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Srdan Verstovsek - One of the best experts on this subject based on the ideXlab platform.
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Givinostat: an emerging treatment for polycythemia vera
Expert opinion on investigational drugs, 2020Co-Authors: Helen T. Chifotides, Prithviraj Bose, Srdan VerstovsekAbstract:Polycythemia vera (PV), a Philadelphia chromosome-negative Myeloproliferative Neoplasm, is characterized by panmyelosis, pancytosis, and a JAK2 mutation. Patients are at increased risk of thrombohe...
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abstract 3836 efficacy of cdk9 inhibitor based combinations as therapy for post Myeloproliferative Neoplasm mpn secondary s aml
Cancer Research, 2019Co-Authors: Dyana T Saenz, Srdan Verstovsek, Warren Fiskus, Taghi Manshouri, Christopher P Mill, Joseph D Khoury, Kapil N BhallaAbstract:Standard AML chemotherapy and JAK inhibitor (ruxolitinib) treatments are ineffective against post-Myeloproliferative Neoplasm (MPN) sAML. Mutations in JAK2, MPL and calreticulin, and co-epimutations, result in a dysregulated transcriptome, which is responsible for transformation of MPN to sAML and for its therapy-refractoriness. CDK9 is the catalytic subunit of pTEFb that phosphorylates serine 2 in the heptad-repeats of the C-terminal domain of RNA pol II (RNAP2). CDK9 also phosphorylates and inactivates negative transcript elongation factors (NELF and SPT5), which induces promoter-proximal pause-release of RNAP2 to enable productive mRNA transcript elongation. The bromodomain extra-terminal (BET) protein BRD4 recruits pTEFb to the chromatin to promote RNAP2-mediated elongation of transcripts, including those of c-Myc, Bcl-xL, PIM1 and MCL1, important for cell growth and survival of post-MPN sAML cells. Here, we determined the effects of inhibiting BRD4-CDK9-RNAP2 axis in post-MPN sAML cells. Treatment with the CDK9 inhibitor (CDK9i) NVP2 or BAY1143572 (B) dose-dependently induced apoptosis of ruxolitinib-sensitive (Rux-S) sAML cultured cells lines HEL92.1.7 (HEL) and SET2, as well as of patient-derived sAML blast progenitor cells (BPCs), while sparing normal CD34+ progenitor cells (HPCs). CDK9i-induced lethality in sAML cells was associated with attenuation of protein levels of S2-phosphorylated RNAP2, as well as depletion of mRNA and protein levels of c-Myc, PIM1, MCL1, Bcl-xL and XIAP. ATAC-Seq analyses demonstrated that treatment with NVP2 or B caused marked alterations in chromatin accessibility, including large peak losses on the chromatin with binding sites of TFs such as ERG, PU.1, STAT5, c-Myc, and RELA. This was associated with attenuation of mRNA expression of cMyb, c-Myc, RUNX1, LMO2, RELB, NFKB2, c-FLIP, MCL1, CDK6 and Bcl-xL. Following engraftment of luciferase transduced HEL cells into NSG mice, daily treatment with B at 10 mg/kg for 3 wks significantly reduced sAML burden and improved survival of the NSG mice (p 10-fold higher ruxolitinib IC50 values than Rux-S cells). This was associated with attenuated protein levels of p-RNAP2, c-Myc, PIM1, Bcl-xL and XIAP. Co-treatment with OTX015 and NVP2 or B synergistically induced apoptosis of not only HEL and SET2 but also HEL-RuxP and SET-RuxP cells, as well as of patient-derived sAML BPCs (CI values Citation Format: Dyana T. Saenz, Warren C. Fiskus, Taghi Manshouri, Christopher P. Mill, Joseph D. Khoury, Srdan Verstovsek, Kapil N. Bhalla. Efficacy of CDK9 inhibitor-based combinations as therapy for post-Myeloproliferative Neoplasm (MPN) secondary (s) AML [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3836.
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proposal of an endpoint for a phase iii clinical study of essential thrombocythemia balancing between short term effects and long term benefits
Journal of Clinical Oncology, 2019Co-Authors: Ruben A. Mesa, Craig Zimmerman, Lih Lisa Kang, Weichung Shih, Oleh Zagrijtschuk, Norio Komatsu, Zhijian Xiao, Chihcheng Chen, Srdan VerstovsekAbstract:7055Background: Essential thrombocythemia (ET) is a chronic Myeloproliferative Neoplasm (MPN), covering broad spectrum of clinical scenarios, from asymptomatic patients with only isolated high plat...
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ruxolitinib for essential thrombocythemia refractory to or intolerant of hydroxyurea long term phase 2 study results
Blood, 2017Co-Authors: Srdan Verstovsek, Francesco Passamonti, G Barosi, Alessandro Rambaldi, Elisa Rumi, Elisabetta Gattoni, Lisa Pieri, Huiling Zhen, Muriel Granier, Albert AssadAbstract:To the editor: Essential thrombocythemia (ET) is a Philadelphia chromosome–negative Myeloproliferative Neoplasm (MPN) characterized by persistent thrombocytosis, excessive bone marrow megakaryocyte proliferation, and normal erythrocyte mass.[1][1] Symptoms may include bone pain, pruritus, night
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decitabine therapy for Myeloproliferative Neoplasm in accelerated mpn ap or blastic acute myeloid leukemia mpn aml phase
Journal of Clinical Oncology, 2014Co-Authors: Talha Badar, Hagop M Kantarjian, Farhad Ravandi, Elias Jabbour, Gautam Borthakur, Jorge E Cortes, Naveen Pemmaraju, Naval Daver, Srdan VerstovsekAbstract:e18006 Background: MPN-AP and MPN-AML are associated with poor response to therapy and shortened survival. DNA methyltransferase inhibitors, e.g. decitabine (DEC), may have clinical activity in this setting. Methods: Retrospective chart review identified 19 MPN-AP, and 24 post MPN-AML pts treated with DEC in our center over last 7 years. MPN-AP was defined as MPN with bone marrow blast 11-19%, or progressive leukocytosis (with WBC >25K). Results: MF-AP pts characteristics: age 66 (50-77) yrs; 13 (68%) male; initial diagnoses: essential thrombocyhtemia (ET) 3 (33%), polycythemia vera (PV) 5 (26%), MF 9 (47%), unclassifiable Myeloproliferative Neoplasm (MPN) 2 (10%) pts; number (no.) of prior therapies for ET/PV/MF/MPN 2 (0-5); time to DEC from diagnosis 19 (0-327) months (mo.); no. DEC cycles given 3 (range 1-31). MPN-AML pts characteristics: age 63 (22-82) yrs; 18 (75%) male; initial diagnoses: ET 6 (25%), PV 5 (21%), MF 11 (46%), MPN 2 (8%) pts; no. of prior therapies for ET/PV/MF/MPN 1 (0-4); time to MP...
Ruben A. Mesa - One of the best experts on this subject based on the ideXlab platform.
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Online yoga in Myeloproliferative Neoplasm patients: results of a randomized pilot trial to inform future research.
BMC Complementary and Alternative Medicine, 2019Co-Authors: Jennifer Huberty, Ryan Eckert, Amylou Dueck, Heidi Kosiorek, Linda Larkey, Krisstina Gowin, Ruben A. MesaAbstract:Myeloproliferative Neoplasm (MPN) patients suffer from significant symptoms, inflammation and reduced quality of life. Yoga improves these outcomes in other cancers, but this hasn’t been demonstrated in MPNs. The purpose of this study was to: (1) explore the limited efficacy (does the program show promise of success) of a 12-week online yoga intervention among MPN patients on symptom burden and quality of life and (2) determine feasibility (practicality: to what extent a measure can be carried out) of remotely collecting inflammatory biomarkers. Patients were recruited nationally and randomized to online yoga (60 min/week of yoga) or wait-list control (asked to maintain normal activity). Weekly yoga minutes were collected with Clicky (online web analytics tool) and self-report. Those in online yoga completed a blood draw at baseline and week 12 to assess inflammation (interleukin-6, tumor necrosis factor-alpha [TNF-α]). All participants completed questionnaires assessing depression, anxiety, fatigue, pain, sleep disturbance, sexual function, total symptom burden, global health, and quality of life at baseline, week seven, 12, and 16. Change from baseline at each time point was computed by group and effect sizes were calculated. Pre-post intervention change in inflammation for the yoga group was compared by t-test. Sixty-two MPN patients enrolled and 48 completed the intervention (online yoga = 27; control group = 21). Yoga participation averaged 40.8 min/week via Clicky and 56.1 min/week via self-report. Small/moderate effect sizes were generated from the yoga intervention for sleep disturbance (d = − 0.26 to − 0.61), pain intensity (d = − 0.34 to − 0.51), anxiety (d = − 0.27 to − 0.37), and depression (d = − 0.53 to − 0.78). A total of 92.6 and 70.4% of online yoga participants completed the blood draw at baseline and week 12, respectively, and there was a decrease in TNF-α from baseline to week 12 (− 1.3 ± 1.5 pg/ml). Online yoga demonstrated small effects on sleep, pain, and anxiety as well as a moderate effect on depression. Remote blood draw procedures are feasible and the effect size of the intervention on TNF-α was large. Future fully powered randomized controlled trials are needed to test for efficacy. This trial was retrospectively registered with clinicaltrials.gov (ID: NCT03503838 ) on 4/19/2018.
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proposal of an endpoint for a phase iii clinical study of essential thrombocythemia balancing between short term effects and long term benefits
Journal of Clinical Oncology, 2019Co-Authors: Ruben A. Mesa, Craig Zimmerman, Lih Lisa Kang, Weichung Shih, Oleh Zagrijtschuk, Norio Komatsu, Zhijian Xiao, Chihcheng Chen, Srdan VerstovsekAbstract:7055Background: Essential thrombocythemia (ET) is a chronic Myeloproliferative Neoplasm (MPN), covering broad spectrum of clinical scenarios, from asymptomatic patients with only isolated high plat...
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smartphone based meditation for Myeloproliferative Neoplasm patients feasibility study to inform future trials
Journal of Medical Internet Research, 2019Co-Authors: Jennifer Huberty, Ryan Eckert, Linda Larkey, Jonathan Kurka, Sue Rodriguez A De Jesus, Wonsuk Yoo, Ruben A. MesaAbstract:Background: Myeloproliferative Neoplasm (MPN) patients often report high symptom burden that persists despite the best available pharmacologic therapy. Meditation has gained popularity in recent decades as a way to manage cancer patient symptoms. Objective: The aim of this study was to examine the feasibility of 2 different consumer-based meditation smartphone apps in MPN patients and to examine the limited efficacy of smartphone-based meditation on symptoms compared with an educational control group. Methods: Patients (n=128) were recruited nationally through organizational partners and social media. Eligible and consented patients were enrolled into 1 of 4 groups, 2 of which received varying orders of 2 consumer-based apps (10% Happier and Calm) and 2 that received one of the apps alone for the second 4 weeks of the 8-week intervention after an educational control condition. Participants were asked to perform 10 min of meditation per day irrespective of the app and the order in which they received the apps. Feasibility outcomes were measured at weeks 5 and 9 with a Web-based survey. Feasibility outcomes were acceptability, demand, and limited efficacy for depression, anxiety, pain intensity, sleep disturbance, sexual function, quality of life, global health, and total symptom burden. Results: A total of 128 patients were enrolled across all 4 groups, with 73.4% (94/128) patients completing the intervention. Of the participants who completed the 10% Happier app, 61% (46/76) enjoyed it, 66% (50/76) were satisfied with the content, and 77% (59/76) would recommend to others. Of those who completed the Calm app, 83% (56/68) enjoyed it, 84% (57/68) were satisfied with the content, and 97% (66/68) would recommend to others. Of those who completed the educational control, 91% (56/61) read it, 87% (53/61) enjoyed it, and 71% (43/61) learned something. Participants who completed the 10% Happier app averaged 31 (SD 33) min/week; patients completing the Calm app averaged 71 (SD 74) min/week. 10% Happier app participants saw small effects on anxiety (P<.001 d=−0.43), depression (P=.02; d=−0.38), sleep disturbance (P=.01; d=−0.40), total symptom burden (P=.13; d=−0.27), and fatigue (P=.06; d=−0.30), and moderate effects on physical health (P<.001; d=0.52). Calm app participants saw small effects on anxiety (P=.29; d=−0.22), depression (P=.09; d=−0.29), sleep disturbance (P=.002; d=−0.47), physical health (P=.005; d=0.44), total symptom burden (P=.13; d=−0.27), and fatigue (P=.13; d=−0.27). Educational control participants (n=61) did not have effects on any patient-reported outcome except for a moderate effect on physical health (P<.001; d=0.77). Conclusions: Delivering meditation via the Calm app is feasible and scored higher in terms of feasibility when compared with the 10% Happier app. The Calm app will be used to implement a randomized controlled trial, testing the effects of meditation on symptom burden in MPNs. Trial Registration: ClinicalTrials.gov NCT03726944; https://clinicaltrials.gov/ct2/show/NCT03726944 (Archived by WebCite at http://www.webcitation.org/77MVdFJwM)
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a randomized study of pomalidomide vs placebo in persons with Myeloproliferative Neoplasm associated myelofibrosis and rbc transfusion dependence
Leukemia, 2017Co-Authors: A Tefferi, Ruben A. Mesa, Francesco Passamonti, Heinz Gisslinger, Haifa Kathrin Alali, G Barosi, T Devos, Qian Jiang, J J Kiladjian, Mary Frances McmullinAbstract:RBC-transfusion dependence is common in persons with Myeloproliferative Neoplasm (MPN)-associated myelofibrosis. The objective of this study was to determine the rates of RBC-transfusion independence after therapy with pomalidomide vs placebo in persons with MPN-associated myelofibrosis and RBC-transfusion dependence. Two hundred and fifty-two subjects (intent-to-treat (ITT) population) including 229 subjects confirmed by central review (modified ITT population) were randomly assigned (2:1) to pomalidomide or placebo. Trialists and subjects were blinded to treatment allocation. Primary end point was proportion of subjects achieving RBC-transfusion independence within 6 months. One hundred and fifty-two subjects received pomalidomide and 77 placebo. Response rates were 16% (95% confidence interval (CI), 11, 23%) vs 16% (8, 26%; P=0.87). Response in the pomalidomide cohort was associated with ⩽4 U RBC/28 days (odds ratio (OR)=3.1; 0.9, 11.1), age ⩽65 (OR=2.3; 0.9, 5.5) and type of MPN-associated myelofibrosis (OR=2.6; 0.7, 9.5). Responses in the placebo cohort were associated with ⩽4 U RBC/28 days (OR=8.6; 0.9, 82.3), white blood cell at randomization >25 × 109/l (OR=4.9; 0.8, 28.9) and interval from diagnosis to randomization >2 years (OR=4.9; 1.1, 21.9). Pomalidomide was associated with increased rates of oedema and neutropenia but these adverse effects were manageable. Pomalidomide and placebo had similar RBC-transfusion-independence response rates in persons with MPN-associated RBC-transfusion dependence.
Di Shao - One of the best experts on this subject based on the ideXlab platform.
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single cell exome sequencing and monoclonal evolution of a jak2 negative Myeloproliferative Neoplasm
Cell, 2012Co-Authors: Yong Hou, Luting Song, Ping Zhu, Bo Zhang, Ye Tao, Jie Liang, Di Shao, Min Jian, Yan Chen, Wei XieAbstract:Tumor heterogeneity presents a challenge for inferring clonal evolution and driver gene identification. Here, we describe a method for analyzing the cancer genome at a single-cell nucleotide level. To perform our analyses, we first devised and validated a high-throughput whole-genome single-cell sequencing method using two lymphoblastoid cell line single cells. We then carried out whole-exome single-cell sequencing of 90 cells from a JAK2-negative Myeloproliferative Neoplasm patient. The sequencing data from 58 cells passed our quality control criteria, and these data indicated that this Neoplasm represented a monoclonal evolution. We further identified essential thrombocythemia (ET)-related candidate mutations such as SESN2 and NTRK1, which may be involved in Neoplasm progression. This pilot study allowed the initial characterization of the disease-related genetic architecture at the single-cell nucleotide level. Further, we established a single-cell sequencing method that opens the way for detailed analyses of a variety of tumor types, including those with high genetic complex between patients.
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single cell exome sequencing and monoclonal evolution of a jak2 negative Myeloproliferative Neoplasm
Cell, 2012Co-Authors: Yong Hou, Luting Song, Ping Zhu, Bo Zhang, Ye Tao, Jie Liang, Xun Xu, Fuqiang Li, Kui Wu, Di ShaoAbstract:Summary Tumor heterogeneity presents a challenge for inferring clonal evolution and driver gene identification. Here, we describe a method for analyzing the cancer genome at a single-cell nucleotide level. To perform our analyses, we first devised and validated a high-throughput whole-genome single-cell sequencing method using two lymphoblastoid cell line single cells. We then carried out whole-exome single-cell sequencing of 90 cells from a JAK2 -negative Myeloproliferative Neoplasm patient. The sequencing data from 58 cells passed our quality control criteria, and these data indicated that this Neoplasm represented a monoclonal evolution. We further identified essential thrombocythemia (ET)-related candidate mutations such as SESN2 and NTRK1 , which may be involved in Neoplasm progression. This pilot study allowed the initial characterization of the disease-related genetic architecture at the single-cell nucleotide level. Further, we established a single-cell sequencing method that opens the way for detailed analyses of a variety of tumor types, including those with high genetic complex between patients.
Jean-jacques Kiladjian - One of the best experts on this subject based on the ideXlab platform.
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Fedratinib, a newly approved treatment for patients with Myeloproliferative Neoplasm-associated myelofibrosis
Leukemia, 2021Co-Authors: Moshe Talpaz, Jean-jacques KiladjianAbstract:Myeloproliferative Neoplasm (MPN)-associated myelofibrosis (MF) is characterized by cytopenias, marrow fibrosis, constitutional symptoms, extramedullary hematopoiesis, splenomegaly, and shortened survival. Constitutive activation of the janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway in MF leads to cell proliferation, inhibition of cell death, and clonal expansion of Myeloproliferative malignant cells. Fedratinib is a selective oral JAK2 inhibitor recently approved in the United States for treatment of adult patients with intermediate-2 or high-risk MF. In mouse models of JAK2 V617F-driven Myeloproliferative disease, fedratinib blocked phosphorylation of STAT5, increased survival, and improved MF-associated disease features, including reduction of white blood cell counts, hematocrit, splenomegaly, and fibrosis. Fedratinib exerts off-target inhibitory activity against bromodomain-containing protein 4 (BRD4); combination JAK/STAT and BRD4 inhibition was shown to synergistically block NF-kB hyperactivation and inflammatory cytokine production, attenuating disease burden and reversing bone marrow fibrosis in animal models of MPNs. In patients, fedratinib is rapidly absorbed and dosed once daily (effective half-life 41 h). Fedratinib showed robust clinical activity in JAK-inhibitor-naïve patients and in patients with MF who were relapsed, refractory, or intolerant to prior ruxolitinib therapy. Fedratinib is effective regardless of JAK2 mutation status. Onset of spleen and symptom responses are typically seen within the first 1–2 months of treatment. The most common adverse events (AEs) with fedratinib are grades 1–2 gastrointestinal events, which are most frequent during early treatment and decrease over time. Treatment discontinuation due to hematologic AEs in clinical trials was uncommon (~3%). Suspected cases of Wernicke’s encephalopathy were reported during fedratinib trials in ~1% of patients; thiamine levels should be monitored before and during fedratinib treatment as medically indicated. Phase III trials are ongoing to assess fedratinib effects on long-term safety, efficacy, and overall survival. The recent approval of fedratinib provides a much-needed addition to the limited therapeutic options available for patients with MF.
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the telomerase inhibitor imetelstat in patients pts with intermediate 2 or high risk myelofibrosis mf previously treated with janus kinase jak inhibitor a phase 2 randomized study
Journal of Clinical Oncology, 2016Co-Authors: A Tefferi, Guido Finazzi, Ronald Hoffman, Jean-jacques Kiladjian, Naseema Gangat, Dietger Niederwieser, Jan Van Droogenbroeck, Maria R Baer, Francisco Cervantes, Jason GotlibAbstract:TPS7079Background: MF is a Philadelphia chromosome negative Myeloproliferative Neoplasm, with a relatively poor prognosis. Ruxolitinib, a JAK1/JAK2 inhibitor, is the only approved therapy for MF, a...
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combination therapy with ruxolitinib plus intensive treatment strategy is feasible in patients with blast phase Myeloproliferative Neoplasms
British Journal of Haematology, 2016Co-Authors: Raynier Devillier, Jean-jacques Kiladjian, Emmanuel Raffoux, Etienne Lengline, Annemarie Ronchetti, Marie Sebert, Nicolas Boissel, Marie Robin, Herve Dombret, Thomas CluzeauAbstract:Keywords: ruxolitinib; Myeloproliferative Neoplasm; blast phase; acute myeloid leukaemia; intensive chemotherapy
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Myeloproliferative Neoplasm (MPN) symptom assessment form total symptom score: prospective international assessment of an abbreviated symptom burden scoring system among patients with MPNs.
Journal of Clinical Oncology, 2012Co-Authors: Robyn M Emanuel, Amylou C Dueck, Holly L Geyer, Jean-jacques Kiladjian, Stefanie Slot, Sonja Zweegman, Peter A W Te Boekhorst, Suzan Commandeur, Harry C Schouten, Federico SackmannAbstract:PURPOSE: Myeloproliferative Neoplasm (MPN) symptoms are troublesome to patients, and alleviation of this burden represents a paramount treatment objective in the development of MPN-directed therapies. We aimed to assess the utility of an abbreviated symptom score for the most pertinent and representative MPN symptoms for subsequent serial use in assessing response to therapy. PATIENTS AND METHODS: The Myeloproliferative Neoplasm Symptom Assessment Form total symptom score (MPN-SAF TSS) was calculated as the mean score for 10 items from two previously validated scoring systems. Questions focus on fatigue, concentration, early satiety, inactivity, night sweats, itching, bone pain, abdominal discomfort, weight loss, and fevers. RESULTS: MPN-SAF TSS was calculable for 1,408 of 1,433 patients with MPNs who had a mean score of 21.2 (standard deviation [SD], 16.3). MPN-SAF TSS results significantly differed among MPN disease subtypes (P
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Myeloproliferative Neoplasm mpn symptom assessment form total symptom score prospective international assessment of an abbreviated symptom burden scoring system among patients with mpns
Journal of Clinical Oncology, 2012Co-Authors: Robyn M Emanuel, Amylou C Dueck, Holly L Geyer, Jean-jacques Kiladjian, Stefanie Slot, Sonja Zweegman, Peter A W Te Boekhorst, Suzan Commandeur, Harry C Schouten, Federico SackmannAbstract:Purpose Myeloproliferative Neoplasm (MPN) symptoms are troublesome to patients, and alleviation of this burden represents a paramount treatment objective in the development of MPN-directed therapies. We aimed to assess the utility of an abbreviated symptom score for the most pertinent and representative MPN symptoms for subsequent serial use in assessing response to therapy. Patients and Methods The Myeloproliferative Neoplasm Symptom Assessment Form total symptom score (MPN-SAF TSS) was calculated as the mean score for 10 items from two previously validated scoring systems. Questions focus on fatigue, concentration, early satiety, inactivity, night sweats, itching, bone pain, abdominal discomfort, weight loss, and fevers. Results MPN-SAF TSS was calculable for 1,408 of 1,433 patients with MPNs who had a mean score of 21.2 (standard deviation [SD], 16.3). MPN-SAF TSS results significantly differed among MPN disease subtypes (P < .001), with a mean of 18.7 (SD, 15.3), 21.8 (SD, 16.3), and 25.3 (SD, 17.2) f...
Yong Hou - One of the best experts on this subject based on the ideXlab platform.
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single cell exome sequencing and monoclonal evolution of a jak2 negative Myeloproliferative Neoplasm
Cell, 2012Co-Authors: Yong Hou, Luting Song, Ping Zhu, Bo Zhang, Ye Tao, Jie Liang, Di Shao, Min Jian, Yan Chen, Wei XieAbstract:Tumor heterogeneity presents a challenge for inferring clonal evolution and driver gene identification. Here, we describe a method for analyzing the cancer genome at a single-cell nucleotide level. To perform our analyses, we first devised and validated a high-throughput whole-genome single-cell sequencing method using two lymphoblastoid cell line single cells. We then carried out whole-exome single-cell sequencing of 90 cells from a JAK2-negative Myeloproliferative Neoplasm patient. The sequencing data from 58 cells passed our quality control criteria, and these data indicated that this Neoplasm represented a monoclonal evolution. We further identified essential thrombocythemia (ET)-related candidate mutations such as SESN2 and NTRK1, which may be involved in Neoplasm progression. This pilot study allowed the initial characterization of the disease-related genetic architecture at the single-cell nucleotide level. Further, we established a single-cell sequencing method that opens the way for detailed analyses of a variety of tumor types, including those with high genetic complex between patients.
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single cell exome sequencing and monoclonal evolution of a jak2 negative Myeloproliferative Neoplasm
Cell, 2012Co-Authors: Yong Hou, Luting Song, Ping Zhu, Bo Zhang, Ye Tao, Jie Liang, Xun Xu, Fuqiang Li, Kui Wu, Di ShaoAbstract:Summary Tumor heterogeneity presents a challenge for inferring clonal evolution and driver gene identification. Here, we describe a method for analyzing the cancer genome at a single-cell nucleotide level. To perform our analyses, we first devised and validated a high-throughput whole-genome single-cell sequencing method using two lymphoblastoid cell line single cells. We then carried out whole-exome single-cell sequencing of 90 cells from a JAK2 -negative Myeloproliferative Neoplasm patient. The sequencing data from 58 cells passed our quality control criteria, and these data indicated that this Neoplasm represented a monoclonal evolution. We further identified essential thrombocythemia (ET)-related candidate mutations such as SESN2 and NTRK1 , which may be involved in Neoplasm progression. This pilot study allowed the initial characterization of the disease-related genetic architecture at the single-cell nucleotide level. Further, we established a single-cell sequencing method that opens the way for detailed analyses of a variety of tumor types, including those with high genetic complex between patients.
