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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
Ningshu Huang, Zhenglan Huang, Miao Gao, Zhenhong Luo, Fangzhu Zhou, Lin Liu, Qing Xiao, Xin Wang, Wenli Feng
BACKGROUND: The bcr-abl fusion gene is the pathological origin of chronic myeloid leukemia (CML) and plays a critical role in the resistance of imatinib. Thus, bcr-abl disruption-based novel therapeutic strategy may warrant exploration. In our study, we were surprised to find that the characteristics of bcr-abl sequences met the design requirements of zinc finger nucleases (ZFNs). METHODS: We constructed the ZFNs targeting bcr-abl with high specificity through simple modular assembly approach...
March 20, 2018: Journal of Experimental & Clinical Cancer Research: CR
Rong Deng, Na Shen, Yang Yang, Hongliang Yu, Shuping Xu, Ying-Wei Yang, Shujun Liu, Kamel Meguellati, Fei Yan
Leukemia remains a fatal disease for most patients and novel therapeutic strategies are urgently needed. Aberrant DNA methylation is an epigenetic modification that is important in the initiation and progression of leukemia. Here, we demonstrated NCL/miR-221/NFκB/DNMT1 axis as a new molecular pathway promoting aggressive acute myeloid leukemia (AML) leukemogenesis and successfully designed and prepared a nuclear localization signal (NLS) peptide-targeted gold nanoparticles with co-loaded anti-221 and AS1411 (NPsN-AS1411/a221), which can specifically target NCL/miR-221/NFκB/DNMT1 signaling pathway in AML...
March 14, 2018: Biomaterials
Laixi Bi, Lan Sun, Zhenlin Jin, Shenghui Zhang, Zhijian Shen
MicroRNAs (miRs) have been demonstrated to perform important roles in normal hematopoiesis and leukemogenesis. Accumulating evidence suggests that miR-10a and miR-10b may behave as novel oncogenes or tumor suppressors in human cancer. The present study reported the function of the miR-10 family in myeloid differentiation and acute myeloid leukemia (AML). The levels of miR-10a/b expression were increased in AML cases compared with normal controls, particularly in M1, M2 and M3 subtypes. The levels of miR-10a/b expression were also upregulated in patients with nucleophosmin-mutated AML and AML patients with t(8;21) and t(9;11), compared with the normal control...
April 2018: Oncology Letters
Zhi-Jie Wu, Xin Zhao, Lauren G Banaszak, Fernanda Gutierrez-Rodrigues, Keyvan Keyvanfar, Shou-Guo Gao, Diego Quinones Raffo, Sachiko Kajigaya, Neal S Young
Additional sex combs-like 1 (ASXL1) is a well‑known tumor suppressor gene and epigenetic modifier. ASXL1 mutations are frequent in myeloid malignances; these mutations are risk factors for the development of myelodysplasia and also appear as small clones during normal aging. ASXL1 appears to act as an epigenetic regulator of cell survival and myeloid differentiation; however, the molecular mechanisms underlying the malignant transformation of cells with ASXL1 mutations are not well defined. Using Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/CRISPR-associated protein-9 nuclease (Cas9) genome editing, heterozygous and homozygous ASXL1 mutations were introduced into human U937 leukemic cells...
April 2018: International Journal of Oncology
Luca Trentin, Manon Queudeville, Sarah Mirjam Eckhoff, Md Nabiul Hasan, Vera Münch, Elena Boldrin, Felix Seyfried, Stefanie Enzenmüller, Klaus-Michael Debatin, Lüder Hinrich Meyer
In contrast to well-established hierarchical concepts of tumor stem cells, leukemia-initiating cells in B-cell precursor acute lymphoblastic leukemia have not yet been phenotypically identified. Different subpopulations as defined by surface markers have shown equal abilities to reconstitute leukemia upon transplantation onto immunodeficient mice. Using a non-obese diabetes/severe combined immunodeficiency human acute lymphoblastic leukemia mouse model and cell cycle analysis annotating cells to distinct cycle phases, we have functionally characterized leukemia-initiating cells and found that cells in all cell cycle stages are able to reconstitute leukemia in vivo, with early cycling cells (G1blow population) exhibiting the highest leukemia-initiating potential...
March 8, 2018: Haematologica
Anneke D van Dijk, Chenyue W Hu, Eveline S J M de Bont, YiHua Qiu, Fieke W Hoff, Suk Young Yoo, Kevin R Coombes, Amina A Qutub, Steven M Kornblau
Post-translational histone tail modifications are known to play a role in leukemogenesis and are therapeutic targets. A global analysis of the level and patterns of expression of multiple histone modifying proteins (HMP) in acute myeloid leukemia (AML) and the effect of different patterns of expression on outcome and prognosis has not been investigated in AML patients. Here we analyzed 20 HMP by reverse phase protein array (RPPA) in a cohort of 205 newly diagnosed AML patients. Protein levels were correlated with patient and disease characteristics, including survival and mutational state...
March 5, 2018: Proteomics
Ken Morita, Chieko Tokushige, Shintaro Maeda, Hiroki Kiyose, Mina Noura, Atsushi Iwai, Maya Yamada, Gengo Kashiwazaki, Junichi Taniguchi, Toshikazu Bando, Masahiro Hirata, Tatsuki R Kataoka, Tatsutoshi Nakahata, Souichi Adachi, Hiroshi Sugiyama, Yasuhiko Kamikubo
Although the function of Runt-related (RUNX) transcription factors has been well characterized in leukemogenesis and regarded as an ideal target in antileukemia strategies, the effect of RUNX-inhibition therapy on bone marrow niche cells andr its impact on the engraftment of acute myeloid leukemia (AML) cells have largely been unknown. Here, we provide evidence suggesting the possible involvement of RUNX transcription factors in the transactivation of E-selectin , a member of selectin family of cell adhesion molecules, on the vascular endothelial cells of the mice bone marrow niche...
March 13, 2018: Blood Advances
Andrés E Quesada, Zhihong Hu, Mark J Routbort, Keyur P Patel, Rajyalakshmi Luthra, Sanam Loghavi, Zhuang Zuo, C Cameron Yin, Rashmi Kanagal-Shamanna, Sa A Wang, Jeffrey L Jorgensen, L Jeffrey Medeiros, Chi Young Ok
Mixed phenotype acute leukemia (MPAL) is an uncommon manifestation of acute leukemia. The aim of this study is to further characterize the genetic landscape of de novo cases of MPAL that fulfill the 2016 World Health Organization (WHO) classification criteria for this entity. We identified 14 cases examined by next generation sequencing (NGS) using 28 ( n = 10), 53 ( n = 3) or 81 ( n = 1) gene panels: 7 cases with a B-cell/myeloid (B/My) immunophenotype, 6 T-cell/myeloid (T/My) immunophenotype, and 1 B-cell/T-cell (B/T) immunophenotype...
February 2, 2018: Oncotarget
Huda Salman, Xiao Shuai, Anh Thu Nguyen-Lefebvre, Banabihari Giri, Mingqiang Ren, Michael Rauchman, Lynn Robbins, Wei Hou, Hasan Korkaya, Yupo Ma
Similar signaling pathways could operate in both normal hematopoietic stem and progenitor cells (HSPCs) and leukemia stem cells (LSCs). Thus, targeting LSCs signaling without substantial toxicities to normal HSPCs remains challenging. SALL1, is a member of the transcriptional network that regulates stem cell pluripotency, and lacks significant expression in most adult tissues, including normal bone marrow (NBM). We examined the expression and functional characterization of SALL1 in NBM and in acute myeloid leukemia (AML) using in vitro and in vivo assays...
January 26, 2018: Oncotarget
Lulu Liu, Xiaoling Wan, Peipei Zhou, Xiaoyuan Zhou, Wei Zhang, Xinhui Hui, Xiujie Yuan, Xiaodan Ding, Ruihong Zhu, Guangxun Meng, Hui Xiao, Feng Ma, He Huang, Xianmin Song, Bin Zhou, Sidong Xiong, Yan Zhang
BACKGROUND: Adenosine triphosphate (ATP)-dependent chromatin remodeling SWI/SNF-like BAF and PBAF complexes have been implicated in the regulation of stem cell function and cancers. Several subunits of BAF or PBAF, including BRG1, BAF53a, BAF45a, BAF180, and BAF250a, are known to be involved in hematopoiesis. Baf200, a subunit of PBAF complex, plays a pivotal role in heart morphogenesis and coronary artery angiogenesis. However, little is known on the importance of Baf200 in normal and malignant hematopoiesis...
February 26, 2018: Journal of Hematology & Oncology
Xuejing Yang, Bin Lu, Xueqin Sun, Cuijuan Han, Chunling Fu, Kailin Xu, Min Wang, Dengju Li, Zhichao Chen, Puneet Opal, Qiang Wen, John D Crispino, Qian-Fei Wang, Zan Huang
Deregulation of key regulators of histone modification is important in the initiation and progression of human leukemia. Acidic leucine-rich nuclear phosphoprotein-32A (ANP32A) participates in histone acetylation and its role in acute myeloid leukemia remains unclear. Here we observed significant upregulation of ANP32A in primary AML cells, which was essential for AML cell proliferation, survival, and colony formation. Integrative analysis of the genome-wide histone H3 acetylation and gene expression demonstrated that ANP32A deficiency reduced histone H3 acetylation, in accordance with changes in gene expression...
February 2, 2018: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Alex C H Wong, John E J Rasko, Justin J-L Wong
Alternative splicing expands the transcriptome thereby promoting protein diversity. It governs critical cellular processes such as differentiation, proliferation and apoptosis in a tissue-specific manner. Aberrant splicing consequent to mutations in splicing factors and disruption of isoform ratios in key regulatory genes provides an important contribution to the pathogenesis of the myelodysplastic syndromes and myeloid leukemia. We review here the central role of alternative splicing in regulating myelopoiesis, and provide clear examples of how global splicing disruption or specific aberrant splicing events might promote leukemogenesis...
January 30, 2018: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Nicolas Duployez, Elise Boudry-Labis, Christophe Roumier, Nicolas Boissel, Arnaud Petit, Sandrine Geffroy, Nathalie Helevaut, Karine Celli-Lebras, Christine Terré, Odile Fenneteau, Wendy Cuccuini, Isabelle Luquet, Hélène Lapillonne, Catherine Lacombe, Pascale Cornillet, Norbert Ifrah, Hervé Dombret, Guy Leverger, Eric Jourdan, Claude Preudhomme
Acute myeloid leukemia (AML) with t(8;21) and inv(16), together referred as core binding factor (CBF)-AML, are recognized as unique entities. Both rearrangements share a common pathophysiology, the disruption of the CBF, and a relatively good prognosis. Experiments have demonstrated that CBF rearrangements were insufficient to induce leukemia, implying the existence of cooperating events. To explore these aberrations, we performed single nucleotide polymorphism (SNP)-array in a well-annotated cohort of 198 patients with CBF-AML...
January 19, 2018: Oncotarget
Hao Wang, Ling Bei, Chirag A Shah, Weiqi Huang, Leonidas C Platanias, Elizabeth A Eklund
Chromosomal translocations involving the MLL1 gene characterize a poor prognosis subset of acute myeloid leukemia (AML), referred to as 11q23-AML. Transcription of the HOXA9 and HOXA10 genes is enhanced in hematopoietic stem and progenitor cells in these leukemias. We previously found the ARIH2 gene was repressed by HoxA9 in myeloid progenitors, but activated by HoxA10 during granulopoiesis. ARIH2 encodes the Triad1 protein, an anti-proliferative E3 ubiquitin ligase. In the current study, we investigate the role of Triad1 in leukemogenesis induced by an MLL1 fusion protein (Mll-Ell)...
February 20, 2018: Oncogene
Xue Liang, Jia Gu, TongJuan Li, Lei Zhao, Xing Fu, Wei Zhang, Jue Wang, Zhen Shang, Wei Huang, Jianfeng Zhou
PAX5 mutations have important role in leukemogenesis and leukemia relapse, cancer cell dormancy participates in cancer relapse, but there was no report about PAX5 mutation inducing cancer cell dormancy. we constructed the PAX5 deletion Raji cell lines using gene editing technology, evaluated dormancy biological characteristics of cell lines. Our results showed PAX5 haploinsufficiency restrained the proliferation of Raji cells, induced G0/G1 arrest of Raji cells, reduced chemotherapy sensitivity. The tumor formation rate reduced in PAX5 mutation Raji cells...
February 14, 2018: Experimental Cell Research
Haiying Li, Chongyun Xing, Bin Zhou, Haige Ye, Jianhua Feng, Jianbo Wu, Shenmeng Gao
The aberrant overexpression of the Wilm's tumor-1 (WT1) in acute myeloid leukemia (AML) plays an important role in blast cell survival through enhancing proliferation and inhibiting apoptosis. However, the mechanism underlying the overexpression of WT1 remains unclear. Here, we identified miR-193a (miR-193a-5p) and miR-600 targeting and degrading WT1. MiR-193a and miR-600 synergistically reduced WT1 expression and suppressed the activity of a luciferase reporter through binding coding sequence (CDS) and 3'-untranslated regions (3'UTR) of WT1 mRNA, respectively...
February 13, 2018: Experimental Hematology
Huseini Kagdi, Maria Antonietta Demontis, Juan Carlos Ramos, Graham P Taylor
Adult T-cell leukaemia/lymphoma (ATL) arises from chronic non-malignant human T lymphotropic virus type-1 (HTLV-1) infection which is characterized by high plasma pro-inflammatory cytokines whereas ATL is characterized by high plasma anti-inflammatory (IL-10) concentrations. The poor prognosis of ATL is partly ascribed to disease-associated immune suppression. ATL cells have a CD4+CCR4+CD26-CD7- immunophenotype but infected cells with this immunophenotype ('ATL-like' cells) are also present in non-malignant HTLV-1 infection...
February 14, 2018: PLoS Pathogens
Laixi Bi, Bin Zhou, Haiying Li, Licai He, Chunjing Wang, Zhonggai Wang, Liqing Zhu, Mengqian Chen, Shenmeng Gao
BACKGROUND: Acute myeloid leukemia (AML) is a heterogeneous group of hematopoietic malignancies due to sophisticated genetic mutations and epigenetic dysregulation. MicroRNAs (miRNAs), a class of small non-coding RNAs, are important regulators of gene expression in all biological processes, including leukemogenesis. Recently, miR-375 has been reported to be a suppressive miRNA in multiple types of cancers, but its underlying anti-leukemia activity in AML is largely unknown. METHODS: Quantitative reverse transcriptase PCR (qRT-PCR) was used to measure the expression of miR-375 and HOXB3 in leukemic cells and normal controls...
February 13, 2018: BMC Cancer
Raj Bhayadia, Kathrin Krowiorz, Nadine Haetscher, Razan Jammal, Stephan Emmrich, Askar Obulkasim, Jan Fiedler, Adrian Schwarzer, Arefeh Rouhi, Michael Heuser, Susanne Wingert, Sabrina Bothur, Konstanze Döhner, Tobias Mätzig, Michelle Ng, Dirk Reinhardt, Hartmut Döhner, C Michel Zwaan, Marry van den Heuvel Eibrink, Dirk Heckl, Maarten Fornerod, Thomas Thum, R Keith Humphries, Michael A Rieger, Florian Kuchenbauer, Jan-Henning Klusmann
Purpose Dysregulated microRNAs are implicated in the pathogenesis and aggressiveness of acute myeloid leukemia (AML). We describe the effect of the hematopoietic stem-cell self-renewal regulating miR-193b on progression and prognosis of AML. Methods We profiled miR-193b-5p/3p expression in cytogenetically and clinically characterized de novo pediatric AML (n = 161) via quantitative real-time polymerase chain reaction and validated our findings in an independent cohort of 187 adult patients. We investigated the tumor suppressive function of miR-193b in human AML blasts, patient-derived xenografts, and miR-193b knockout mice in vitro and in vivo...
February 12, 2018: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
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