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leukemogenesis

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https://www.readbyqxmd.com/read/27913501/mutations-in-aml-prognostic-and-therapeutic-implications
#1
Courtney D DiNardo, Jorge E Cortes
Acute myeloid leukemia (AML) is a heterogeneous hematologic malignancy characterized by the proliferation and aberrant differentiation of immature clonal myeloid cells. The prognosis of AML is variable, based on clinical features such as patient age, performance status, and comorbidities, as well as leukemia-specific genetic features including cytogenetics and molecular classification. The modern application of next-generation sequencing technology has uncovered marked heterogeneity and genomic complexity within AML, based on the presence or absence of cooperating mutations within functional categories such as epigenetic regulators, cell signaling and proliferation pathways, and master hematopoietic transcription factors...
December 2, 2016: Hematology—the Education Program of the American Society of Hematology
https://www.readbyqxmd.com/read/27910027/recurrent-cytogenetic-abnormalities-in-acute-myeloid-leukemia
#2
John J Yang, Tae Sung Park, Thomas S K Wan
The spectrum of chromosomal abnormality associated with leukemogenesis of acute myeloid leukemia (AML) is broad and heterogeneous when compared to chronic myeloid leukemia and other myeloid neoplasms. Recurrent chromosomal translocations such as t(8;21), t(15;17), and inv(16) are frequently detected, but hundreds of other uncommon chromosomal aberrations from AML also exist. This chapter discusses 22 chromosomal abnormalities that are common structural, numerical aberrations, and other important but infrequent (less than 1 %) translocations emphasized in the WHO classification...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/27903646/whole-transcriptome-sequencing-identified-a-distinct-subtype-of-acute-lymphoblastic-leukemia-with-predominant-genomic-abnormalities-of-ep300-and-crebbp
#3
Maoxiang Qian, Hui Zhang, Shirley Kow-Yin Kham, Shuguang Liu, Chuang Jiang, Xujie Zhao, Yi Lu, Charnise Goodings, Ting-Nien Lin, Ranran Zhang, Takaya Moriyama, Zhaohong Yin, Zhenhua Li, Thuan Chong Quah, Hany Ariffin, Ah Moy Tan, Shuhong Shen, Deepa Bhojwani, Shaoyan Hu, Suning Chen, Huyong Zheng, Ching-Hon Pui, Allen Eng-Juh Yeoh, Jun J Yang
Chromosomal translocations are a genomic hallmark of many hematologic malignancies. Often as initiating events, these structural abnormalities result in fusion proteins involving transcription factors important for hematopoietic differentiation and/or signaling molecules regulating cell proliferation and cell cycle. In contrast, epigenetic regulator genes are more frequently targeted by somatic sequence mutations, possibly as secondary events to further potentiate leukemogenesis. Through comprehensive whole transcriptome sequencing of 231 children with acute lymphoblastic leukemia (ALL), we identified 58 putative functional and predominant fusion genes in 54...
November 30, 2016: Genome Research
https://www.readbyqxmd.com/read/27896663/significant-role-of-segmental-duplications-and-sidd-sites-in-chromosomal-translocations-of-hematological-malignancies-a-multi-parametric-bioinformatic-analysis
#4
Aditi Daga, Afzal Ansari, Medha Pandya, Krupa Shah, Shanaya Patel, Rakesh Rawal, Valentina Umrania
Recurrent non-random chromosomal translocations are hallmark characteristics of leukemogenesis, and however, molecular mechanisms underlying these rearrangements are less explored. The fundamental question is, why and how chromosomes break and reunite so precisely in the genome. Meticulous understanding of mechanism leading to chromosomal rearrangement can be achieved by characterizing breakpoints. To address this hypothesis, a novel multi-parametric computational approach for characterization of major leukemic translocations within and around breakpoint region was performed...
November 28, 2016: Interdisciplinary Sciences, Computational Life Sciences
https://www.readbyqxmd.com/read/27893200/clinical-impact-of-overexpression-of-foxp3-and-wt1-on-disease-outcome-in-egyptian-acute-myeloid-leukemia-patients
#5
Magda Assem, Ahmed Osman, Eman Kandeel, Reham Elshimy, Hanan Nassar, Radwa Ali
Background: In the last decade, it has become clear that change of gene expression may alter the hematopoietic cell quiescent state and consequently play a major role in leukemogenesis. WT1 is known to be a player in acute myeloid leukemia (AML) and FOXP3 has a crucial role in regulating the immune response. Objectives: To evaluate the impact of overexpression of WT1and FOXP3 genes on clinical course in adult and pediatric AML patients in Egypt. Patients and methods: Bone marrow and peripheral blood samples were obtained from 97 de novo non M3 AML patients (63 adult and 34 pediatric)...
January 10, 2016: Asian Pacific Journal of Cancer Prevention: APJCP
https://www.readbyqxmd.com/read/27889185/nup98-fusion-proteins-interact-with-the-nsl-and-mll1-complexes-to-drive-leukemogenesis
#6
Haiming Xu, Daria G Valerio, Meghan E Eisold, Amit Sinha, Richard P Koche, Wenhuo Hu, Chun-Wei Chen, S Haihua Chu, Gerard L Brien, Christopher Y Park, James J Hsieh, Patricia Ernst, Scott A Armstrong
The nucleoporin 98 gene (NUP98) is fused to a variety of partner genes in multiple hematopoietic malignancies. Here, we demonstrate that NUP98 fusion proteins, including NUP98-HOXA9 (NHA9), NUP98-HOXD13 (NHD13), NUP98-NSD1, NUP98-PHF23, and NUP98-TOP1 physically interact with mixed lineage leukemia 1 (MLL1) and the non-specific lethal (NSL) histone-modifying complexes. Chromatin immunoprecipitation sequencing illustrates that NHA9 and MLL1 co-localize on chromatin and are found associated with Hox gene promoter regions...
November 15, 2016: Cancer Cell
https://www.readbyqxmd.com/read/27888797/tumorigenicity-of-ewing-sarcoma-is-critically-dependent-on-the-trithorax-proteins-mll1-and-menin
#7
Laurie K Svoboda, Natashay Bailey, Raelene A Van Noord, Melanie A Krook, Ashley Harris, Cassondra Cramer, Brooke Jasman, Rajiv M Patel, Dafydd Thomas, Dmitry Borkin, Tomasz Cierpicki, Jolanta Grembecka, Elizabeth R Lawlor
Developmental transcription programs are epigenetically regulated by the competing actions of polycomb and trithorax (TrxG) protein complexes, which repress and activate genes, respectively. Ewing sarcoma is a developmental tumor that is associated with widespread de-regulation of developmental transcription programs, including HOX programs. Posterior HOXD genes are abnormally over-expressed by Ewing sarcoma and HOXD13, in particular, contributes to the tumorigenic phenotype. In MLL1 fusion-driven leukemia, aberrant activation of HOXA genes is epigenetically mediated by the TrxG complex and HOXA gene expression and leukemogenesis are critically dependent on the protein-protein interaction between the TrxG proteins MLL1 and menin...
November 18, 2016: Oncotarget
https://www.readbyqxmd.com/read/27888632/ventx-induces-expansion-of-primitive-erythroid-cells-and-contributes-to-the-development-of-acute-myeloid-leukemia-in-mice
#8
Eva Gentner, Naidu M Vegi, Medhanie A Mulaw, Tamoghna Mandal, Shiva Bamezai, Rainer Claus, Alpaslan Tasdogan, Leticia Quintanilla-Martinez, Alexander Grunenberg, Konstanze Döhner, Hartmut Döhner, Lars Bullinger, Torsten Haferlach, Christian Buske, Vijay P S Rawat, Michaela Feuring-Buske
Homeobox genes are key regulators in normal and malignant hematopoiesis. The human Vent-like homeobox gene VENTX, a putative homolog of the Xenopus laevis Xvent-2 gene, was shown to be highly expressed in normal myeloid cells and in patients with acute myeloid leukemia. We now demonstrate that constitutive expression of VENTX suppresses expression of genes responsible for terminal erythroid differentiation in normal CD34+ stem and progenitor cells. Transplantation of bone marrow progenitor cells retrovirally engineered to express VENTX caused massive expansion of primitive erythroid cells and partly acute erythroleukemia in transplanted mice...
November 24, 2016: Oncotarget
https://www.readbyqxmd.com/read/27888400/repression-of-cdkn2c-caused-by-pml-rar%C3%AE-binding-promotes-the-proliferation-and-differentiation-block-in-acute-promyelocytic-leukemia
#9
Xiaoling Wang, Yun Tan, Yizhen Li, Jingming Li, Wen Jin, Kankan Wang
Inappropriate cell proliferation during oncogenesis is often accompanied by inactivation of components involved in the cell cycle machinery. Here, we report that cyclin-dependent kinase inhibitor 2C (CDKN2C) as a member of the cyclin-dependent kinase inhibitors is a target of the PML/RARα oncofusion protein in leukemogenesis of acute promyelocytic leukemia (APL).We found that CDKN2C was markedly downregulated in APL blasts compared with normal promyelocytes. Chromatin immunoprecipitation combined with quantitative polymerase chain reaction demonstrated that PML/RARα directly bound to the CDKN2C promoter in the APL patient-derived cell line NB4...
November 23, 2016: Frontiers of Medicine
https://www.readbyqxmd.com/read/27882114/apc2-and-cyp1b1-methylation-changes-in-the-bone-marrow-of-acute-myeloid-leukemia-patients-during-chemotherapy
#10
Yongming Xia, Qingxiao Hong, Xiaoying Chen, Huadan Ye, Lili Fang, Annan Zhou, Yuting Gao, Danjie Jiang, Shiwei Duan
Aberrant promoter DNA methylation is a major mechanism of leukemogenesis in hematologic malignancies, including acute myeloid leukemia (AML). However, the association between promoter methylation with chemotherapeutic outcomes remains unknown. In the present study, bone marrow samples were collected prior to and following chemotherapy in 30 AML patients. Methylation-specific polymerase chain reaction technology was used to examine the promoter methylation status of adenomatous polyposis col 2 (APC2) and cytochrome P450 family 1 subfamily B polypeptide 1 (CYP1B1)...
November 2016: Experimental and Therapeutic Medicine
https://www.readbyqxmd.com/read/27881875/loss-of-p300-accelerates-mds-associated-leukemogenesis
#11
G Cheng, F Liu, T Asai, F Lai, N Man, H Xu, S Chen, S Greenblatt, P-J Hamard, K Ando, C Martinez, M Tadi, L Wang, M Xu, F-C Yang, R Shiekhattar, S D Nimer
The role that changes in DNA methylation and histone modifications play in human malignancies is poorly understood. p300 and CBP, two distinct but highly homologous lysine acetyltransferases (KATs), are mutated in several cancers, suggesting their role as tumor suppressors. In the current study, we found that deletion of p300, but not CBP, markedly accelerated the leukemogenesis of Nup98-HoxD13 (NHD13) transgenic mice, an animal model that phenotypically copies human myelodysplastic syndrome (MDS). p300 deletion restored the ability of NHD13 expressing hematopoietic stem and progenitor cells (HSPCs) to self-renew in vitro, and to expand in vivo, with an increase in stem cell symmetric self-renewal divisions and a decrease in apoptosis...
November 24, 2016: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/27881872/in-vitro-and-in-vivo-assessment-of-direct-effects-of-simulated-solar-and-galactic-cosmic-radiation-on-human-hematopoietic-stem-progenitor-cells
#12
C Rodman, G Almeida-Porada, S George, J Moon, S Soker, T Pardee, M Beaty, P Guida, S P Sajuthi, C D Langefeld, S J Walker, P F Wilson, C D Porada
Future deep space missions to Mars and near-Earth asteroids will expose astronauts to chronic solar energetic particles (SEP) and galactic cosmic ray (GCR) radiation, and likely one or more solar particle events (SPEs). Given the inherent radiosensitivity of hematopoietic cells and short latency period of leukemias, space radiation-induced hematopoietic damage poses a particular threat to astronauts on extended missions. We show that exposing human hematopoietic stem/progenitor cells (HSC) to extended mission-relevant doses of accelerated high-energy protons and iron ions: 1) introduces mutations that are frequently located within genes involved in hematopoiesis and are distinct from those induced by γ-radiation; 2) dramatically reduces in vitro colony-formation; 3) markedly alters engraftment and lineage commitment in vivo; and 4) leads to the development, in vivo, of what appears to be T-ALL...
November 24, 2016: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/27865805/transcriptional-activation-by-mll-fusion-proteins-in-leukemogenesis
#13
REVIEW
Akihiko Yokoyama
Chromosomal translocations involving the mixed lineage leukemia (MLL) gene cause aggressive leukemia. Fusion proteins of MLL and a component of the AF4 family/ENL family/P-TEFb complex (AEP) are responsible for two-thirds of MLL-associated leukemia cases. MLL-AEP fusion proteins trigger aberrant self-renewal of hematopoietic progenitors by constitutively activating self-renewal-related genes. MLL-AEP fusion proteins activate transcription initiation by loading the TATA-binding protein (TBP) to the TATA element via selectivity factor 1...
November 16, 2016: Experimental Hematology
https://www.readbyqxmd.com/read/27864780/inhibition-of-the-nuclear-export-of-p65-and-iqcg-in-leukemogenesis-by-nup98-iqcg
#14
Mengmeng Pan, Qiyao Zhang, Ping Liu, Jinyan Huang, Yueying Wang, Saijuan Chen
NUP98 fuses with approximately 34 different partner genes via translocation in hematological malignancies. Transgenic or retrovirus-mediated bone marrow transplanted mouse models reveal the leukemogenesis of some NUP98-related fusion genes. We previously reported the fusion protein NUP98-IQ motif containing G (IQCG) in a myeloid/T lymphoid bi-phenoleukemia patient with t(3;11) and confirmed its leukemogenic ability. Herein, we demonstrated the association of NUP98-IQCG with CRM1, and found that NUP98-IQCG expression inhibits the CRM1-mediated nuclear export of p65 and enhances the transcriptional activity of nuclear factor-κB...
November 18, 2016: Frontiers of Medicine
https://www.readbyqxmd.com/read/27859216/cooperation-of-mll-af10-om-lz-with-ptpn11-activating-mutation-induced-monocytic-leukemia-with-a-shorter-latency-in-a-mouse-bone-marrow-transplantation-model
#15
Jen-Fen Fu, Sung-Tzu Liang, Ying-Jung Huang, Kung-Hao Liang, Tzung-Hai Yen, Der-Cherng Liang, Lee-Yung Shih
PTPN11 mutation, a RAS signaling pathway mutation, is associated with MLL translocations in acute leukemia. A girl with MLL/AF10 AML was found to carry PTPN11(G503A) . To study the impact of PTPN11 (G503A) cooperating with MLL/AF10 on leukemogenesis, we established a retroviral transduction/transplantation mouse model. Compared with the MLL/AF10(OM-LZ) leukemia cells harboring PTPN11 (wt) , the cells harboring PTPN11(G503A) were hypersensitive to GM-CSF and IL3, and more resistant to death upon treatment with daunorubicin but sensitive to cytarabine...
November 14, 2016: International Journal of Cancer. Journal International du Cancer
https://www.readbyqxmd.com/read/27846391/instructive-role-of-mll-fusion-proteins-revealed-by-a-model-of-t-4-11-pro-b-acute-lymphoblastic-leukemia
#16
Shan Lin, Roger T Luo, Anetta Ptasinska, Jon Kerry, Salam A Assi, Mark Wunderlich, Toshihiko Imamura, Joseph J Kaberlein, Ahmad Rayes, Mark J Althoff, John Anastasi, Maureen M O'Brien, Amom Ruhikanta Meetei, Thomas A Milne, Constanze Bonifer, James C Mulloy, Michael J Thirman
The t(4;11)(q21;q23) fuses mixed-lineage leukemia (MLL) to AF4, the most common MLL-fusion partner. Here we show that MLL fused to murine Af4, highly conserved with human AF4, produces high-titer retrovirus permitting efficient transduction of human CD34(+) cells, thereby generating a model of t(4;11) pro-B acute lymphoblastic leukemia (ALL) that fully recapitulates the immunophenotypic and molecular aspects of the disease. MLL-Af4 induces a B ALL distinct from MLL-AF9 through differential genomic target binding of the fusion proteins leading to specific gene expression patterns...
November 14, 2016: Cancer Cell
https://www.readbyqxmd.com/read/27843138/mutations-in-the-ccnd1-and-ccnd2-genes-are-frequent-events-in-adult-patients-with-t-8-21-q22-q22-acute-myeloid-leukemia
#17
A-K Eisfeld, J Kohlschmidt, S Schwind, D Nicolet, J S Blachly, S Orwick, C Shah, M Bainazar, K W Kroll, C J Walker, A J Carroll, B L Powell, R M Stone, J E Kolitz, M R Baer, A de la Chapelle, K Mrózek, J C Byrd, C D Bloomfield
Core-binding factor acute myeloid leukemia (CBF-AML) is defined by the presence of either t(8;21)(q22;q22)/RUNX1-RUNX1T1 or inv(16)(p13.1q22)/t(16;16)(p13.1;q22)/CBFB-MYH11. The resulting fusion genes require a 'second hit' to initiate leukemogenesis. Mutation assessment of 177 adults with CBF-AML, including 68 with t(8;21) and 109 with inv(16)/t(16;16), identified not only mutations well-known in CBF-AML, but also mutations in the CCND1 and CCND2 genes, which represent novel frequent molecular alterations in AML with t(8;21)...
November 15, 2016: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/27836891/cd98-promotes-acute-myeloid-leukemia-initiation-and-growth
#18
(no author information available yet)
CD98-mediated adhesion to endothelium drives LSC maintenance and leukemogenesis.
November 11, 2016: Cancer Discovery
https://www.readbyqxmd.com/read/27834816/targeting-the-tam-receptors-in-leukemia
#19
REVIEW
Madeline G Huey, Katherine A Minson, H Shelton Earp, Deborah DeRyckere, Douglas K Graham
Targeted inhibition of members of the TAM (TYRO-3, AXL, MERTK) family of receptor tyrosine kinases has recently been investigated as a novel strategy for treatment of hematologic malignancies. The physiologic functions of the TAM receptors in innate immune control, natural killer (NK) cell differentiation, efferocytosis, clearance of apoptotic debris, and hemostasis have previously been described and more recent data implicate TAM kinases as important regulators of erythropoiesis and megakaryopoiesis. The TAM receptors are aberrantly or ectopically expressed in many hematologic malignancies including acute myeloid leukemia, B- and T-cell acute lymphoblastic leukemia, chronic lymphocytic leukemia, and multiple myeloma...
November 8, 2016: Cancers
https://www.readbyqxmd.com/read/27833035/tumor-necrosis-factor-%C3%AE-in-the-onset-and-progression-of-leukemia
#20
REVIEW
Xiaoxi Zhou, Zhuoya Li, Jianfeng Zhou
Tumor necrosis factor alpha (TNF-α), originally described as an anti-neoplastic cytokine, has been found, in apparent contradiction to its name, to play an important role in promoting the development and progression of malignant disease. Targeting TNF-α with TNF antagonists has elicited an objective response in certain solid tumors in phase I and II clinical trials. This review focuses on the relationship of TNF-α expressed by leukemia cells and adverse clinical features of leukemia. TNF-α is involved in all steps of leukemogenesis, including cellular transformation, proliferation, angiogenesis, and extramedullary infiltration...
November 8, 2016: Experimental Hematology
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