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Himalee S Sabnis, Heath L Bradley, Shweta Tripathi, Wen-Mei Yu, William Tse, Cheng-Kui Qu, Kevin D Bunting
Current therapy for acute myeloid leukemia (AML) primarily includes high-dose cytotoxic chemotherapy with or without allogeneic stem cell transplantation. Targeting unique cellular metabolism of cancer cells is a potentially less toxic approach. Monotherapy with mitochondrial inhibitors like metformin have met with limited success since escape mechanisms such as increased glycolytic ATP production, especially in hyperglycemia, can overcome the metabolic blockade. As an alternative strategy for metformin therapy, we hypothesized that the combination of 6-benzylthioinosine (6-BT), a broad-spectrum metabolic inhibitor, and metformin could block this drug resistance mechanism...
October 5, 2016: Leukemia Research
Sergio Pina-Oviedo, Carlos A Torres-Cabala, Roberto N Miranda, Michael T Tetzlaff, Selina Singh, Ronald P Rapini, Victor G Prieto, Phyu P Aung
Leukemia cutis develops in <4% of all acute leukemias. Concurrent acute myeloid leukemia (AML) and Langerhans cell histiocytosis (LCH) is rare, with most cases involving lymph nodes or spleen, and no cutaneous involvement. We report the case of a 59-year-old man who presented with fever, malaise, and fatigue. The CBC showed leukocytosis (30.4 × 10/L, 9% blasts), anemia, and thrombocytopenia. Bone marrow biopsy was diagnosed with AML, not otherwise specified, with mutations of FLT3 and IDH2 (R140Q). The patient developed skin rash on the right flank with the clinical differential diagnosis of herpes simplex virus or varicella-zoster virus infection/reactivation versus leukemia cutis...
October 18, 2016: American Journal of Dermatopathology
Naftali Stern
As both the rate of hypertension and cancer rise with age, concomitant hypertension in patients receiving treatment for cancer is very common. Increase in blood pressure during cancer treatment requires careful clinical assessment. Distinction between discontinuation or malabsorption of antihypertensive treatment due to factors such as nausea/vomiting/diarrhea and anti-cancer drug specific effects must be first made. De-novo hypertension during cancer treatment is likely related to anticancer drugs per se. Classical chemotherapeutic agents such as cyclophosphamide, cisplatin and busulfan have been previously linked to rising blood pressure...
September 2016: Journal of Hypertension
Singkome Tima, Siriporn Okonogi, Chadarat Ampasavate, Chad Pickens, Cory Berkland, Songyot Anuchapreeda
This study aimed at developing a curcumin (CM) nanoparticle targeted to Feline McDonough Sarcoma (FMS)-like tyrosine kinase 3 (FLT3) protein on the surface of leukemic cells and at evaluating their properties, specificity, cytotoxicity, and inhibitory effect on FLT3 protein level in FLT3-overexpressing leukemic cells, EoL-1, and MV-4-11 cells. FLT3-specific peptides were conjugated onto modified poloxamer 407 using the copper-catalyzed azide-alkyne cycloaddition reaction. The thin film hydration method was performed for FLT3-specific CM-loaded polymeric micelles (FLT3-CM-micelles) preparation...
October 14, 2016: Journal of Pharmaceutical Sciences
M Wu, M Hamaker, L Li, D Small, A S Duffield
The FMS-like tyrosine kinase-3 (FLT3) gene is the most commonly mutated gene in acute myeloid leukemia (AML), and patients carrying internal tandem duplication (ITD) mutations have a poor prognosis. Long-term inhibition of FLT3 activity in these patients has been elusive. To provide a more complete understanding of FLT3 biology, a mass spectroscopy-based screen was performed to search for FLT3-interacting proteins. The screen identified dedicator of cytokinesis 2 (DOCK2), which is a guanine nucleotide exchange factor for Rho GTPases, and its expression is limited to hematolymphoid cells...
October 17, 2016: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Anita Chopra, Sushant Soni, Haraprasad Pati, Dev Kumar, Rahul Diwedi, Deepak Verma, Garima Vishwakama, Sameer Bakhshi, Suman Kumar, Ajay Gogia, Rajive Kumar
BACKGROUND & OBJECTIVES: Mutation of nucleophosmin (NPM1) gene in the absence of FLT3-ITD (FMS related tyrosine kinase 3 - internal tandem duplications) mutation carries a good prognosis in cytogenetically normal acute myeloid leukaemia (AML). NPM1, a multifunctional nucleolar phosphoprotein that shuttles between nucleus and cytoplasm, gets trapped in the cytoplasm when mutated. Immunohistochemical (IHC) demonstration of its aberrant cytoplasmic location (NPMc+) has been suggested as a simple substitute for the standard screening molecular method...
June 2016: Indian Journal of Medical Research
Surender Kumar Sharawat, Vinod Raina, Lalit Kumar, Atul Sharma, Radhika Bakhshi, Sreenivas Vishnubhatla, Ritu Gupta, Sameer Bakhshi
BACKGROUND & OBJECTIVES: Mutations in fms-like tyrosine kinase 3 (FLT3) receptor have significant role in assessing outcome in patients with acute myeloid leukaemia (AML). Data for FLT3 surface expression in relation to FLT3 internal tandem duplication (ITD) status and outcome are not available from India. The objective of the current study was to investigate adult patients with AML for FLT3 expression and FLT3 ITD mutation, and their association with long-term outcome. METHODS: Total 51 consecutive de novo AML patients aged 18-60 yr were enrolled in the study...
May 2016: Indian Journal of Medical Research
Elisabetta Zappone, Marzia Defina, Lara Aprile, Alessandro Gozzetti, Giulia Bartalucci, Monica Bocchia
In recent years there has been a great improvement in molecular characterization of acute myeloid leukemia (AML) allowing the stratification of patients in different rate of risk. Patients with FLT3 mutated AML have poor prognosis because of resistance to induction chemotherapy or early relapse. Several first and second generation molecules, able to inhibit FLT3 signaling have been developed and many single agent or combination studies are ongoing. Of these, quizartinib seems to have the best clinical activity...
October 10, 2016: Anti-cancer Agents in Medicinal Chemistry
Joanna D Nowacka, Christian Baumgartner, Cristiana Pelorosso, Mareike Roth, Johannes Zuber, Manuela Baccarini
The dual-specificity kinases MEK1 and MEK2 act downstream of RAS/RAF to induce ERK activation, which is generally considered protumorigenic. Activating MEK mutations have not been discovered in leukemia, in which pathway activation is caused by mutations in upstream components such as RAS or Flt3. The anti-leukemic potential of MEK inhibitors is being tested in clinical trials; however, downregulation of MEK1 promotes Eμ-Myc-driven lymphomagenesis and MEK1 ablation induces myeloproliferative disease in mice, raising the concern that MEK inhibitors may be inefficient or counterproductive in this context...
October 10, 2016: Oncotarget
María Abáigar, Cristina Robledo, Rocío Benito, Fernando Ramos, María Díez-Campelo, Lourdes Hermosín, Javier Sánchez-Del-Real, Jose M Alonso, Rebeca Cuello, Marta Megido, Juan N Rodríguez, Guillermo Martín-Núñez, Carlos Aguilar, Manuel Vargas, Ana A Martín, Juan L García, Alexander Kohlmann, M Consuelo Del Cañizo, Jesús M Hernández-Rivas
To explore novel genetic abnormalities occurring in myelodysplastic syndromes (MDS) through an integrative study combining array-based comparative genomic hybridization (aCGH) and next-generation sequencing (NGS) in a series of MDS and MDS/myeloproliferative neoplasms (MPN) patients. 301 patients diagnosed with MDS (n = 240) or MDS/MPN (n = 61) were studied at the time of diagnosis. A genome-wide analysis of DNA copy number abnormalities was performed. In addition, a mutational analysis of DNMT3A, TET2, RUNX1, TP53 and BCOR genes was performed by NGS in selected cases...
2016: PloS One
Na Gao, Wen-Zheng Yu, Nong-Jian Guo, Xue-Xia Wang, Jian-Rong Sun
Galectin-3 plays an increasingly important role in development and progression of tumor. However, little is known about the clinical impact of galectin-3 in non-acute promyelocytic leukemia (non-M3 AML). Peripheral blood of 298 patients with primary non-M3 AML and 30 normal donors was collected for measurement of galectin-3. Galectin-3 levels were significantly higher compared with the control group (p < .001). Patients with higher galectin-3 levels had lower CR rates (p = .001) and 1-year overall survival (OS) rates (p = ...
October 13, 2016: Leukemia & Lymphoma
Akbar Ali, Rosemary E Gale, Abdul Rauf Shakoori
Acute myeloid leukemia (AML) is characterized by an increase in the number of myeloid cells in the marrow and an arrest in their maturation. Various genetic mutations are associated with AML. FMS-like tyrosine kinase 3 (FLT3), a member of the class III receptor tyrosine kinase family, plays an important role in stem cell survival, and the development of dendritic and natural killer cells. FLT3/TKD mutations are generally missense mutations or in-frame alterations of residues D835 and I836 within the activation loop of the FLT3 protein...
October 13, 2016: Journal of Cellular Biochemistry
Yan Xiu, Wingel Y Xue, Allyn Lambertz, Mariah Leidinger, Katherine Gibson-Corley, Chen Zhao
Previously we have shown that loss of non-canonical NF-κB signaling impairs self-renewal of hematopoietic stem/progenitor cells (HSPCs). This prompted us to investigate whether persistent activation of the non-canonical NF-κB signaling will have supportive effects on HSPC self-renewal. NF-κB-inducing kinase (NIK) is an important kinase that mainly activates the non-canonical pathway through directly phosphorylating IKKα. In contrast to our expectations, constitutive activation of NIK in the hematopoietic system leads to bone marrow failure and postnatal lethality due to intrinsic impairment of HSPC self-renewal and extrinsic disruption of bone marrow microenvironment through enhancing osteoclastogenesis...
October 12, 2016: Stem Cells
Stephen S Y Lam, Eric S K Ho, Bai-Liang He, Wui-Wing Wong, Chae-Yin Cher, Nelson K L Ng, Cheuk-Him Man, Harinder Gill, Alice M S Cheung, Ho-Wan Ip, Chi-Chiu So, Jerome Tamburini, Chi Wai Eric So, Dona N Ho, Chun-Hang Au, Tsun-Leung Chan, Edmond S K Ma, Raymond Liang, Yok-Lam Kwong, Anskar Y H Leung
An in vitro drug-screening platform on patient samples was developed and validated to design personalized treatment for relapsed/refractory acute myeloid leukemia (AML). Unbiased clustering and correlation showed that homoharringtonine (HHT), also known as omacetaxine mepesuccinate, exhibited preferential antileukemia effect against AML carrying internal tandem duplication of fms-like tyrosine kinase 3 (FLT3-ITD). It worked synergistically with FLT3 inhibitors to suppress leukemia growth in vitro and in xenograft mouse models...
October 5, 2016: Science Translational Medicine
Philipp G Hemmati, Lam G Vuong, Theis H Terwey, Christian F Jehn, Philipp le Coutre, Olaf Penack, Il-Kang Na, Bernd Dörken, Renate Arnold
OBJECTIVES: The purpose of this study was to evaluate the predictive capacity of the European LeukemiaNet (ELN) classification of genetic risk in patients with acute myeloid leukemia (AML) undergoing allogeneic stem cell transplantation (alloSCT). METHODS: We retrospectively analyzed 274 patients transplanted at our center between 2004 and 2014. RESULTS: The ELN grouping is comparable to the Southwest Oncology Group/Eastern Cooperative Oncology Group (SWOG/ECOG) stratification in predicting the outcome after alloSCT (overall p=0...
October 5, 2016: European Journal of Haematology
Wafa Bouleftour, Renata Neves Granito, Arnaud Vanden-Bossche, Odile Sabido, Bernard Roche, Mireille Thomas, Marie Thérèse Linossier, Jane E Aubin, Marie-Hélène Lafage-Proust, Laurence Vico, Luc Malaval
The bone organ integrates the activity of bone tissue, bone marrow and blood vessels and the factors ensuring this coordination remain ill defined. Bone sialoprotein (BSP) is with osteopontin (OPN) a member of the Small Integrin Binding Ligand N-Linked Glycoprotein (SIBLING) family, involved in bone formation, hematopoiesis and angiogenesis. In rodents, bone marrow ablation induces a rapid formation of medullary bone which peaks by ∼8 days (d8) and is blunted in BSP-/- mice. We investigated the coordinate hematopoietic and vascular recolonization of the bone shaft after marrow ablation of 2 month old BSP + /+ and BSP-/- mice...
October 5, 2016: Journal of Cellular Physiology
Takahide Hayano, Hiroshi Matsui, Hirofumi Nakaoka, Nobuaki Ohtake, Kazuyoshi Hosomichi, Kazuhiro Suzuki, Ituro Inoue
Prostate cancer (PC) is the second most common cancer in men. Family history is the major risk factor for PC. Only two susceptibility genes were identified in PC, BRCA2 and HOXB13. A comprehensive search of germline variants for patients with PC has not been reported in Japanese families. In this study, we conducted exome sequencing followed by Sanger sequencing to explore responsible germline variants in 140 Japanese patients with PC from 66 families. In addition to known susceptibility genes, BRCA2 and HOXB13, we identified TRRAP variants in a mutually exclusive manner in seven large PC families (three or four patients per family)...
2016: PloS One
S Struski, S Lagarde, P Bories, C Puiseux, N Prade, W Cuccuini, M-P Pages, A Bidet, C Gervais, M Lafage-Pochitaloff, C Roche-Lestienne, C Barin, D Penther, N Nadal, I Radford-Weiss, M-A Collonge-Rame, B Gaillard, F Mugneret, C Lefebvre, A Petit, G Leverger, C Broccardo, I Luquet, M Pasquet, E Delabesse
Pediatric acute myeloid leukemia (AML) is a rare disease whose prognosis is highly variable according to factors such as chromosomal abnormalities. Recurrent genomic rearrangements are detected in half of pediatric AML by karyotype. NUcleoPorin 98 (NUP98) gene is rearranged with 31 different fusion partner genes. These rearrangements are frequently undetected by conventional cytogenetics, since the NUP98 gene is located at the end of the chromosome 11 short arm (11p15). By screening a series of 574 pediatric AML, we detected a NUP98 rearrangement in 22 cases (3...
October 3, 2016: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Zhuojun Zheng, Xiaodong Li, Yuandong Zhu, Weiying Gu, Xiaobao Xie, Jingting Jiang
This study was designed to perform an acceptable prognostic nomogram for acute myeloid leukemia. The clinical data from 311 patients from our institution and 165 patients generated with Cancer Genome Atlas Research Network were reviewed. A prognostic nomogram was designed according to the Cox's proportional hazard model to predict overall survival (OS). To compare the capacity of the nomogram with that of the current prognostic system, the concordance index (C-index) was used to validate the accuracy as well as the calibration curve...
September 26, 2016: Oncotarget
Adam J de Smith, Juhi Ojha, Stephen S Francis, Erica Sanders, Alyson A Endicott, Helen M Hansen, Ivan Smirnov, Amanda M Termuhlen, Kyle M Walsh, Catherine Metayer, Joseph L Wiemels
High hyperdiploidy (HD), the most common cytogenetic subtype of B-cell acute lymphoblastic leukemia (B-ALL), is largely curable but significant treatment-related morbidity warrants investigating the biology and identifying novel drug targets. Targeted deep-sequencing of 538 cancer-relevant genes was performed in 57 HD-ALL patients lacking overt KRAS and NRAS hotspot mutations and lacking common B-ALL deletions to enrich for discovery of novel driver genes. One-third of patients harbored damaging mutations in epigenetic regulatory genes, including the putative novel driver DOT1L (n=4)...
September 24, 2016: Oncotarget
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