from apoptosis-inducing agents via mechanisms that are incompletely understood. We previously showed SDF-1 (CXCL-12), a chemokine readily abundant within the bone marrow microenvironment, induces apoptosis in acute myeloid leukemia (AML) cells that express high levels of the SDF-1 receptor CXCR4. However, differentiating osteoblasts found within this niche protect cocultured AML cells from apoptosis. Additionally, this protection was abrogated upon treatment of the differentiating osteoblasts with histone deacetylase inhibitors (HDACi)...
June 18, 2018: Journal of Immunology: Official Journal of the American Association of Immunologists
Karthik M Kodigepalli, Serena Bonifati, Nagaraja Tirumuru, Li Wu
Sterile alpha motif and HD domain-containing protein 1 (SAMHD1) is a mammalian dNTP hydrolase that acts as a negative regulator in the efficacy of cytarabine treatment against acute myeloid leukemia (AML). However, the role of SAMHD1 in AML development and progression remains unknown. We have reported that SAMHD1 knockout (KO) in the AML-derived THP-1 cells results in enhanced proliferation and reduced apoptosis, but the underlying mechanisms are unclear. Here we show that SAMHD1 KO in THP-1 cells increased PI3K activity and reduced expression of the tumor suppressor PTEN...
June 18, 2018: Cell Cycle
Katsuya Yamamoto, Kimikazu Yakushijin, Hiroya Ichikawa, Seiji Kakiuchi, Shinichiro Kawamoto, Hisayuki Matsumoto, Yuji Nakamachi, Jun Saegusa, Hiroshi Matsuoka, Hironobu Minami
No abstract text is available yet for this article.
June 18, 2018: Leukemia & Lymphoma
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