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https://www.readbyqxmd.com/read/29683667/optimization-of-selective-mitogen-activated-protein-kinase-interacting-kinases-1-and-2-mnk1-2-inhibitors-for-the-treatment-of-blast-crisis-leukemia
#1
Hai Yan Yang, Lohitha Rao Chennamaneni, Melvyn Wai Tuck Ho, Shi Hua Ang, Eldwin Sum Wai Tan, Duraiswamy Athisayamani Jeyaraj, Yoon Sheng Yeap, Boping Liu, Esther Hq Ong, Joma Kanikadu Joy, John Liang Kuan Wee, Perlyn Kwek, Priya Retna, Nurul Dinie, Thuy Thi Hanh Nguyen, Shi Jing Tai, Vithya Manoharan, Vishal Pendharkar, Choon Bing Low, Yun Shan Chew, Susmitha Vuddagiri, Kanda Sangthongpitag, Meng Ling Choong, May Ann Lee, Srinivasaraghavan Kannan, Chandra S Verma, Anders Poulsen, Sharon Lim, Charles Chuah, Tiong Sin Ong, Jeffrey Hill, Alex Matter, Kassoum Nacro
Chronic Myeloid Leukemia (CML) is a myeloproliferative disease caused by bcr-abl1, a constitutively active tyrosine kinase fusion gene responsible for an abnormal proliferation of leukemic stem cells (LSCs). Inhibition of BCR-ABL1 kinase activity offers long term relief to CML patients. However, for a proportion of them, BCR-ABL1 inhibition will become ineffective at treating the disease and CML will progress to blast crisis (BC) CML with poor prognosis. BC-CML is often associated with excessive phosphorylated eukaryotic translation initiation factor 4E (eIF4E) which renders LSCs capable of proliferating via self-renewal, oblivious to BCR-ABL1 inhibition...
April 23, 2018: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29681510/germline-genetic-ikzf1-variation-and-predisposition-to-childhood-acute-lymphoblastic-leukemia
#2
Michelle L Churchman, Maoxiang Qian, Geertruy Te Kronnie, Ranran Zhang, Wenjian Yang, Hui Zhang, Tobia Lana, Paige Tedrick, Rebekah Baskin, Katherine Verbist, Jennifer L Peters, Meenakshi Devidas, Eric Larsen, Ian M Moore, Zhaohui Gu, Chunxu Qu, Hiroki Yoshihara, Shaina N Porter, Shondra M Pruett-Miller, Gang Wu, Elizabeth Raetz, Paul L Martin, W Paul Bowman, Naomi Winick, Elaine Mardis, Robert Fulton, Martin Stanulla, William E Evans, Mary V Relling, Ching-Hon Pui, Stephen P Hunger, Mignon L Loh, Rupert Handgretinger, Kim E Nichols, Jun J Yang, Charles G Mullighan
Somatic genetic alterations of IKZF1, which encodes the lymphoid transcription factor IKAROS, are common in high-risk B-progenitor acute lymphoblastic leukemia (ALL) and are associated with poor prognosis. Such alterations result in the acquisition of stem cell-like features, overexpression of adhesion molecules causing aberrant cell-cell and cell-stroma interaction, and decreased sensitivity to tyrosine kinase inhibitors. Here we report coding germline IKZF1 variation in familial childhood ALL and 0.9% of presumed sporadic B-ALL, identifying 28 unique variants in 45 children...
April 16, 2018: Cancer Cell
https://www.readbyqxmd.com/read/29661755/a-cd123-targeting-antibody-drug-conjugate-imgn632-designed-to-eradicate-aml-while-sparing-normal-bone-marrow-cells
#3
Yelena Kovtun, Gregory E Jones, Sharlene Adams, Lauren Harvey, Charlene A Audette, Alan Wilhelm, Chen Bai, Lingyun Rui, Rassol Laleau, Fenghua Liu, Olga Ab, Yulius Setiady, Nicholas C Yoder, Victor S Goldmacher, Ravi V J Chari, Jan Pinkas, Thomas Chittenden
The outlook for patients with refractory/relapsed acute myeloid leukemia (AML) remains poor, with conventional chemotherapeutic treatments often associated with unacceptable toxicities, including severe infections due to profound myelosuppression. Thus there exists an urgent need for more effective agents to treat AML that confer high therapeutic indices and favorable tolerability profiles. Because of its high expression on leukemic blast and stem cells compared with normal hematopoietic stem cells and progenitors, CD123 has emerged as a rational candidate for molecularly targeted therapeutic approaches in this disease...
April 24, 2018: Blood Advances
https://www.readbyqxmd.com/read/29658352/chronic-subdural-collection-overlying-an-intra-axial-hemorrhagic-lesion-in-chronic-myelomonocytic-leukemia-special-report-and-review-of-the-literature
#4
Anne-Laure Bernat, Stefano Maria Priola, Ahmad Elsawy, Faisal Farrash, Shervin Taslimi, Fred Gentili
Chronic myelomonocytic leukaemia (CMML) is a clonal hematopoietic stem cell disorder characterized by the presence of an absolute monocytosis in the peripheral blood (>1 x 109 /L) and the presence of myelodysplastic and myeloproliferative features in the bone marrow. Involvement of the central nervous system (CNS) is uncommon in CMML. Areas covered: Herein described is a case report of a CMML patient who presents with symptomatic chronic subdural collection overlying a haemorrhagic brain lesion, along with diffuse dural infiltration, after two cycles of azacytidine...
April 16, 2018: Expert Review of Neurotherapeutics
https://www.readbyqxmd.com/read/29652746/fluorine-18-fluorodeoxyglucose-pet-ct-in-hematopoietic-stem-cell-transplant-patients-with-fusariosis-initial-findings-of-a-case-series-review
#5
Marcelo R Schirmer, Michel P Carneiro, Luiz S Machado, Alessandra L da S Chaves, Flávia P P L Lopes
BACKGROUND: Fusariosis is an opportunistic fungal infection that affects mostly leukemic and hematopoietic stem cell transplant patients. Locally invasive and disseminated infection may occur. Treatment is challenging, and besides evaluation of immune status, one also needs to take into account organ involvement to predict the duration and prognosis. OBJECTIVE: The aim of this study was to present the findings and clinical follow-up from a series of cases of Fusarium spp...
April 12, 2018: Nuclear Medicine Communications
https://www.readbyqxmd.com/read/29649617/reversal-of-t-cell-exhaustion-by-the-first-donor-lymphocyte-infusion-is-associated-with-the-persistently-effective-anti-leukemic-responses-in-patients-with-relapsed-aml-after-allo-hsct
#6
Long Liu, Ying-Jun Chang, Lan-Ping Xu, Xiao-Hui Zhang, Yu Wang, Kai-Yan Liu, Xiao-Jun Huang
Donor lymphocyte infusion is an effective approach to treat acute myeloid leukemia (AML) relapse after allogeneic hematopoietic stem cell transplantation (allo-HSCT) that significantly improves the survival of relapsed patients. However, the mechanism of an effective anti-leukemic response following DLI in AML relapse remains elusive. Here, we investigated the role of T cell exhaustion in AML relapse after allo-HSCT in prospective cohorts of 41 patients with the first AML relapse and 41 non-relapsed AML controls after allo-HSCT and determined whether DLI exerts effective anti-leukemic effects by reversing T cell exhaustion in the relapsed cohorts by detecting the phenotypes and functions of T cells using flow cytometry...
April 9, 2018: Biology of Blood and Marrow Transplantation
https://www.readbyqxmd.com/read/29644709/optimizing-the-pretransplant-regimen-for-autologous-stem-cell-transplantation-in-acute-myelogenous-leukemia-better-outcomes-with-busulfan-and-melphalan-compared-with-busulfan-and-cyclophosphamide-in-high-risk-patients-autografted-in-first-complete-remission
#7
Norbert Claude Gorin, Myriam Labopin, Didier Blaise, Pierre-Yves Dumas, Thomas Pabst, Silvia Maria Trisolini, William Arcese, Mohamed Houhou, Mohamad Mohty, Arnon Nagler
Autologous stem cell transplantation (ASCT) remains a clinical option to consolidate some adult patients with acute myelogenous leukemia (AML) in first complete remission (CR1). In a small cohort of patients, we have previously shown better outcomes following Busulfan and Melphalan (BUMEL) over Busulfan and Cyclophosphamide (BUCY). To identify the subpopulations that might get the highest benefit with BUMEL, we designed a larger study. All adult patients with primary AML and available cytogenetics, autografted from January 2000 to December 2016 in CR1, were included: 1137 patients received BUCY and 512 BUMEL...
April 12, 2018: American Journal of Hematology
https://www.readbyqxmd.com/read/29643228/dual-inhibition-of-mdmx-and-mdm2-as-a-therapeutic-strategy-in-leukemia
#8
Luis A Carvajal, Daniela Ben Neriah, Adrien Senecal, Lumie Benard, Victor Thiruthuvanathan, Tatyana Yatsenko, Swathi-Rao Narayanagari, Justin C Wheat, Tihomira I Todorova, Kelly Mitchell, Charles Kenworthy, Vincent Guerlavais, D Allen Annis, Boris Bartholdy, Britta Will, Jesus D Anampa, Ioannis Mantzaris, Manuel Aivado, Robert H Singer, Robert A Coleman, Amit Verma, Ulrich Steidl
The tumor suppressor p53 is often inactivated via its interaction with endogenous inhibitors mouse double minute 4 homolog (MDM4 or MDMX) or mouse double minute 2 homolog (MDM2), which are frequently overexpressed in patients with acute myeloid leukemia (AML) and other cancers. Pharmacological disruption of both of these interactions has long been sought after as an attractive strategy to fully restore p53-dependent tumor suppressor activity in cancers with wild-type p53. Selective targeting of this pathway has thus far been limited to MDM2-only small-molecule inhibitors, which lack affinity for MDMX...
April 11, 2018: Science Translational Medicine
https://www.readbyqxmd.com/read/29643185/expression-of-mutant-asxl1-perturbs-hematopoiesis-and-promotes-susceptibility-to-leukemic-transformation
#9
Reina Nagase, Daichi Inoue, Alessandro Pastore, Takeshi Fujino, Hsin-An Hou, Norimasa Yamasaki, Susumu Goyama, Makoto Saika, Akinori Kanai, Yasuyuki Sera, Sayuri Horikawa, Yasunori Ota, Shuhei Asada, Yasutaka Hayashi, Kimihito Cojin Kawabata, Reina Takeda, Hwei-Fang Tien, Hiroaki Honda, Omar Abdel-Wahab, Toshio Kitamura
Additional sex combs like 1 ( ASXL1 ) is frequently mutated in myeloid malignancies and clonal hematopoiesis of indeterminate potential (CHIP). Although loss of ASXL1 promotes hematopoietic transformation, there is growing evidence that ASXL1 mutations might confer an alteration of function. In this study, we identify that physiological expression of a C-terminal truncated Asxl1 mutant in vivo using conditional knock-in (KI) results in myeloid skewing, age-dependent anemia, thrombocytosis, and morphological dysplasia...
April 11, 2018: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/29623856/investigation-of-the-roles-of-non-neuronal-acetylcholine-in-chronic-myeloid-leukemic-cells-and-their-erythroid-or-megakaryocytic-differentiated-lines
#10
Banu Aydin, Hulya Cabadak, Zafer Mehmet Goren
Many studies suggested that acetylcholine (ACh) might serve as an autocrine/ paracrine growth factor in several types of tumors or tumor cell lines. Therefore, cholinergic signaling seems to be functionally important in cancer. High levels of acetylcholinesterase (AChE) activity have been reported in primary brain tumors, ovarian, colon and lung tumors. K562 cells were derived from a chronic myelogenous leukemia patient during blast crisis serving as pluripotent hematopoietic stem cells. K562 cells were incubated with various cholinergic agonists or antagonists to investigate the role of ACh in different differentiated cell lines...
April 6, 2018: Anti-cancer Agents in Medicinal Chemistry
https://www.readbyqxmd.com/read/29616837/outcome-of-ph-negative-myeloproliferative-neoplasms-transforming-to-accelerated-or-leukemic-phase
#11
Lise-Marie Mollard, Aurélie Chauveau, Françoise Boyer-Perrard, Nathalie Douet-Guilbert, Roch Houot, Isabelle Quintin-Roué, Marie-Anne Couturier, Anaig Dagorne, Mohamed Malou, Ronan Le Calloch, Odile Luycx, Sylvain Thepot, Mathilde Hunault, Gaelle Guillerm, Christian Berthou, Valérie Ugo, Éric Lippert, Jean-Christophe Ianotto
Myeloproliferative neoplasms (MPN) are chronic disorders that can sometimes evolve into accelerated or leukemic phases. We retrospectively identified 122 patients with such blastic phases. The overall median survival was four months: 10.2 months for patients treated with intensive treatments compared to three months for best supportive care (p = .005). Azacytidine, intensive chemotherapies, or allogeneic stem cell transplantation gave the highest median survivals with 9, 10.2, and 19.4 months, respectively...
April 4, 2018: Leukemia & Lymphoma
https://www.readbyqxmd.com/read/29602066/new-synergistic-combinations-of-differentiation-inducing-agents-in-the-treatment-of-acute-promyelocytic-leukemia-cells
#12
Amir Amanzadeh, Vahid Molla-Kazemiha, Saeed Samani, Mahdi Habibi-Anbouhi, Kayhan Azadmanesh, Mohsen Abolhassani, Mohammad Ali Shokrgozar
Acute promyelocytic leukemia (APL) was considered to be one of the most lethal forms of leukemia in adults before the introduction of the vitamin A metabolite all-trans retinoic acid (ATRA). Surprisingly, it has been confirmed that FICZ (6-Formylindolo (3, 2-b) carbazole) enhances ATRA-induced differentiation. Moreover, a number of studies have demonstrated that anti CD44 monoclonal antibody (mAb) induces to bring back differentiation blockage the leukemic stem cells. The level of differentiation markers including CD11b and CD11c in NB4 cells was assessed by flow cytometry...
January 17, 2018: Leukemia Research
https://www.readbyqxmd.com/read/29588856/diagnosis-of-gata2-haplo-insufficiency-in-a-young-woman-prompted-by-pancytopenia-with-deficiencies-of-b-cell-and-dendritic-cell-development
#13
Allen Sanyi, David L Jaye, Cecilia B Rosand, Amanda Box, Chandrakasan Shanmuganathan, Edmund K Waller
Background: GATA2 deficiency presents with a spectrum of phenotypes including increased susceptibility to viral and bacterial infections, multi-lineage cytopenias, aplastic anemia, leukemic transformation and lymphedema. Allogeneic transplantation is only curative therapy for GATA2 deficiency, but is associated with significant treatment related morbidity and mortality. Given the spectrum of clinical presentation, accurate diagnosis of GATA2 deficiency is necessary to identify patients early in their disease course when allogeneic bone marrow transplantation may be of clinical benefit...
2018: Biomarker Research
https://www.readbyqxmd.com/read/29580554/paramunity-inducing-factors-pinds-in-dendritic-cell-dc-cultures-lead-to-impaired-antileukemic-functionality-of-dc-stimulated-t-cells
#14
Christian Ansprenger, Valentin Vogt, Julia Schick, Annika Hirn-Lopez, Yvonne Vokac, Ihor Harabacz, Marion Braeu, Tanja Kroell, Axel Karenberg, Hans-Jochem Kolb, Helga Schmetzer
INTRODUCTION: Paramunity-inducing-Factors (PINDs) consist of attenuated/inactivated viruses of various poxvirus-genera, used in veterinary medicine as non-antigen-specific, non-immunising stimulators of the innate immune system against infectious and malignant diseases. Their danger-signaling-interactions were tested for their capacity to improve leukemic antigen-presentation on DC generated from AML-patients' blasts ('DCleu ') and DC-stimulation/activation of antileukemic T-cells. METHODS: We analyzed, whether the addition of PINDs during DC cultures (15 healthy, 22 leukemic donors) and mixed lymphocyte culture (MLC, n = 15) with autologous (n = 6), allogeneic (n = 2) or T-cells after stem cell transplantation (SCT; n = 7) would alter the quality and quantity of DC, the composition of T-cell-subsets, and/or their antileukemic functionality (AF) as studied by FACS and functional Fluorolysis-cytotoxicity-assays...
March 16, 2018: Cellular Immunology
https://www.readbyqxmd.com/read/29566751/engineering-a-multicellular-vascular-niche-to-model-hematopoietic-cell-trafficking
#15
Surya S Kotha, Brian J Hayes, Kiet T Phong, Meredith A Redd, Karol Bomsztyk, Aravind Ramakrishnan, Beverly Torok-Storb, Ying Zheng
BACKGROUND: The marrow microenvironment and vasculature plays a critical role in regulating hematopoietic cell recruitment, residence, and maturation. Extensive in vitro and in vivo studies have aimed to understand the marrow cell types that contribute to hematopoiesis and the stem cell environment. Nonetheless, in vitro models are limited by a lack of complex multicellular interactions, and cellular interactions are not easily manipulated in vivo. Here, we develop an engineered human vascular marrow niche to examine the three-dimensional cell interactions that direct hematopoietic cell trafficking...
March 23, 2018: Stem Cell Research & Therapy
https://www.readbyqxmd.com/read/29556020/tracking-preleukemic-cells-in-vivo-to-reveal-the-sequence-of-molecular-events-in-radiation-leukemogenesis
#16
Tom Verbiest, Rosemary Finnon, Natalie Brown, Lourdes Cruz-Garcia, Paul Finnon, Grainne O'Brien, Eleanor Ross, Simon Bouffler, Cheryl L Scudamore, Christophe Badie
Epidemiological studies have demonstrated an increased leukemia incidence following ionizing radiation exposure, but to date, the target cells and underlying mechanisms of radiation leukemogenesis remain largely unidentified. We engineered a mouse model carrying a different fluorescent marker on each chromosome 2, located inside the minimum deleted region occurring after radiation exposure and recognized as the first leukemogenic event. Using this tailored model, we report that following radiation exposure, more than half of asymptomatic CBA Sfpi1 GFP/mCh mice presented with expanding clones of preleukemic hematopoietic cells harboring a hemizygous interstitial deletion of chromosome 2...
March 3, 2018: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/29553571/comprehensive-protocol-to-sample-and-process-bone-marrow-for-measuring-measurable-residual-disease-and-leukemic-stem-cells-in-acute-myeloid-leukemia
#17
Jacqueline Cloos, Jeffrey R Harris, Jeroen J W M Janssen, Angele Kelder, F Huang, Gerrit Sijm, Maike Vonk, Alexander N Snel, Jennifer R Scheick, Willemijn J Scholten, Jannemieke Carbaat-Ham, Dennis Veldhuizen, Diana Hanekamp, Yvonne J M Oussoren-Brockhoff, Gertjan J L Kaspers, Gerrit J Schuurhuis, A Kate Sasser, Gert Ossenkoppele
Response criteria in acute myeloid leukemia (AML) has recently been re-established, with morphologic examination utilized to determine whether patients have achieved complete remission (CR). Approximately half of the adult patients who entered CR will relapse within 12 months due to the outgrowth of residual AML cells in the bone marrow. The quantitation of these remaining leukemia cells, known as minimal or measurable residual disease (MRD), can be a robust biomarker for the prediction of these relapses. Moreover, retrospective analysis of several studies has shown that the presence of MRD in the bone marrow of AML patients correlates with poor survival...
March 5, 2018: Journal of Visualized Experiments: JoVE
https://www.readbyqxmd.com/read/29549921/microparticles-in-hematological-malignancies-role-in-coagulopathy-and-tumor-pathogenesis
#18
REVIEW
Somedeb Ball, Kenneth Nugent
Microparticles (MP) are submicron vesicles released from various cells in response to activation, injury or apoptosis. They contain different structural and functional proteins and RNAs, which contribute to physiological intercellular "crosstalk" and to the pathogenesis of various diseases including cancer. In hematological malignancies, these MPs participate in the initiation and propagation of thrombosis through different pathways. They have a role in the angiogenesis, malignant cell survival and metastasis...
March 2018: American Journal of the Medical Sciences
https://www.readbyqxmd.com/read/29549529/isocitrate-dehydrogenase-2-mutations-correlate-with-leukemic-transformation-and-are-predicted-by-2-hydroxyglutarate-in-myelodysplastic-syndromes
#19
Peipei Lin, Yingwan Luo, Shuanghong Zhu, Dominic Maggio, Haiyang Yang, Chao Hu, Jinghan Wang, Hua Zhang, Yanling Ren, Xinping Zhou, Chen Mei, Liya Ma, Weilai Xu, Li Ye, Zhengping Zhuang, Jie Jin, Hongyan Tong
PURPOSE: The myelodysplastic syndromes (MDS) are a group of hematologic disorders characterized by the presence of somatically mutated hematopoietic stem cells (HSCs) that increase the risk of progression to secondary acute myeloid leukemia (sAML). Mutations in isocitrate dehydrogenase (IDHmut ) are thought to correlate with the increased production of the oncogenic protein 2-hydroxyglutarate (2-HG) in AML. The aim of this study was to examine whether serum 2-HG has utility as a prognostic biomarker, and whether elevated 2-HG levels are predictive of IDH mutations in patients with MDS...
March 16, 2018: Journal of Cancer Research and Clinical Oncology
https://www.readbyqxmd.com/read/29549053/senescent-human-hematopoietic-progenitors-show-elevated-expression-of-transposable-elements-and-inflammatory-genes
#20
Stephen Capone, Kwasi M Connor, Anthony Colombo, Xin Li, Tim J Triche, Giridharan Ramsingh
Genomic transposable elements (TEs) constitute majority of the genome. Expression of TEs is known to activate the double-stranded RNA recognition pathway ("viral mimicry") leading to the activation of interferon-stimulated genes, inflammation and immune mediated cell death. We recently showed that the expression of TEs is suppressed along with immune pathways in leukemic stem cells (LSC) in acute myeloid leukemia, suggesting a potential mechanism for immune escape of LSC. This indicated that during oncogenesis, where there is escape from senescence, expression of TEs is suppressed...
March 13, 2018: Experimental Hematology
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