17 results on '"Xin, Ying"'
Search Results
2. In Vivo Drug Incorporation and Intracellular Dynamics of Injectable Versus Oral Azacytidine: A Phase II Open Label Multicentre Trial
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Pimanda, John E., primary, Thoms, Julie A.I., additional, Hampton, Henry R., additional, Davidson, Sarah, additional, Joshi, Swapna, additional, Sarowar, Chowdhury H., additional, Lim, Xin Ying, additional, Nunez, Andrea C., additional, Kakadia, Purvi M., additional, Pickford, Russell, additional, Raftery, Mark, additional, Hough, Sally, additional, Buckland, Griselda, additional, Bailey, Michelle, additional, Ghodke, Yuvaraj, additional, Absar, Noorul, additional, Vaughan, Lachlin, additional, Pasalic, Leonardo, additional, Fong, Chun Yew, additional, Kenealy, Melita, additional, Hiwase, Devendra, additional, Stoddart, Rohanna, additional, Mohammed, Soma, additional, Lee, Linda, additional, Passam, Freda H., additional, Spring, Kevin, additional, Skarratt, Kristy K., additional, Rebeiro, Patricia, additional, Larsen, Stephen R, additional, Presgrave, Peter, additional, Stevenson, William S, additional, Ling, Silvia, additional, Tiley, Campbell, additional, Fuller, Stephen, additional, Roncolato, Fernando, additional, Enjeti, Anoop Kumar, additional, Hoenemann, Dirk, additional, Lemech, Charlotte, additional, Bohlander, Stefan K., additional, Olivier, Jake, additional, Hertzberg, Mark, additional, Unnikrishnan, Ashwin, additional, and Polizzotto, Mark N., additional
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- 2022
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3. Estimation of the Impact on Treatment Costs of a Switch to Nonacog Beta Pegol (N9-GP) for the Treatment of Adults with Hemophilia B in Canada Based on Real-World Factor IX (FIX) Consumption and Clinical Outcomes Pre- and Post-Switch
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MacDonald, Vance, primary, Lee, Xin Ying, additional, Caillaud, Alexandre, additional, Luckevich, Maria, additional, and Bentley, Anthony, additional
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- 2020
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4. In Vivo Assessment of Intracellular Dynamics Comparing Injection Versus Oral Azacitidine in a Phase IIb Investigator Initiated Clinical Trial
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Unnikrishnan, Ashwin, primary, Lim, Xin Ying, additional, Joshi, Swapna, additional, Nunez, Andrea C., additional, Vaughan, Lachlin, additional, Pickford, Russell, additional, Hough, Sally, additional, Davidson, Sarah, additional, Fong, Chun, additional, Kenealy, Melita, additional, Hiwase, Devendra K, additional, Pasalic, Leonardo, additional, Mohammed, Soma, additional, Lee, Linda, additional, Passam, Freda H., additional, Spring, Kevin, additional, Rebeiro, Patricia, additional, Ling, Silvia, additional, Fuller, Stephen, additional, Presgrave, Peter, additional, Roncolato, Fernando, additional, Larsen, Stephen, additional, Enjeti, Anoop K, additional, Stevenson, William S., additional, Tiley, Campbell, additional, Campbell, Peter J, additional, Lemech, Charlotte, additional, Olivier, Jake, additional, Hertzberg, Mark, additional, Polizzotto, Mark N., additional, and Pimanda, John, additional
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- 2019
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5. Concizumab Subcutaneous Prophylaxis Improves Health-Related Quality-of-Life Measures in Patients with Congenital Hemophilia with Inhibitors: Phase 2 Trial Results
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Lee, Xin Ying, primary, Cepo, Katarina, additional, and Porstmann, Thomas, additional
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- 2019
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6. Estimation of the Impact on Treatment Costs of a Switch to Nonacog Beta Pegol (N9-GP) for the Treatment of Adults with Hemophilia B in Canada Based on Real-World Factor IX (FIX) Consumption and Clinical Outcomes Pre- and Post-Switch
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Alexandre Caillaud, Maria Luckevich, Anthony Bentley, Xin Ying Lee, and Vance MacDonald
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Consumption (economics) ,Clotting factor ,Pediatrics ,medicine.medical_specialty ,business.industry ,Immunology ,Cell Biology ,Hematology ,Biochemistry ,Blood Disorder ,Breakthrough bleeding ,medicine ,Current employment ,medicine.symptom ,Treatment costs ,business ,Pre and post ,Factor IX ,medicine.drug - Abstract
Introduction: Congenital hemophilia B is a rare blood disorder, caused by mutations in the F9 gene that lead to dysfunctional, reduced, or no clotting factor IX (FIX), resulting in prolonged bleeding episodes and in severe cases, spontaneous bleeding episodes. Maintaining sufficient FIX activity in the bloodstream through routine prophylactic administration of FIX, is the standard of care for prevention of bleeds in hemophilia B patients in Canada. Breakthrough bleeding (BTB) episodes are treated acutely with additional doses of FIX. In Canada, real-world data for patients with hemophilia B, including clinical outcomes and consumption rates of FIX, are recorded in the Canadian Bleeding Disorders Registry (CBDR). FIX products for patients with hemophilia B are subject to national competitive procurement processes administered by the Canadian Blood Service (CBS) and Héma-Québec. Nonacog beta pegol (N9-GP), an extended half-life (EHL) recombinant FIX concentrate, was recently awarded a CBS contract and subsequently made available across Canada (except Québec) from April 1, 2018 to adult patients. For those patients already on another EHL FIX treatment, a forced switch to N9-GP occurred. The objective of the present study was to estimate the impact on treatment costs of switching from a prior FIX to N9-GP, based on real-world annualized bleed rates (ABRs) and FIX consumption volumes (pre- and post-N9-GP switch) for patients on prophylaxis with their previous treatment and N9-GP, as recorded in the CBDR as of 30 September 2019. Methods: Real-world data from the CBDR for FIX consumption and ABR were used to inform a cost consequence model, developed in Microsoft Excel. Only patients for whom data existed in the CBDR for 6-months pre-switch to N9-GP and who had received ≥3 months of N9-GP treatment were included. Since April 2018, N9-GP replaced eftrenonacog alfa as the EHL product available to adult patients covered by CBS, while nonacog alfa continued to be the recombinant standard half-life (SHL) product available. Based on this, it was assumed that the EHL to N9-GP switches were from eftrenonacog alfa and the SHL switches are from nonacog alfa. For comparison of N9-GP with nonacog alfa and eftrenonacog alfa, treatment of adult males (assumed body weight of 70 kg) with severe hemophilia B was modeled over a 1-year time horizon. Since the competitive procurement process used in Canada results in confidential per-unit FIX prices, a price from a similar market was used for assessment of the cost impact. The German market was selected because all recombinant FIX products available in Canada are reimbursed in Germany. Converting the German per-IU prices, as published in the Lauer-Taxe®, using the Bank of Canada average exchange rate for the previous year, resulted in a price of CAD $2.54, $1.50 and $2.18 per IU for N9-GP, nonacog alfa, and eftrenonacog alfa, respectively. Real-world annualized mean FIX consumption volumes for prophylaxis, per BTB and real-world mean total ABRs for each product were then multiplied by the price per IU for each FIX product to derive estimates of real-world annual treatment costs associated with the use of nonacog alfa and eftrenonacog alfa (pre-switch), and N9-GP (post-switch). Results: Real-world annual prophylaxis consumption volumes, as reported in the CBDR, were reduced following treatment switch to N9-GP (Table 1). The switch to N9-GP was associated with improved ABRs, from 7.38 to 2.56 and 4.76 to 2.68 for patients on prior treatment with nonacog alfa and eftrenonacog alfa, respectively. Comparative treatment costs (for prophylaxis and BTB) based on real-world data were reduced from $643,400 to $412,700 when switching from nonacog alfa to N9-GP and from $486,938 to $358,822 when switching from eftrenonacog alfa to N9-GP. Treatment with N9-GP was therefore associated with a 35.8% and 26.3% reduction in costs following a switch from nonacog alfa, and eftrenonacog alfa, respectively. Conclusion: Real-world FIX consumption and bleeding outcomes data demonstrate that N9-GP is cost-saving compared with nonacog alfa and eftrenonacog alfa (assuming per-IU prices based on German costs converted to Canadian dollars) while also achieving a reduction in ABR, regardless of whether patients previously received an SHL or EHL FIX product. N9-GP can therefore be considered a dominant treatment option compared with nonacog alfa and eftrenonacog alfa for the treatment of hemophilia B. Disclosures MacDonald: Novo Nordisk Canada Inc: Current Employment. Lee:Novo Nordisk A/S: Current Employment. Caillaud:Novo Nordisk Canada Inc: Current Employment. Luckevich:Novo Nordisk Canada Inc.: Current Employment. Bentley:Mtech Access: Consultancy, Other: Consultant for Novo Nordisk.
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- 2020
7. Concizumab Subcutaneous Prophylaxis Improves Health-Related Quality-of-Life Measures in Patients with Congenital Hemophilia with Inhibitors: Phase 2 Trial Results
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Xin Ying Lee, Thomas Porstmann, and Katarina Cepo
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Health related quality of life ,Pediatrics ,medicine.medical_specialty ,business.industry ,Concizumab ,Immunology ,Cell Biology ,Hematology ,Recombinant coagulation factor VIIa ,Pain management ,Physical function ,Biochemistry ,Quality of life ,Hemophilias ,medicine ,In patient ,business - Abstract
Introduction Concizumab is an anti-tissue factor pathway inhibitor (TFPI) monoclonal antibody in clinical development for the subcutaneous prophylactic treatment of hemophilia patients. We present exploratory analyses assessing the impact of concizumab prophylaxis on health-related quality-of-life (HRQoL) in hemophilia A and B with inhibitor (HAwI/HBwI) patients compared with recombinant activated factor VII (rFVIIa) on-demand treatment in a phase 2 trial (NCT03196284; explorer4). HRQoL is impaired in patients with hemophilia relative to the general population and this impairment is more pronounced among patients with inhibitors, including HBwI patients for whom treatment options are particularly limited. Methods HAwI and HBwI patients were randomized 2:1 to concizumab prophylaxis (n=17) or rFVIIa on demand (recombinant activated factor VII; n=9). Patients completed the 36-item Short Form Health Survey (SF-36v2; 4-week recall) questionnaire at baseline and at the end of the main phase of the trial (24 weeks). Scoring was conducted according to the SF-36v2 scoring software (version 5.0). The change in SF-36v2 scores after treatment onset from baseline to Week 24 was analyzed with an analysis of covariance (ANCOVA model) with regimen as factor and baseline score as a covariate. Improvement in SF-36v2 scores was assessed at both group and individual patient level. At group level, SF-36v2 score improvement was assessed based on minimally important difference (MID) criteria as recommended by the SF-36v2 manual (3rd edition; 2013) (Table 1). A responder analysis was also conducted to identify the proportion of patients who had an improvement in the Physical Component Summary (PCS) in terms of meeting the recommended individual level response threshold of 3.4 points (established based on the 2009 United States general population norms; SF-36v2 manual). Results Overall, improved HRQoL was observed in patients receiving concizumab prophylaxis as reflected by improvements (higher scores) in all SF-36v2 domain scores. At a group level, the difference in improvement from baseline for concizumab prophylaxis vs rFVIIa on-demand for the PCS score met the MID criterion (Table 1), as did the difference in improvement from baseline for the following SF-36v2 domains: Social Functioning, Vitality Score, Health Perception, Bodily Pain and Physical Functioning (Table 2). This difference in improvement between the two groups was not statistically significant, as the study was not powered to show significance for this endpoint. In addition, a larger percentage of patients on concizumab prophylaxis achieved an improvement that met or exceeded the response threshold on the PCS score scale compared with patients receiving rFVIIa on-demand treatment. Conclusions Hemophilia patients have been reported to have a worse HRQoL than members of the general population, particularly in relation to physical activity and pain. In results from the concizumab phase 2 explorer4 trial presented here, HAwI and HBwI patients on concizumab prophylaxis reported higher values for change from baseline in all SF-36v2 domain scores compared with patients receiving rFVIIa on demand after 24 weeks of treatment, indicating better functional health and well-being. A reduction in bleeding rate in these patients is likely to have a positive effect on physical function and reduce pain. In explorer4, there was a 78% reduction in the estimated annualized bleeding rate (ABR) among patients on concizumab prophylaxis vs those on rFVIIa on-demand treatment (Shapiro et al., ASH 2019; abstract submitted). The larger reduction in ABR observed with concizumab subcutaneous prophylaxis may have contributed to the larger improvement in HRQoL relative to the rFVIIa on-demand treatment arm. The potential beneficial effect of concizumab prophylaxis on HRQoL in all hemophilia patients will be investigated further in the phase 3 trials. Disclosures Lee: Novo Nordisk A/S: Employment. Cepo:Novo Nordisk A/S: Employment. Porstmann:Novo Nordisk Health Care AG: Employment, Honoraria.
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- 2019
8. In Vivo Assessment of Intracellular Dynamics Comparing Injection Versus Oral Azacitidine in a Phase IIb Investigator Initiated Clinical Trial
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Devendra K Hiwase, Freda H. Passam, William Stevenson, Soma Mohammed, Stephen Fuller, Jake Olivier, Charlotte Lemech, Andrea Nuñez, Anoop K Enjeti, Chun Fong, Leonardo Pasalic, Sally Hough, Ashwin Unnikrishnan, Linda Lee, Fernando Roncolato, John E. Pimanda, Patricia Rebeiro, Kevin J. Spring, Swapna Joshi, Melita Kenealy, Sarah Davidson, Campbell Tiley, Stephen Larsen, Russell Pickford, Mark Hertzberg, Xin Ying Lim, Lachlin S. Vaughan, Silvia Ling, Peter J. Campbell, Peter Presgrave, and Mark N. Polizzotto
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Oncology ,medicine.medical_specialty ,business.industry ,Immunology ,Azacitidine ,Complete remission ,Cell Biology ,Hematology ,Biochemistry ,Oral Azacitidine ,Clinical trial ,chemistry.chemical_compound ,chemistry ,In vivo ,Internal medicine ,medicine ,Deoxycytidine ,business ,Intracellular ,medicine.drug - Abstract
Introduction: 5'-Azacitidine (AZA), a DNA demethylating agent, is the primary drug for the treatment of high-risk Myelodysplastic Syndrome (MDS) and Chronic Myelomonocytic Leukaemia (CMML). Response is associated with improved survival. However, only half of patients respond, and these responses are rarely durable. We recently reported that primary AZA resistance is associated with a molecular signature of cell cycle quiescence within bone marrow (BM) hematopoietic progenitor cells (Unnikrishnan et al, Cell Reports, 20:572-585 (2017)). As DNA incorporation of the deoxyribonucleic form of AZA (5-aza-2′-deoxycytidine, DAC) occurs during DNA replication, cell cycle quiescence is predicted to lead to less DAC in DNA and concomitantly less DNA demethylation. We recently developed a quantitative multi-parameter assay, AZA-MS (Unnikrishnan, Vo et al, Leukemia 32:900-910 (2018)), to measure the intracellular dynamics of AZA in patients. Using AZA-MS, we reported data supporting the predicted resistance model. CC486 is an oral formulation of AZA. A 28-day cycle of CC486 involves 21 continuous days (21/28) versus the standard 7/28 subcutaneous (SC) injection AZA scheme. Whether levels of in vivo DAC incorporation into DNA during a cycle of CC486 are comparable with that of SC AZA is unknown. AZA-MS provides us with a unique opportunity to empirically assess the in vivo intracellular dynamics of SC versus oral AZA. Study Design and Methods: To directly assess in vivo DAC incorporation and concomitant DNA demethylation with SC AZA and CC486 in the same patient, we initiated a phase II clinical trial (NCT03493646; Fig A). MDS (IPSS; intermediate-2 or high-risk), CMML (bone marrow [BM] blasts 10-29%) and AML (20-30%) patients were recruited for six cycles of SC AZA (75mg/m^2/day for 7/28 days) followed by six cycles of CC486 (100mg bid for 21/28 days in C7-C8 and 150mg bid for 21/28 in C9-C12). Clinical response was assessed at the end of C6 and C12 using International Working Group criteria. Clinical responders and non-responders to SC AZA at C6 received CC486 from C7 onwards. From each patient, 36 peripheral blood (PB) samples and five BM samples were collected over the study period. DNA, RNA and intracellular fractions were isolated from the PB MNCs, for intracellular DAC/AZA measurements by AZA-MS (primary endpoint; Fig A). BM MNCs were utilised for AZA-MS as well as flow cytometry-based cell cycle measurements (secondary endpoint). Results: 31 of 42 consented patients have commenced treatment since trial opening (Fig B-C). We applied the AZA-MS assay on the longitudinal PB and BM samples collected from the seven patients who had completed six months AZA and commenced CC486 as at 26th June 2019 (Fig D). DAC incorporation into DNA and DNA methylation levels were quantified within the same cells, in addition to measuring other parameters (Fig E). As represented by patient 61213-005 (Fig F) who had a complete response (CR) at cycle 6, after 7 days of injection AZA we observed robust incorporation of DAC within PB MNCs (left panel, Fig F) together with concomitant DNA demethylation (right panel, Fig F). DAC levels diminished upon cessation of AZA within a cycle, with corresponding increases in DNA methylation. There were quantitatively higher levels of DAC incorporated in DNA during SC AZA cycles versus CC486. The trend observed is also appreciated from 2.3x higher area under the curve (AUC) measurements in 61213-005 during the SC AZA cycle. DAC incorporation was higher at C9/10 (CC486 150mg bid 21/28) than at C7/8 (CC486 100mg bid 21/28) without appreciable changes in DNA demethylation. During SC AZA cycles, higher DAC levels (top panel, Fig G) and greater DNA methylation (lower panel, Fig G) were seen in the BM MNCs. In a non-responding patient at cycle 6 (61290-002, SD), we saw less DAC incorporation and DNA demethylation (Fig H). We also observed a positive correlation between baseline proportions of cycling BM cells (LIN-CD34+CD38+) and the amount of DAC incorporated in BM MNCs at C1 day 8 (Fig I). Conclusion: AZA-MS can be used to reliably measure in vivo DAC incorporation and concomitant DNA demethylation in PB MNCs and inform appropriate CC486 dosing. Figure Disclosures Unnikrishnan: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Fong:Astellas: Consultancy; Novartis: Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; Amgen: Consultancy, Research Funding, Speakers Bureau. Roncolato:St. George Hospital: Employment. Enjeti:Roche: Honoraria, Speakers Bureau; Bayer and Sanofi: Honoraria, Speakers Bureau; Astellas: Consultancy; Novartis: Consultancy; Abbvie: Consultancy. Hertzberg:BMS: Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees. Polizzotto:Janssen: Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; ViiV: Research Funding. Pimanda:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.
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- 2019
9. HOX11L2 expression defines a clinical subtype of pediatric T-ALL associated with poor prognosis
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Ballerini, Paola, Blaise, Annick, Busson-Le Coniat, Maryvonne, Su, Xin Ying, Zucman-Rossi, Jessica, Adam, Mircea, van den Akker, Jacqueline, Perot, Christine, Pellegrino, Beatrice, Landman-Parker, Judith, Douay, Luc, Berger, Roland, and Bernard, Olivier A.
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- 2002
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10. Studies on Treatment of Acute Promyelocytic Leukemia With Arsenic Trioxide: Remission Induction, Follow-Up, and Molecular Monitoring in 11 Newly Diagnosed and 47 Relapsed Acute Promyelocytic Leukemia Patients
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Niu, Chao, Yan, Hua, Yu, Ting, Sun, Hui-Ping, Liu, Jian-Xiang, Li, Xiu-Song, Wu, Wen, Zhang, Fen-Qin, Chen, Yu, Zhou, Li, Li, Jun-Min, Zeng, Xiao-Ying, Yang, Ren-Rong Ou, Yuan, Mi-Man, Ren, Mei-Yu, Gu, Feng-Ying, Cao, Qi, Gu, Bo-Wei, Su, Xin-Ying, Chen, Guo-Qiang, Xiong, Shu-Min, Zhang, Ting-dong, Waxman, Samuel, Wang, Zhen-Yi, Chen, Zhu, Hu, Jiong, Shen, Zhi-Xiang, and Chen, Sai-Juan
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- 1999
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11. HOX11L2/TLX3 is transcriptionally activated through T-cell regulatory elements downstream of BCL11B as a result of the t(5;14)(q35;q32)
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Virginie Penard-Lacronique, Isabelle André-Schmutz, Xin-Ying Su, Roland Berger, Paola Ballerini, Claudie Lemercier, Véronique Della-Valle, Francine Mugneret, Serge Romana, Michel Lessard, Isabelle Radford-Weiss, Marina Lafage-Pochitaloff, Olivier Bernard, Génétique des hémopathies humaines ( EMI 210 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Developpement Normal et Pathologique du Système Immunitaire, Contrôle moléculaire de la réponse immune specifique, Université Joseph Fourier - Grenoble 1 ( UJF ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Laboratoire de Cytogénétique, Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris Descartes - Paris 5 ( UPD5 ) -CHU Necker - Enfants Malades [AP-HP], Service d'Hématologie Biologique, Assistance publique - Hôpitaux de Paris (AP-HP), Laboratoire d'Hématologie, CHU Strasbourg, Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Laboratoire de cytogénétique (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Génétique des hémopathies humaines (EMI 210), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Joseph Fourier - Grenoble 1 (UJF)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Descartes - Paris 5 (UPD5)-CHU Necker - Enfants Malades [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)
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Oncogene Proteins, Fusion ,Transcription, Genetic ,T-Lymphocytes ,BCL11B ,Chromosomal translocation ,MESH : Promoter Regions, Genetic ,MESH : Oncogene Proteins, Fusion ,Biochemistry ,Jurkat cells ,Translocation, Genetic ,Jurkat Cells ,MESH : Chromosomes, Human, Pair 5 ,0302 clinical medicine ,MESH : Translocation, Genetic ,Transcription (biology) ,MESH: Jurkat Cells ,Leukemia-Lymphoma, Adult T-Cell ,MESH: Leukemia-Lymphoma, Adult T-Cell ,MESH : Homeodomain Proteins ,Promoter Regions, Genetic ,MESH : Jurkat Cells ,Oncogene Proteins ,0303 health sciences ,MESH : Chromosomes, Human, Pair 14 ,MESH : Oncogene Proteins ,MESH : Tumor Suppressor Proteins ,Cell Differentiation ,Hematology ,Transfection ,MESH: Translocation, Genetic ,DNA-Binding Proteins ,medicine.anatomical_structure ,MESH: Repressor Proteins ,030220 oncology & carcinogenesis ,Chromosomes, Human, Pair 5 ,MESH : DNA-Binding Proteins ,MESH : Repressor Proteins ,MESH : Cell Differentiation ,MESH: Cell Differentiation ,MESH: Chromosomes, Human, Pair 5 ,T cell ,Immunology ,Biology ,03 medical and health sciences ,MESH: Oncogene Proteins ,MESH: Promoter Regions, Genetic ,MESH: Homeodomain Proteins ,medicine ,Humans ,MESH: Tumor Suppressor Proteins ,[SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology ,[ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology ,030304 developmental biology ,Chromosomes, Human, Pair 14 ,Homeodomain Proteins ,MESH : T-Lymphocytes ,MESH: Humans ,Recombinase activity ,Tumor Suppressor Proteins ,MESH: Transcription, Genetic ,MESH : Humans ,MESH : Transcription, Genetic ,Cell Biology ,T lymphocyte ,Molecular biology ,MESH : Leukemia-Lymphoma, Adult T-Cell ,Repressor Proteins ,MESH: T-Lymphocytes ,MESH: Chromosomes, Human, Pair 14 ,MESH: DNA-Binding Proteins ,MESH: Oncogene Proteins, Fusion - Abstract
International audience; The t(5;14)(q35;q32) chromosomal translocation is specifically observed in up to 20% of childhood T-cell acute lymphoblastic leukemia (T-ALL). It affects the BCL11B/CTIP2 locus on chromosome 14 and the RANBP17-TLX3/HOX11L2 region on chromosome 5. It leads to ectopic activation of TLX3/HOX11L2. To investigate the reasons of the association between t(5;14) and T-ALL, we isolated the translocation breakpoints in 8 t(5;14) patients. Sequence analyses did not involve recombinase activity in the genesis of the translocation. We used DNAse1 hypersensitive experiments to locate transcriptional regulatory elements downstream of BCL11B. By transient transfection experiments, 2 of the 6 regions demonstrated cis-activation properties in T cells and were also effective on the TLX3 promoter. Our data indicate that the basis of the specific association between t(5;14) and T-ALL lies on the juxtaposition of TLX3 to long-range cis-activating regions active during T-cell differentiation.
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- 2006
12. HOX11L2 expression defines a clinical subtype of pediatric T-ALL associated with poor prognosis
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Paola Ballerini, Maryvonne Busson-Le Coniat, Beatrice Pellegrino, Christine Perot, Mircea Adam, Roland Berger, Jessica Zucman-Rossi, Xin Ying Su, Luc Douay, Annick Blaise, Olivier Bernard, Jacqueline Van Den Akker, and Judith Landman-Parker
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Male ,medicine.medical_specialty ,Leukemia, T-Cell ,Neoplasm, Residual ,Adolescent ,Immunology ,Locus (genetics) ,Biology ,Biochemistry ,Immunophenotyping ,Proto-Oncogene Proteins ,Acute lymphocytic leukemia ,Metalloproteins ,Basic Helix-Loop-Helix Transcription Factors ,medicine ,Humans ,Gene family ,Child ,Cyclin-Dependent Kinase Inhibitor p16 ,T-Cell Acute Lymphocytic Leukemia Protein 1 ,Adaptor Proteins, Signal Transducing ,Chromosome Aberrations ,Homeodomain Proteins ,Oncogene Proteins ,Gene Expression Profiling ,Cytogenetics ,Infant ,Cell Biology ,Hematology ,Gene rearrangement ,LIM Domain Proteins ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,Prognosis ,medicine.disease ,Survival Analysis ,Minimal residual disease ,Neoplasm Proteins ,DNA-Binding Proteins ,Childhood T Acute Lymphoblastic Leukemia ,Child, Preschool ,Cytogenetic Analysis ,Cancer research ,Female ,Transcription Factors ,TAL1 - Abstract
The most frequent oncogenic activation events characterized in childhood T acute lymphoblastic leukemia (T-ALL) result in the transcriptional activation of genes coding for transcription factors. The main genes are TAL1/SCL, a member of the basic region helix-loop-helix gene family, and HOX11L2, a member of the homeobox-containing protein family. To gain insight into the pathogenesis of this type of hematologic malignancy, we analyzed 28 T-ALL samples. SIL-TAL1/SCL fusion was detected in 6 patients; expression of HOX11L2 was observed in 6 patients and of HOX11 in 3 patients. With one exception, these activations did not occur simultaneously in the same patients, and they allowed the subclassification of 50% of the patients.SIL-TAL1 fusion was detected in association withHOX11 expression in one patient and with a t(8;14) (q24;q11) in another. High expression of LYL1,LMO2, or TAL1 was observed mainly in samples negative for HOX11L2 expression. HOX11L1 andHOX11 expression were observed in one instance each, in the absence of detectable chromosomal abnormality of their respective loci, on chromosomes 2 and 10, respectively. HOX11L2 expression was associated with a chromosome 5q abnormality, the location of theHOX11L2 locus in each case tested. Finally, our data show that HOX11L2 expression was a suitable marker for minimal residual disease follow-up and was significantly associated with relapse (P = .02).
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- 2002
13. Studies on treatment of acute promyelocytic leukemia with arsenic trioxide: remission induction, follow-up, and molecular monitoring in 11 newly diagnosed and 47 relapsed acute promyelocytic leukemia patients
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Chao Niu, Sai-Juan Chen, Xiao-Ying Zeng, Mei-Yu Ren, Zhu Chen, Jian-Xiang Liu, Zhen-Yi Wang, Yu Ting, Huiping Sun, Ting-Dong Zhang, Xiu-Song Li, Samuel Waxman, Feng-Ying Gu, Qi Cao, Shu-Min Xiong, Hua Yan, Mi-Man Yuan, Jiong Hu, Xin-Ying Su, Guo-Qiang Chen, Wen Wu, Junmin Li, Bo-Wei Gu, Ren-Rong Ou Yang, Yu Chen, Li Zhou, Fen-Qin Zhang, and Zhi-Xiang Shen
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Acute promyelocytic leukemia ,Adult ,Male ,medicine.medical_specialty ,Pathology ,Leukocytosis ,medicine.medical_treatment ,Immunology ,Population ,Antineoplastic Agents ,Biology ,Biochemistry ,Gastroenterology ,Arsenicals ,Disease-Free Survival ,Translocation, Genetic ,chemistry.chemical_compound ,Arsenic Trioxide ,Leukemia, Promyelocytic, Acute ,Recurrence ,Internal medicine ,White blood cell ,medicine ,Humans ,Arsenic trioxide ,education ,APL Differentiation Syndrome ,Chemotherapy ,education.field_of_study ,Remission Induction ,Cell Differentiation ,Oxides ,Cell Biology ,Hematology ,Middle Aged ,medicine.disease ,Chemotherapy regimen ,Leukemia ,medicine.anatomical_structure ,chemistry ,Female ,Drug Monitoring ,Follow-Up Studies - Abstract
Fifty-eight acute promyelocytic leukemia (APL) patients (11 newly diagnosed and 47 relapsed) were studied for arsenic trioxide (As2O3) treatment. Clinical complete remission (CR) was obtained in 8 of 11 (72.7%) newly diagnosed cases. However, As2O3 treatment resulted in hepatic toxicity in 7 cases including 2 deaths, in contrast to the mild liver dysfunction in one third of the relapsed patients. Forty of forty-seven (85.1%) relapsed patients achieved CR. Two of three nonresponders showed clonal evolution at relapse, with disappearance of t(15;17) and PML-RAR fusion gene in 1 and shift to a dominant AML-1-ETO population in another, suggesting a correlation between PML-RAR expression and therapeutic response. In a follow-up of 33 relapsed cases over 7 to 48 months, the estimated disease-free survival (DFS) rates for 1 and 2 years were 63.6% and 41.6%, respectively, and the actual median DFS was 17 months. Patients with white blood cell (WBC) count below 10 × 109/L at relapse had better survival than those with WBC count over 10 × 109/L (P = .038). The duration of As2O3-induced CR was related to postremission therapy, because there was only 2 of 11 relapses in patients treated with As2O3 combined with chemotherapy, compared with 12 of 18 relapses with As2O3 alone (P = .01). Reverse transcription polymerase chain reaction (RT-PCR) analysis in both newly diagnosed and relapsed groups showed long-term use of As2O3 could lead to a molecular remission in some patients. We thus recommend that ATRA be used as first choice for remission induction in newly diagnosed APL cases, whereas As2O3 can be either used as a rescue for relapsed cases or included into multidrug consolidation/maintenance clinical trials.
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- 1999
14. HOX11L2/TLX3is transcriptionally activated through T-cell regulatory elements downstream of BCL11Bas a result of the t(5;14)(q35;q32)
- Author
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Su, Xin-Ying, Della-Valle, Véronique, Andre-Schmutz, Isabelle, Lemercier, Claudie, Radford-Weiss, Isabelle, Ballerini, Paola, Lessard, Michel, Lafage-Pochitaloff, Marina, Mugneret, Francine, Berger, Roland, Romana, Serge P., Bernard, Olivier A., and Penard-Lacronique, Virginie
- Abstract
The t(5;14)(q35;q32) chromosomal translocation is specifically observed in up to 20% of childhood T-cell acute lymphoblastic leukemia (T-ALL). It affects the BCL11B/CTIP2locus on chromosome 14 and the RANBP17-TLX3/HOX11L2region on chromosome 5. It leads to ectopic activation of TLX3/HOX11L2.To investigate the reasons of the association between t(5;14) and T-ALL, we isolated the translocation breakpoints in 8 t(5;14) patients. Sequence analyses did not involve recombinase activity in the genesis of the translocation. We used DNAse1 hypersensitive experiments to locate transcriptional regulatory elements downstream of BCL11B.By transient transfection experiments, 2 of the 6 regions demonstrated cis-activation properties in T cells and were also effective on the TLX3promoter. Our data indicate that the basis of the specific association between t(5;14) and T-ALL lies on the juxtaposition of TLX3to long-range cis-activating regions active during T-cell differentiation.
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- 2006
- Full Text
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15. HOX11L2/TLX3 is transcriptionally activated through T-cell regulatory elements downstream of BCL11B as a result of the t(5;14)(q35;q32)
- Author
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Su, Xin-Ying, Della-Valle, Véronique, Andre-Schmutz, Isabelle, Lemercier, Claudie, Radford-Weiss, Isabelle, Ballerini, Paola, Lessard, Michel, Lafage-Pochitaloff, Marina, Mugneret, Francine, Berger, Roland, Romana, Serge P., Bernard, Olivier A., and Penard-Lacronique, Virginie
- Abstract
The t(5;14)(q35;q32) chromosomal translocation is specifically observed in up to 20% of childhood T-cell acute lymphoblastic leukemia (T-ALL). It affects the BCL11B/CTIP2 locus on chromosome 14 and the RANBP17-TLX3/HOX11L2 region on chromosome 5. It leads to ectopic activation of TLX3/HOX11L2. To investigate the reasons of the association between t(5;14) and T-ALL, we isolated the translocation breakpoints in 8 t(5;14) patients. Sequence analyses did not involve recombinase activity in the genesis of the translocation. We used DNAse1 hypersensitive experiments to locate transcriptional regulatory elements downstream of BCL11B. By transient transfection experiments, 2 of the 6 regions demonstrated cis-activation properties in T cells and were also effective on the TLX3 promoter. Our data indicate that the basis of the specific association between t(5;14) and T-ALL lies on the juxtaposition of TLX3 to long-range cis-activating regions active during T-cell differentiation.
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- 2006
- Full Text
- View/download PDF
16. HOX11L2expression defines a clinical subtype of pediatric T-ALL associated with poor prognosis
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Ballerini, Paola, Blaise, Annick, Busson-Le Coniat, Maryvonne, Su, Xin Ying, Zucman-Rossi, Jessica, Adam, Mircea, van den Akker, Jacqueline, Perot, Christine, Pellegrino, Beatrice, Landman-Parker, Judith, Douay, Luc, Berger, Roland, and Bernard, Olivier A.
- Abstract
The most frequent oncogenic activation events characterized in childhood T acute lymphoblastic leukemia (T-ALL) result in the transcriptional activation of genes coding for transcription factors. The main genes are TAL1/SCL, a member of the basic region helix-loop-helix gene family, and HOX11L2, a member of the homeobox-containing protein family. To gain insight into the pathogenesis of this type of hematologic malignancy, we analyzed 28 T-ALL samples. SIL-TAL1/SCL fusion was detected in 6 patients; expression of HOX11L2was observed in 6 patients and of HOX11in 3 patients. With one exception, these activations did not occur simultaneously in the same patients, and they allowed the subclassification of 50% of the patients.SIL-TAL1fusion was detected in association withHOX11expression in one patient and with a t(8;14) (q24;q11) in another. High expression of LYL1,LMO2, or TAL1was observed mainly in samples negative for HOX11L2expression. HOX11L1andHOX11expression were observed in one instance each, in the absence of detectable chromosomal abnormality of their respective loci, on chromosomes 2 and 10, respectively. HOX11L2expression was associated with a chromosome 5q abnormality, the location of theHOX11L2locus in each case tested. Finally, our data show that HOX11L2expression was a suitable marker for minimal residual disease follow-up and was significantly associated with relapse (P= .02).
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- 2002
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17. In VivoAssessment of Intracellular Dynamics Comparing Injection Versus Oral Azacitidine in a Phase IIb Investigator Initiated Clinical Trial
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Unnikrishnan, Ashwin, Lim, Xin Ying, Joshi, Swapna, Nunez, Andrea C., Vaughan, Lachlin, Pickford, Russell, Hough, Sally, Davidson, Sarah, Fong, Chun, Kenealy, Melita, Hiwase, Devendra K, Pasalic, Leonardo, Mohammed, Soma, Lee, Linda, Passam, Freda H., Spring, Kevin, Rebeiro, Patricia, Ling, Silvia, Fuller, Stephen, Presgrave, Peter, Roncolato, Fernando, Larsen, Stephen, Enjeti, Anoop K, Stevenson, William S., Tiley, Campbell, Campbell, Peter J, Lemech, Charlotte, Olivier, Jake, Hertzberg, Mark, Polizzotto, Mark N., and Pimanda, John
- Abstract
Introduction:
- Published
- 2019
- Full Text
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