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Ivar O Kommers, Paul A Bartley, Bradley Budgen, Sue Latham, Ashanka Beligaswatte, Shane G Supple, Alberto Catalano, Harry J Iland, Alexander A Morley, David M Ross
No abstract text is available yet for this article.
November 30, 2016: Leukemia & Lymphoma
Zhen-Hua Chen, Wen-Tao Wang, Wei Huang, Ke Fang, Yu-Meng Sun, Shu-Rong Liu, Xue-Qun Luo, Yue-Qin Chen
Increasing evidence has indicated that long noncoding RNAs (lncRNAs) are of great importance in different cell contexts. However, only a very small number of lncRNAs have been experimentally validated and functionally annotated during human hematopoiesis. Here, we report an lncRNA, HOTAIRM1, which is associated with myeloid differentiation and has pivotal roles in the degradation of oncoprotein PML-RARA and in myeloid cell differentiation by regulating autophagy pathways. We first revealed that HOTAIRM1 has different variants that are expressed at different levels in cells and that the expression pattern of HOTAIRM1 is closely related to that of the PML-RARA oncoprotein in acute promyelocytic leukemia (APL) patients...
October 14, 2016: Cell Death and Differentiation
V T Premkumar, Sooriyakumar, Sivaramasubramanian, Muralidharan, Dhanus Sadasivan Nair
No abstract text is available yet for this article.
January 2016: Journal of the Association of Physicians of India
Osamu Imataki, Makiko Uemura
BACKGROUND: The recent study described a better outcome in acute promyelocytic leukemia patients treated with all-trans retinoic acid and arsenic oxide compared to those treated with all-trans retinoic acid combined with conventional chemotherapy. The pivotal study indicated that favorable-risk acute promyelocytic leukemia patients can be cured without any cytotoxic chemotherapy. Even high-risk patients are treatable with cytotoxic agents. Acute promyelocytic leukemia does not develop only by the dedifferentiation caused by PML-RARA...
2016: BMC Clinical Pathology
Guillermo Velasco
No abstract text is available yet for this article.
October 2016: Haematologica
Ariz Akhter, Muhammad Kashif Mughal, Ghaleb Elyamany, Gary Sinclair, Raja Zahratul Azma, Noraidah Masir, Salwati Shuib, Fariborz Rashid-Kolvear, Meer-Taher Shabani-Rad, Douglas Allan Stewart, Adnan Mansoor
BACKGROUND: The World Health Organization (WHO) classification system defines recurrent chromosomal translocations as the sole diagnostic and prognostic criteria for acute leukemia (AL). These fusion transcripts are pivotal in the pathogenesis of AL. Clinical laboratories universally employ conventional karyotype/FISH to detect these chromosomal translocations, which is complex, labour intensive and lacks multiplexing capacity. Hence, it is imperative to explore and evaluate some newer automated, cost-efficient multiplexed technologies to accommodate the expanding genetic landscape in AL...
2016: Diagnostic Pathology
Nélida Inés Noguera, Maria Liliana Piredda, Riccardo Taulli, Gianfranco Catalano, Giulia Angelini, Girish Gaur, Clara Nervi, Maria Teresa Voso, Andrea Lunardi, Pier Paolo Pandolfi, Francesco Lo-Coco
Acute promyelocitic leukemia (APL) is characterized by the pathognomonic presence in leukemic blasts of the hybrid protein PML/RARA, that acts as a transcriptional repressor impairing the expression of genes that are critical to myeloid differentiation. Here, we show that primary blasts from APL patients express lower levels of the oncosuppressor protein PTEN, as compared to blast cells from other AML subtypes or normal bone marrow, and demonstrate that PML-RARA directly inhibits PTEN expression. We show that All-Trans Retinoic Acid (ATRA) triggers in APL cells an active chromatin status at the core regulatory region of the PTEN promoter, that allows the binding of the myeloid-regulating transcription factor PU...
September 10, 2016: Oncotarget
Tilmann Bochtler, Stefan Fröhling, Wilko Weichert, Volker Endris, Christian Thiede, Barbara Hutter, Michael Hundemer, Anthony D Ho, Alwin Krämer
Here, we report the case of an acute promyelocytic leukemia (APL) patient who-although negative for FLT3 mutations at diagnosis-developed isolated FLT3 tyrosine kinase II domain (FLT3-TKD)-positive meningeal relapse, which, in retrospect, could be traced back to a minute bone marrow subclone present at first diagnosis. Initially, the 48-yr-old female diagnosed with high-risk APL had achieved complete molecular remission after standard treatment with all-trans retinoic acid (ATRA) and chemotherapy according to the AIDA (ATRA plus idarubicin) protocol...
September 2016: Cold Spring Harbor Molecular Case Studies
S Ganesan, A A Alex, E Chendamarai, N Balasundaram, H K Palani, S David, U Kulkarni, M Aiyaz, R Mugasimangalam, A Korula, A Abraham, A Srivastava, R A Padua, C Chomienne, B George, P Balasubramanian, V Mathews
Arsenic trioxide (ATO) mediates PML-RARA (promyelocytic leukemia-retinoic acid receptor-α) oncoprotein degradation via the proteasome pathway and this degradation appears to be critical for achieving cure in acute promyeloytic leukemia (APL). We have previously demonstrated significant micro-environment-mediated drug resistance (EMDR) to ATO in APL. Here we demonstrate that this EMDR could be effectively overcome by combining a proteasome inhibitor (bortezomib) with ATO. A synergistic effect on combining these two agents in vitro was noted in both ATO-sensitive and ATO-resistant APL cell lines...
November 2016: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Omar Ferhi, Laurent Pérès, Sarah Tessier, Hugues de Thé, Valérie Lallemand-Breitenbach
Fasci et al proposed that a SENP1-mediated switch from SUMO2 to SUMO1 conjugation on Lys(65) in promyelocytic leukemia protein (PML) is required for arsenic-induced PML degradation, the basis for the antileukemic activity of arsenic. We found that PML or PML/RARA (retinoic acid receptor α) mutants that cannot be SUMO-conjugated on this specific site nevertheless underwent immediate arsenic-triggered SUMO modification. Moreover, these mutants were efficiently degraded in cells and even in vivo, demonstrating that SUMOylation of Lys(65) was dispensable for arsenic response...
2016: Science Signaling
P Kosik, M Skorvaga, I Belyaev
The diagnostics of leukemia relies upon multi-parametric approach involving a number of different pathology disciplines such as flow cytometry, histopathology, cytogenetics and molecular genetics [fluorescent in situ hybridization (FISH) and polymerase chain reaction (PCR)]. Childhood leukemia is often determined by the presence of specific chromosomal translocation that entails the generation of preleukemic fusion genes (PFG). In the last two decades, several studies have reported observations that PFG are present in healthy population and not necessarily result in leukemia...
2016: Neoplasma
D Hu, W Zhou, F Wang, S M Shu, L L Fan, J He, P Wang, Y L He, W Du, J H Zhang, J X Duan, L Sun, J Zheng, X Q Li, H Y Li, X L Feng, S A Huang
INTRODUCTION: Detection of leukemogenic fusion transcripts in acute myeloid leukemia (AML) is critical for AML diagnosis. NanoString nCounter system is a novel probe-based gene expression platform capable of measuring up to 800 targets with advantages of reproducibility, accuracy, and sample type flexibility. To study the potential application of NanoString in leukemia at clinic, we used this technology to detect AML leukemogenic fusion transcripts and compared the performances with clinical molecular assays...
December 2016: International Journal of Laboratory Hematology
Karen Keeshan, Pauline Vieugué, Shahzya Chaudhury, Loveena Rishi, Coline Gaillard, Lu Liang, Elaine Garcia, Takuro Nakamura, Nader Omidvar, Scott C Kogan
The PML/RARA fusion protein occurs as a result of the t(15;17) translocation in the acute promyelocytic leukemia subtype of human acute myeloid leukemia. Gain of chromosome 8 is the most common chromosomal gain in human acute myeloid leukemia, including acute promyelocytic leukemia. We previously demonstrated that gain of chromosome 8-containing MYC is of central importance in trisomy 8, but the role of the nearby TRIB1 gene has not been experimentally addressed in this context. We have now tested the hypothesis that both MYC and TRIB1 have functional roles underlying leukemogenesis of trisomy 8 by using retroviral vectors to express MYC and TRIB1 in wild-type bone marrow and in marrow that expressed a PML/RARA transgene...
October 2016: Haematologica
Aleksandra Mamorska-Dyga, Jingjing Wu, Pallavi Khattar, Faisal M H Ronny, Humayun Islam, Karen Seiter, Delong Liu
The V617F mutation of Janus-associated kinase 2 (JAK2) is commonly seen in myeloproliferative neoplasms (MPN). Transformation of JAK2 positive MPNs to acute leukemia has been reported. We here report a case of acute promyelocytic leukemia which was later confirmed to have a co-existing JAK2 V617F positive MPN. In addition, the patient was found to have FLT3-TKD mutation, which, together with PML/RARa, could play a role in the MPN transformation to APL.
2016: Stem Cell Investigation
Michael J Kluk, Ryan P Abo, Ronald D Brown, Frank C Kuo, Paola Dal Cin, Olga Pozdnyakova, Elizabeth A Morgan, Neal I Lindeman, Daniel J DeAngelo, Jon C Aster
We describe the case of a patient presenting with several weeks of symptoms related to pancytopenia associated with a maturation arrest at the late promyelocyte/early myelocyte stage of granulocyte differentiation. A diagnosis of acute promyelocytic leukemia was considered, but the morphologic features were atypical for this entity and conventional tests for the presence of a PML-RARA fusion gene were negative. Additional analysis using a custom next-generation sequencing assay revealed a rearrangement producing a STAT5B-RARA fusion gene, which was confirmed by reverse transcription polymerase chain reaction (RT-PCR) and supplementary cytogenetic studies, allowing the diagnosis of a morphologically atypical form of acute promyelocytic leukemia to be made...
October 2015: Cold Spring Harbor Molecular Case Studies
Hui Zeng, Ling-Di Yin, Ping Li, Yan-Hui Yuan, Chao-Yang Guan, Ting Xie, Qi-Guo Zhang
INTRODUCTION: The increased flow cytometry enumeration of peripheral blood circulating CD34+ cells in patients with acute leukemia has been found in our previous work. In this study, we also demonstrated that acute promyelocytic leukemia (APL) patients not only had elevated CD34+ cell count, but also had some clinical features. METHODS: Fifty APL patients and 19 healthy volunteers were included in the study. The enumeration of circulating CD34+ cells, cytogenetic subgroup, immunophenotype analysis, and leukemic-related gene mutation detection were performed...
October 2016: Hematology (Amsterdam, Netherlands)
V Madan, P Shyamsunder, L Han, A Mayakonda, Y Nagata, J Sundaresan, D Kanojia, K Yoshida, S Ganesan, N Hattori, N Fulton, K-T Tan, T Alpermann, M-C Kuo, S Rostami, J Matthews, M Sanada, L-Z Liu, Y Shiraishi, S Miyano, E Chendamarai, H-A Hou, G Malnassy, T Ma, M Garg, L-W Ding, Q-Y Sun, W Chien, T Ikezoe, M Lill, A Biondi, R A Larson, B L Powell, M Lübbert, W J Chng, H-F Tien, M Heuser, A Ganser, M Koren-Michowitz, S M Kornblau, H M Kantarjian, D Nowak, W-K Hofmann, H Yang, W Stock, A Ghavamzadeh, K Alimoghaddam, T Haferlach, S Ogawa, L-Y Shih, V Mathews, H P Koeffler
Acute promyelocytic leukemia (APL) is a subtype of myeloid leukemia characterized by differentiation block at the promyelocyte stage. Besides the presence of chromosomal rearrangement t(15;17), leading to the formation of PML-RARA (promyelocytic leukemia-retinoic acid receptor alpha) fusion, other genetic alterations have also been implicated in APL. Here, we performed comprehensive mutational analysis of primary and relapse APL to identify somatic alterations, which cooperate with PML-RARA in the pathogenesis of APL...
August 2016: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Sungsin Jo, Young Lim Lee, Sojin Kim, Hongki Lee, Heekyoung Chung
Arsenic trioxide (ATO) is a therapeutic agent for acute promyelocytic leukemia (APL) which induces PML-RARA protein degradation via enhanced UBE2I-mediated sumoylation. PCGF2, a Polycomb group protein, has been suggested as an anti-SUMO E3 protein by inhibiting the sumoylation of UBE2I substrates, HSF2 and RANGAP1, via direct interaction. Thus, we hypothesized that PCGF2 might play a role in ATO-induced PML-RARA degradation by interacting with UBE2I. PCGF2 protein was down-regulated upon ATO treatment in human APL cell line, NB4...
July 2016: Biochimica et Biophysica Acta
Linda Olsson, Sofia Zettermark, Andrea Biloglav, Anders Castor, Mikael Behrendtz, Erik Forestier, Kajsa Paulsson, Bertil Johansson
Cytogenetic analyses of a consecutive series of 67 paediatric (median age 8 years; range 0-17) de novo acute myeloid leukaemia (AML) patients revealed aberrations in 55 (82%) cases. The most common subgroups were KMT2A rearrangement (29%), normal karyotype (15%), RUNX1-RUNX1T1 (10%), deletions of 5q, 7q and/or 17p (9%), myeloid leukaemia associated with Down syndrome (7%), PML-RARA (7%) and CBFB-MYH11 (5%). Single nucleotide polymorphism array (SNP-A) analysis and exon sequencing of 100 genes, performed in 52 and 40 cases, respectively (39 overlapping), revealed ≥1 aberration in 89%; when adding cytogenetic data, this frequency increased to 98%...
July 2016: British Journal of Haematology
Jessica N Nichol, Matthew D Galbraith, Claudia L Kleinman, Joaquín M Espinosa, Wilson H Miller
Perturbation in the transcriptional control of genes driving differentiation is an established paradigm whereby oncogenic fusion proteins promote leukemia. From a retinoic acid (RA)-sensitive acute promyelocytic leukemia (APL) cell line, we derived an RA-resistant clone characterized by a block in transcription initiation, despite maintaining wild-type PML/RARA expression. We uncovered an aberrant interaction among PML/RARA, nucleophosmin (NPM), and topoisomerase II beta (TOP2B). Surprisingly, RA stimulation in these cells results in enhanced chromatin association of the nucleosome remodeler BRG1...
March 29, 2016: Cell Reports
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