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Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K

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https://www.readbyqxmd.com/read/28725044/cord-blood-nk-cells-engineered-to-express-il-15-and-a-cd19-targeted-car-show-long-term-persistence-and-potent-anti-tumor-activity
#1
E Liu, Y Tong, G Dotti, H Shaim, B Savoldo, M Mukherjee, J Orange, X Wan, X Lu, A Reynolds, M Gagea, P Banerjee, R Cai, M H Bdaiwi, R Basar, M Muftuoglu, L Li, D Marin, W Wierda, M Keating, R Champlin, E Shpall, K Rezvani
Chimeric antigen receptors (CARs) have been used to redirect the specificity of autologous T-cells against leukemia and lymphoma with promising clinical results.(1-3) Extending this approach to allogeneic T-cells is problematic as they carry a significant risk of graft-versus-host disease (GVHD). Natural killer (NK) cells are highly cytotoxic effectors, killing their targets in a non-antigen specific manner without causing GVHD. Cord blood (CB) offers an attractive, allogeneic, off-the-self source of NK cells for immunotherapy...
July 20, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28720765/c-ebp%C3%AE-deregulation-as-a-paradigm-for-leukemogenesis
#2
REVIEW
J A Pulikkan, D G Tenen, G Behre
Myeloid master regulator CCAAT enhancer binding protein alpha (C/EBPα) is deregulated by multiple mechanisms in leukemia. Inhibition of C/EBPα function plays pivotal roles in leukemogenesis. While much is known about how C/EBPα orchestrates granulopoiesis, our understanding of molecular transformation events, the role(s) of cooperating mutations and clonal evolution during C/EBPα deregulation in leukemia remains elusive. In this review we will summarize the latest research addressing these topics with special emphasis on CEBPΑ mutations...
July 19, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28720764/high-expression-of-abcg2-induced-by-ezh2-disruption-plays-pivotal-roles-in-mds-pathogenesis
#3
Kimihito C Kawabata, Yasutaka Hayashi, Daichi Inoue, Hiroko Meguro, Hiroko Sakurai, Tomofusa Fukuyama, Yosuke Tanaka, Shuhei Asada, Tsuyoshi Fukushima, Reina Nagase, Reina Takeda, Yuka Harada, Jiro Kitaura, Susumu Goyama, Hironori Harada, Hiroyuki Aburatani, Toshio Kitamura
Both proto-oncogenic and tumor-suppressive functions have been reported for EZH2. To investigate the effects of its inactivation, a mutant EZH2 lacking its catalytic domain was prepared (EZH2-dSET). In a mouse bone marrow transplant (BMT) model, EZH2-dSET expression in bone marrow cells (BMCs) induced an MDS-like disease in transplanted mice. Analysis of these mice identified Abcg2 as a direct target of EZH2. Intriguingly, Abcg2 expression alone induced the same disease in the transplanted mice, where stemness genes were enriched...
July 19, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28720763/high-frequency-of-runx1-mutation-in-myelodysplastic-syndrome-patients-with-whole-arm-translocation-of-der-1-7-q10-p10
#4
T Zhang, Y Xu, J Pan, H Li, Q Wang, L Wen, D Wu, A Sun, S Chen
Leukemia accepted article preview online, 19 July 2017. doi:10.1038/leu.2017.228.
July 19, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28701730/the-mll-recombinome-of-acute-leukemias-in-2017
#5
C Meyer, T Burmeister, D Gröger, G Tsaur, L Fechina, S Renneville, R Sutton, N C Venn, M Emerenciano, M S Pombo-de-Oliveira, C Barbieri Blunck, B Almeida Lopes, J Zuna, J Trka, P Ballerini, H Lapillonne, M De Braekeleer, G Cazzaniga, L Corral Abascal, V H J van der Velden, E Delabesse, T S Park, S H Oh, M L M Silva, T Lund-Aho, V Juvonen, A S Moore, O Heidenreich, J Vormoor, E Zerkalenkova, Y Olshanskaya, C Bueno, P Menendez, S Teigler-Schlegel, U Zur Stadt, J Lentes, G Göhring, S Kustanovich, O Aleinikova, B W Schäfer, S Kubetzko, H O Madsen, B Gruhn, X Duarte, P Gameiro, E Lippert, S Bidet, J M Cayuela, E Clappier, C N Alonso, C M Zwaan, M M van den Heuvel-Eibrink, S Izraeli, L Trakhtenbrot, P Archer, J Hancock, A Möricke, J Alten, M Schrappe, M Stanulla, S Strehl, A Attarbaschi, M Dworzak, O A Haas, R Panzer-Grümayer, L Sedék, T Szczepański, S Caye, L Suarez, H Cavé, R Marschalek
Chromosomal rearrangements of the human MLL/KMT2A gene are associated with infant, pediatric, adult and therapy-induced acute leukemias. Here, we present the data obtained from 2345 acute leukemia patients. Genomic breakpoints within the MLL gene and the involved translocation partner genes (TPGs) were determined and 11 novel TPGs were identified. Thus, a total of 135 different MLL rearrangements habe been identified so far, of which 94 TPGs are now characterized at the molecular level. Thirty-five out of these 94 TPGs occur recurrently, but only 9 specific gene fusions account for more than 90% of all illegitimate recombinations of the MLL gene...
July 13, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28690315/targeting-nucleolin-for-better-survival-in-diffuse-large-b-cell-lymphoma
#6
N Jain, H Zhu, T Khashab, Q Ye, B George, R Mathur, R K Singh, Z Berkova, J F Wise, F K Braun, X Wang, K Patel, Z Y Xu-Monette, J Courty, K H Young, L Sehgal, F Samaniego
Anthracyclines have been a cornerstone in the cure of diffuse large B-cell lymphoma (DLBCL) and other hematological cancers. The ability of anthracyclines to eliminate DLBCL depends on the presence of topoisomerase-II-alpha (TopIIA), a DNA repair enzyme complex. We identified nucleolin as a novel binding partner of TopIIA. Abrogation of nucleolin sensitized DLBCL cells to TopIIA targeting agents (doxorubicin/etoposide). Silencing nucleolin and challenging DLBCL cells with doxorubicin enhanced the phosphorylation of H2AX (γH2AX-marker of DNA damage) and allowed DNA fragmentation...
July 10, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28690314/evolution-of-npm1-negative-therapy-related-myelodysplastic-syndromes-following-curative-treatment-of-npm1-mutant-aml
#7
S Herold, K Sockel, C Sayehli, R Herbst, U Dührsen, U Oelschlägel, A Böttner, H Hindahl, J Kullmer, S Helas, M Sauer, B Mohr, A Mies, M Bornhäuser, G Ehninger, C Röllig, C Thiede, U Platzbecker
Leukemia accepted article preview online, 10 July 2017. doi:10.1038/leu.2017.217.
July 10, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28690313/the-hdac-inhibitor-panobinostat-lbh589-exerts-in-vivo-anti-leukaemic-activity-against-mll-rearranged-acute-lymphoblastic-leukaemia-and-involves-the-rnf20-rnf40-wac-h2b-ubiquitination-axis
#8
P G Castro, E H J van Roon, S S M Pinhanços, L Trentin, P Schneider, M Kerstjens, G Te Kronnie, O Heidenreich, R Pieters, R W Stam
MLL-rearranged acute lymphoblastic leukaemia (ALL) represents an aggressive malignancy in infants (<1 year of age), associated with poor outcome. Current treatment intensification is not further possible, and novel therapy strategies are needed. Notably, MLL-rearranged ALL is characterised by a strongly deregulated epigenome and shows sensitivity to epigenetic perturbators. Here, we demonstrate the in vivo efficacy of the histone deacetylase inhibitor Panobinostat (LHB589) using xenograft mouse models of MLL-rearranged ALL...
July 10, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28676669/carfilzomib-resistance-due-to-abcb1-mdr1-overexpression-is-overcome-by-nelfinavir-and-lopinavir-in-multiple-myeloma
#9
A Besse, S C Stolze, L Rasche, N Weinhold, G J Morgan, M Kraus, J Bader, H S Overkleeft, L Besse, C Driessen
Proteasome inhibitor carfilzomib has activity superior to bortezomib and is increasingly incorporated in multiple myeloma (MM) frontline therapy and relapsed settings. Most MM patients ultimately experience proteasome inhibitor-refractory disease, an unmet medical need with poorly understood biology and dismal outcome. Pharmacologic targeting of ABCB1 improved patient outcomes, including MM, but suffered from adverse drug effects and insufficient plasma concentrations. Proteomics analysis identified ABCB1 overexpression as the most significant change in carfilzomib-resistant MM cells...
July 5, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28676668/the-calreticulin-calr-exon-9-mutations-are-promising-targets-for-cancer-immune-therapy
#10
M O Holmström, E Martinenaite, S M Ahmad, Ö Met, C Friese, L Kjær, C H Riley, P Thor Straten, I M Svane, H C Hasselbalch, M H Andersen
The CALR exon 9 mutations are found in approximately 30% of patients with essential thrombocythemia and primary myelofibrosis. Recently, we reported spontaneous immune responses against the CALR mutations. Here, we describe that CALR-mutant (CALRmut)-specific T-cells are able to specifically recognize CALRmut cells. First, we established a T-cell culture specific for a CALRmut epitope. These specific T-cells were able to recognize several epitopes in the CALRmut C-terminus. Next, we established a CALRmut specific CD4(+) T-cell clone by limiting dilution...
July 5, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28674423/a-four-gene-lincrna-expression-signature-predicts-risk-in-multiple-cohorts-of-acute-myeloid-leukemia-patients
#11
D Beck, J A I Thoms, C Palu, T Herold, A Shah, J Olivier, L Boelen, Y Huang, D Chacon, A Brown, M Babic, C Hahn, M Perugini, X Zhou, B J Huntly, A Schwarzer, J-H Klusmann, W E Berdel, B Wörmann, T Büchner, W Hiddemann, S K Bohlander, L B To, H S Scott, I D Lewis, R J D'Andrea, J W H Wong, J E Pimanda
Prognostic gene expression signatures have been proposed as clinical tools to clarify therapeutic options in Acute Myeloid Leukemia (AML). However, these signatures rely on measuring large numbers of genes and often perform poorly when applied to independent cohorts or those with older patients. Long intergenic noncoding RNAs (lincRNAs) are emerging as important regulators of cell identity and oncogenesis, but knowledge of their utility as prognostic markers in AML is limited. Here we analyse transcriptomic data from multiple cohorts of clinically annotated AML patients and report that (i) microarrays designed for coding gene expression can be repurposed to yield robust lincRNA expression data, (ii) some lincRNA-genes are located in close proximity to hematopoietic coding-genes and show strong expression correlations in AML, (iii) lincRNA-gene expression patterns distinguish cytogenetic and molecular subtypes of AML, (iv) lincRNA-signatures composed of three or four genes are independent predictors of clinical outcome and further dichotomise survival in ELN risk groups, and (v) an analytical tool based on logistic regression analysis of quantitative PCR measurement of four lincRNA genes (LINC4) can be used to determine risk in AML...
July 4, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28663582/bet-protein-proteolysis-targeting-chimera-protac-exerts-potent-lethal-activity-against-mantle-cell-lymphoma-cells
#12
B Sun, W Fiskus, Y Qian, K Rajapakshe, K Raina, K G Coleman, A P Crew, A Shen, D T Saenz, C P Mill, A J Nowak, N Jain, L Zhang, M Wang, J D Khoury, C Coarfa, C M Crews, K N Bhalla
Bromodomain extraterminal protein (BETP) inhibitors transcriptionally repress oncoproteins and NFkB target genes, which undermines the growth and survival of MCL cells. However, BETi treatment causes accumulation of BETPs, associated with reversible binding and incomplete inhibition of BRD4, which potentially compromises the activity of BETi in MCL cells. Unlike BETi, BET-PROTACs (proteolysis-targeting chimera) ARV-825 and ARV-771 (Arvinas, Inc.) recruit and utilize an E3-ubiquitin ligase to effectively degrade BETPs in MCL cells...
June 30, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28663581/heavy-light-chain-monitoring-correlates-with-clinical-outcome-in-multiple-myeloma-patients
#13
M Michallet, C Chapuis-Cellier, T Dejoie, C Lombard, H Caillon, M Sobh, P Moreau, M Attal, H Avet-Loiseau
Novel anti-myeloma agents have improved patient response rates, which are historically based on reductions of the M-protein. These methods can be inaccurate for quantifying M-proteins at low concentrations. We compared the consistency and clinical impact of response assignment by electrophoretic and heavy+light chain (HLC) immunoassays post-consolidation in 463 newly diagnosed patients. The two methods gave similar assignments in patients with partial (PR; 79% agreement) or complete response (⩾CR; 92%). However, in patients achieving very good PR (VGPR) there was poor concordance between methods (45%)...
June 30, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28663580/an-atlas-of-bloodstream-accessible-bone-marrow-proteins-for-site-directed-therapy-of-acute-myeloid-leukemia
#14
L Angenendt, S Reuter, D Kentrup, A S Benk, F Neumann, J Hüve, A C Martens, C Schwöppe, T Kessler, L H Schmidt, T Sauer, C Brand, J-H Mikesch, G Lenz, R M Mesters, C Müller-Tidow, W Hartmann, E Wardelmann, D Neri, W E Berdel, C Roesli, C Schliemann
The concept of arming antibodies with bioactive payloads for a site-specific therapy of cancer has gained considerable interest in recent years. However, a successful antibody-based targeting approach critically relies on the availability of a tumor-associated target that is not only preferentially expressed in the tumor tissue but is also easily accessible for antibody therapeutics coming from the bloodstream. Here, we perfused the vasculature of healthy and acute myeloid leukemia (AML)-bearing rats with a reactive ester derivative of biotin and subsequently quantified the biotinylated proteins to identify AML-associated bone marrow (BM) antigens accessible from the bloodstream...
June 30, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28663579/genetic-deletion-or-small-molecule-inhibition-of-the-arginine-methyltransferase-prmt5-exhibit-anti-tumoral-activity-in-mouse-models-of-mll-rearranged-aml
#15
S Kaushik, F Liu, K Veazey, G Gao, P Das, L Neves, K Li, Y Zhong, Y Lu, V Giuliani, M T Bedford, S D Nimer, M A Santos
The hematological malignancies classified as Mixed Lineage leukemias (MLL) harbor fusions of the MLL1 gene to partners that are members of transcriptional elongation complexes. MLL-rearranged leukemias are associated with extremely poor prognosis and response to conventional therapies and efforts to identify molecular targets are urgently needed. Using mouse models of MLL-rearranged acute myeloid leukemia (AML), here we show that genetic inactivation or small molecule inhibition of the protein arginine methyltransferase PRMT5 exhibit anti-tumoral activity in MLL-fusion protein driven transformation...
June 30, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28663575/new-drugs-in-myeloma-beware-of-phase-i-trial-results-beware-of-cost-and-demand-for-new-trials
#16
P Moreau
No abstract text is available yet for this article.
June 30, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28659618/an-oncogenic-axis-of-stat-mediated-batf3-upregulation-causing-myc-activity-in-classical-hodgkin-lymphoma-and-anaplastic-large-cell-lymphoma
#17
A Lollies, S Hartmann, M Schneider, T Bracht, A Weiß, J Arnolds, L Klein-Hitpass, B Sitek, M-L Hansmann, R Küppers, M A Weniger
Classical Hodgkin lymphoma (cHL) and anaplastic large cell lymphoma (ALCL) feature high expression of AP-1 transcription factors, which regulate various physiological processes but also promote lymphomagenesis. The AP-1 factor basic leucine zipper transcription factor, ATF-like 3 (BATF3) is highly transcribed in cHL and ALCL; however, its functional importance in lymphomagenesis is unknown. Here we show that proto-typical CD30(+) lymphomas, namely cHL (21/30) and primary mediastinal B-cell lymphoma (8/9), but also CD30(+) diffuse large B-cell lymphoma (15/20) frequently express BATF3 protein...
June 29, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28656959/do-we-need-to-distinguish-exosomes-from-microvesicles-in-hematological-malignancies
#18
A Caivano, L Del Vecchio, P Musto
Leukemia accepted article preview online, 28 June 2017. doi:10.1038/leu.2017.205.
June 28, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28655925/natural-history-of-t-11-14-multiple-myeloma
#19
A Lakshman, M A Moustafa, S V Rajkumar, A Dispenzieri, M A Gertz, F K Buadi, M Q Lacy, D Dingli, A L Fonder, S R Hayman, M A Hobbs, W I Gonsalves, Y L Hwa, P Kapoor, N Leung, R S Go, Y Lin, T V Kourelis, J A Lust, S J Russell, S R Zeldenrust, R A Kyle, S K Kumar
Translocation (11;14) on interphase FISH in plasma cells is regarded as a standard risk prognostic marker in multiple myeloma (MM) based on studies conducted before introduction of current therapies. We identified 365 patients with t(11;14), and 730 matched controls:132 patients with non-(11;14) translocations and 598 with no chromosomal translocation. The median progression-free survival (PFS) for the three groups were 23.0 (95% CI, 20.8-27.6), 19.0 (95% CI, 15.8-22.7) and 28.3 (95% CI, 25.7-30.6) months respectively [P<0...
June 27, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28652579/hla-dpb1-mismatch-induces-a-graft-versus-leukemia-effect-without-severe-acute-gvhd-after-single-unit-umbilical-cord-blood-transplantation
#20
T Yabe, F Azuma, K Kashiwase, K Matsumoto, T Orihara, H Yabe, S Kato, K Kato, S Kai, T Mori, S Morishima, M Satake, M Takanashi, K Nakajima, Y Morishima
Although it is known that human leukocyte antigen (HLA)-DPB1 disparity has a strong impact on outcomes in unrelated hematopoietic transplantation with induction of acute graft-versus-host disease (GVHD) and a graft-versus-leukemia (GVL) effect, its role in unrelated umbilical cord blood transplantation (UR-CBT) has yet to be fully clarified. Our current study is being conducted to elucidate the impact of HLA-DPB1 mismatch, along with the effect of other HLA loci mismatches at the allele level. HLA six loci alleles were retrospectively typed in 1157 Japanese donors and patients with leukemia or myelodysplastic syndrome who underwent transplantation with a single unit of cord blood...
June 27, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
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