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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/28643785/dnmt3a-mutant-transcript-levels-persist-in-remission-and-do-not-predict-outcome-in-patients-with-acute-myeloid-leukemia
#1
V I Gaidzik, D Weber, P Paschka, A Kaumanns, S Krieger, A Corbacioglu, J Krönke, S Kapp-Schwoerer, D Krämer, H-A Horst, I Schmidt-Wolf, G Held, A Kündgen, M Ringhoffer, K Götze, T Kindler, W Fiedler, M Wattad, R F Schlenk, L Bullinger, V Teleanu, B Schlegelberger, F Thol, M Heuser, A Ganser, H Döhner, K Döhner
We investigated the prognostic impact of minimal residual disease (MRD) monitoring in acute myeloid leukemia (AML) patients harboring DNA methyltransferase 3A-R882H/-R882C mutations (DNMT3A(mut)). MRD was determined by real-time quantitative polymerase chain reaction (RQ-PCR) in 1,494 samples of 181 DNMT3A(mut) patients. At the time of diagnosis, DNMT3A(mut) transcript levels did not correlate with presenting clinical characteristics, concurrent gene mutations as well as the survival endpoints. In Cox regression analyses, bone marrow DNMT3A(mut) transcript levels (log 10 transformed continuous variable) were not associated with the rate of relapse or death...
June 23, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28642594/differential-effects-on-gene-transcription-and-hematopoietic-differentiation-correlate-with-gata2-mutant-disease-phenotypes
#2
C-E Chong, P Venugopal, P H Stokes, Y K Lee, P J Brautigan, D T O Yeung, M Babic, G A Engler, S W Lane, M Klingler-Hoffmann, J M Matthews, R J D'Andrea, A L Brown, C N Hahn, H S Scott
Heterozygous GATA2 mutations underlie an array of complex hematopoietic and lymphatic diseases. Analysis of the literature reporting three recurrent GATA2 germline (g) mutations (gT354M, gR396Q, gR398W) revealed different phenotype tendencies. While all three mutants differentially predispose to myeloid malignancies, there was no difference in leukemia-free survival for GATA2 patients. Despite intense interest, the molecular pathogenesis of GATA2 mutation is poorly understood. We functionally characterized a GATA2 mutant allelic series representing major disease phenotypes caused by germline and somatic (s) mutations in zinc finger (ZF) 2...
June 23, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28642593/transforming-growth-factor-%C3%AE-1-regulates-the-nascent-hematopoietic-stem-cell-niche-by-promoting-gluconeogenesis
#3
C-Y Zhang, H-M Yin, H Wang, D Su, Y Xia, L-F Yan, B Fang, W Liu, Y-M Wang, A-H Gu, Y Zhou
The understanding of hematopoietic stem cell (HSC) emergence is important to generate HSCs from pluripotent precursors. However, integrated signaling network that regulates the niche of nascent HSCs remains unclear. Herein, we uncovered a novel role of TGF-β1 in the metabolic niche of HSC emergence using the tgf-β1b(-/-) zebrafish. Our findings first showed that Tgf-β1 transcripts were enriched in the nascent HSCs. Loss of tgf-β1b caused a decrease of nascent HSCs within the aorta-gonad-mesonephros. Moreover, tgf-β1b(+) cells were runx1(+) HSCs and underwent an endothelial-to-hematopoietic-transition process...
June 23, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28642592/integrative-network-analysis-identifies-novel-drivers-of-pathogenesis-and-progression-in-newly-diagnosed-multiple-myeloma
#4
A Laganà, D Perumal, D Melnekoff, B Readhead, B A Kidd, V Leshchenko, P-Y Kuo, J Keats, M DeRome, J Yesil, D Auclair, S Lonial, A Chari, H J Cho, B Barlogie, S Jagannath, J T Dudley, S Parekh
Multiple Myeloma (MM) is an incurable malignancy of bone marrow plasma cells characterized by wide clinical and molecular heterogeneity. In this study we applied an integrative network biology approach to molecular and clinical data measured from 450 patients with newly diagnosed MM from the MMRF CoMMpass study. A novel network model of myeloma (MMNet) was constructed, revealing complex molecular disease patterns and novel associations between clinical traits and genomic markers. Genomic alterations and groups of co-expressed genes correlate with disease stage, tumor clonality, and early progression...
June 23, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28642591/donor-and-recipient-age-gender-and-abo-incompatibility-regardless-of-donor-source-validated-criteria-for-donor-selection-for-hematopoietic-transplants
#5
Y Wang, D-P Wu, Q-F Liu, L-P Xu, K-Y Liu, X-H Zhang, Y Xu, F Huang, X-J Huang
Prior data indicate similar outcomes after transplants from HLA-haplotype-matched relatives, HLA-identical siblings and HLA-matched unrelated donors. We used our prospective dataset to answer a clinically important question: who is the best donor for a person with acute leukemia transplanted in 1st complete remission. Patients were randomly divided into training (n=611) and validation (n=588) sets. 1199 consecutive subjects received a transplant from an HLA-haplotype-matched relative using granulocyte colony-stimulating factor (G-CSF) and anti-thymocyte globulin (ATG) (n=685) or an HLA-identical sibling (n=514); 3-year leukaemia-free survivals (LFSs) were 75 and 74% (P=0...
June 23, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28630439/recurrent-cyclin-d2-mutations-in-myeloid-neoplasms
#6
V Khanna, C A Eide, C E Tognon, J E Maxson, B Wilmot, D Bottomly, S McWeeney, D K Edwards V, B J Druker, J W Tyner
Leukemia accepted article preview online, 20 June 2017. doi:10.1038/leu.2017.195.
June 20, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28630438/the-molecular-pathogenesis-of-the-nup98-hoxa9-fusion-protein-in-acute-myeloid-leukemia
#7
A Rio-Machin, G Gomez-Lopez, J Muñoz, F Garcia-Martinez, A Maiques-Diaz, S Alvarez, R N Salgado, M Shrestha, R Torres, C Haferlach, M J Larrayoz, M J Calasanz, J Fitzgibbon, J C Cigudosa
Leukemia accepted article preview online, 20 June 2017. doi:10.1038/leu.2017.194.
June 20, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28626220/a-phase-3-randomized-placebo-controlled-trial-of-darbepoetin-alfa-in-patients-with-anemia-and-lower-risk-myelodysplastic-syndromes
#8
U Platzbecker, A Symeonidis, E N Oliva, J S Goede, M Delforge, J Mayer, B Slama, S Badre, E Gasal, B Mehta, J Franklin
Use of darbepoetin alfa to treat anemia in patients with lower-risk myelodysplastic syndromes (MDS) was evaluated in a phase 3 trial. Eligible patients had low/intermediate-1 risk MDS, hemoglobin ⩽10 g/dl, low transfusion burden, and serum erythropoietin ⩽500 mU/ml. Patients were randomized 2:1 to receive 24 weeks of subcutaneous darbepoetin alfa 500 μg or placebo every 3 weeks (Q3W), followed by 48 weeks of open-label darbepoetin alfa. A total of 147 patients were randomized, with median hemoglobin of 9...
June 19, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28626219/base-excision-repair-proteins-couple-activation-induced-cytidine-deaminase-and-endonuclease-g-during-replication-stress-induced-mll-destabilization
#9
B Gole, E Mian, M Rall, L Wiesmüller
The breakpoint cluster region of the MLL gene (MLLbcr) is frequently rearranged in therapy-related and infant acute leukaemia, but the destabilizing mechanism is poorly understood. We recently proposed that DNA replication stress results in MLLbcr cleavage via Endonuclease G (EndoG) and represents the common denominator of genotoxic therapy-induced MLL destabilization. Here we performed a siRNA screen for new factors involved in replication stress-induced MLL rearrangements employing an EGFP-based reporter system...
June 19, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28626218/molecular-characterization-of-ezh2-mutant-patients-with-myelodysplastic-myeloproliferative-neoplasms
#10
J Rinke, J P Müller, M F Blaess, A Chase, M Meggendorfer, V Schäfer, N Winkelmann, C Haferlach, N C P Cross, A Hochhaus, T Ernst
Mutations in the epigenetic regulator gene EZH2 are frequently observed in patients with myelodysplastic/myeloproliferative neoplasms (MDS/MPN; 10-13%) and are associated with a poor outcome. To gain more insight into EZH2 pathology we sought to genetically characterize a cohort of 41 EZH2-mutated MDS/MPN patients using targeted deep next generation sequencing (NGS), colony forming progenitor assays and transcriptome analysis. Stable shRNA-mediated downregulation of EZH2 was performed in MDS derived F-36P, MOLM-13 and OCI-M2 cells to study EZH2 specific changes...
June 19, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28626217/irf8-regulates-the-progression-of-myeloproliferative-neoplasm-mpn-like-syndrome-via-mertk-signaling-in-zebrafish
#11
F Zhao, Y Shi, Y Huang, Y Zhan, L Zhou, Y Li, Y Wan, H Li, H Huang, H Ruan, L Luo, L Li
Interferon regulatory factor (IRF)-8 is a critical transcription factor involved in the pathogenesis of myeloid neoplasia. However, the underlying mechanisms in vivo are not well known. Investigation of irf8 mutant zebrafish in this study indicated that Irf8 is evolutionarily conserved as an essential neoplastic suppressor through tight control of the proliferation and longevity of myeloid cells. Surviving irf8 mutants quickly developed a myeloproliferative neoplasm (MPN)-like disease with enhanced output of the myeloid precursors, which recurred after transplantation...
June 19, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28626216/therapeutic-effects-of-csf1r-blocking-antibodies-in-multiple-myeloma
#12
Q Wang, Y Lu, R Li, Y Jiang, Y Zheng, J Qian, E Bi, C Zhang, J Hou, S Wang, Q Yi
Our previous studies showed that macrophages (MФs), especially myeloma-associated MФs (MAMs) induce chemoresistance in human myeloma. Here we explored the potential of targeting MФs, by using colony-stimulating factor 1 receptor (CSF1R)-blocking mAbs, to treat myeloma. Our results showed that CSF1R blockade specifically inhibited the differentiation, proliferation and survival of murine M2 MФs and MAMs, and repolarized MAMs towards M1-like MФs in vitro. CSF1R blockade alone inhibited myeloma growth in vivo, by partially depleting MAMs, polarizing MAMs to the M1 phenotype, and inducing a tumor-specific cytotoxic CD4(+) T cell response...
June 19, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28607471/gemtuzumab-ozogamicin-in-acute-myeloid-leukemia
#13
REVIEW
C D Godwin, R P Gale, R B Walter
CD33 is variably expressed on leukemia blasts in almost all patients with acute myeloid leukemia (AML) and possibly leukemia stem cells in some. Efforts to target CD33 therapeutically have focused on gemtuzumab ozogamicin (GO; Mylotarg®), an antibody-drug conjugate delivering a DNA-damaging calicheamicin derivative. GO is most effective in acute promyelocytic leukemia but induces remissions in other AML types and received accelerated approval in the US in 2000. However, because a large follow-up study showed no survival improvement and increased early deaths the drug manufacturer voluntarily withdrew the US New Drug Application in 2010...
June 13, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28607470/a-phase-ii-multicentre-trial-of-decitabine-in-higher-risk-chronic-myelomonocytic-leukemia
#14
V Santini, B Allione, G Zini, D Gioia, M Lunghi, A Poloni, D Cilloni, A Sanna, E Masiera, M Ceccarelli, O Abdel-Wahab, A Terenzi, E Angelucci, C Finelli, F Onida, A M Pelizzari, D Ferrero, G Saglio, M Figueroa, A Levis
Chronic myelomonocytic leukemia (CMML) is a complex clonal hematological disorder classified among myelodysplastic/myeloproliferative neoplasms (MDS/MPNs). Prognosis is poor and there is a lack of effective treatments. The hypomethylating agent decitabine has shown activity against MDS and elderly acute myeloid leukemia, but there is little data focusing specifically on its efficacy in CMML. In this prospective, phase 2 Italian study, CMML patients received i.v. decitabine 20 mg/m(2)/day on Days 1 to 5 of a 28-day treatment cycle...
June 13, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28592889/extended-follow-up-and-impact-of-high-risk-prognostic-factors-from-the-phase-3-resonate-tm-study-in-patients-with-previously-treated-cll-sll
#15
J R Brown, P Hillmen, S O'Brien, J C Barrientos, N M Reddy, S E Coutre, C S Tam, S P Mulligan, U Jaeger, P M Barr, R R Furman, T J Kipps, F Cymbalista, P Thornton, F Caligaris-Cappio, J Delgado, M Montillo, S DeVos, C Moreno, J M Pagel, T Munir, J A Burger, D Chung, J Lin, L Gau, B Chang, G Cole, E Hsu, D F James, J C Byrd
In the phase 3 RESONATE(TM) study, ibrutinib demonstrated superior progression-free survival (PFS), overall survival (OS), and overall response rate (ORR) compared with ofatumumab in relapsed/refractory CLL patients with high-risk prognostic factors. We report updated results from RESONATE in these traditionally chemotherapy resistant high-risk genomic subgroups at a median follow-up of 19 months. Mutations were detected by Foundation One Heme Panel. Baseline mutations in the ibrutinib arm included TP53 (51%), SF3B1 (31%), NOTCH1 (28%), ATM (19%), and BIRC3 (14%)...
June 8, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28592888/tcr%C3%AE-rearrangments-identify-a-subgroup-of-nkl-deregulated-adult-t-alls-associated-with-favorable-outcome
#16
P Villarese, C Lours, A Trinquand, S Le Noir, M Belhocine, L Lhermitte, A Cieslak, M Tesio, A Petit, M LeLorch, S Spicuglia, N Ifrah, H Dombret, A W Langerak, N Boissel, E Macintyre, V Asnafi
T-cell acute lymphoblastic leukemia (T-ALL) results from leukemic transformation of T-cell precursors arrested at specific differentiation stages, including an 'early-cortical' thymic maturation arrest characterized by expression of cytoplasmic TCRβ but no surface TCR and frequent ectopic expression of the TLX1/3 NK-Like homeotic proteins (NKL). We designed a TCRα VJC PCR to identify clonal TCRα rearrangements in 32% of 127T-ALLs, including 0/52 immature/TCRγδ lineage cases and 41/75 (55%) TCRαβ lineage cases...
June 8, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28592887/chip-icus-ccus-and-other-four-letter-words
#17
R Bejar
Leukemia accepted article preview online, 08 June 2017. doi:10.1038/leu.2017.181.
June 8, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28592886/mds-with-deletions-in-the-long-arm-of-chromosome-11-are-associated-with-a-high-frequency-of-sf3b1-mutations
#18
A Stengel, W Kern, M Meggendorfer, T Haferlach, C Haferlach
Leukemia accepted article preview online, 08 June 2017. doi:10.1038/leu.2017.180.
June 8, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28588253/nucleotide-excision-repair-ner-is-a-potential-therapeutic-target-in-multiple-myeloma
#19
R Szalat, M K Samur, M Fulciniti, M Lopez, P Nanjappa, A Cleynen, K Wen, S Kumar, T Perrini, A S Calkins, E Reznichenko, D Chauhan, Y-T Tai, M Shammas, J-P Fermand, B Arnulf, H Avet-Loiseau, J-B Lazaro, N C Munshi
Nucleotide excision repair is active in multiple myeloma cells.Inhibition of NER increases sensitivity to alkylating agent.NER is a potential target for multiple myeloma treatment. Despite the development of novel drugs, alkylating agents remain an important component of therapy in multiple myeloma (MM). DNA repair processes contribute towards sensitivity to alkylating agents, therefore we here evaluate the role of nucleotide excision repair (NER) which is involved in the removal of bulky adducts and DNA crosslinks in MM...
June 7, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28584254/whole-genome-sequencing-of-chronic-lymphocytic-leukemia-reveals-distinct-differences-in-the-mutational-landscape-between-ighv-mut-and-ighv-unmut-subgroups
#20
A Burns, R Alsolami, J Becq, A Timbs, D Bruce, P Robbe, D Vavoulis, M Cabes, H Dreau, J Taylor, S J L Knight, R Mansson, D Bentley, R Beekman, J I Martín-Subero, E Campo, R S Houlston, K E Ridout, A Schuh
Chronic lymphocytic leukemia (CLL) consists of two biologically and clinically distinct subtypes defined by the abundance of somatic hypermutation (SHM) affecting the Ig variable heavy chain locus (IgHV). The molecular mechanisms underlying these subtypes are incompletely understood. Here, we present a comprehensive whole genome sequencing (WGS) analysis of somatically acquired genetic events from 46 CLL patients, including a systematic comparison of coding and non-coding SNVs, CNVs and structural variants, regions of kataegis and mutation signatures between IgHV(mut) and IgHV(unmut) subtypes...
June 6, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
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