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Article: Ensemble-based design of tau to inhibit aggregation while preserving biological activity.

Bali, Sofia / Singh, Ruhar / Wydorski, Pawel M / Wosztyl, Aleksandra / Perez, Valerie A / Chen, Dailu / Rizo, Josep / Joachimiak, Lukasz A

Research square

2024

Abstract: The microtubule-associated protein tau is implicated in neurodegenerative diseases characterized by amyloid formation. Mutations associated with frontotemporal dementia increase tau aggregation propensity and disrupt its endogenous microtubule-binding ... ...

Abstract	The microtubule-associated protein tau is implicated in neurodegenerative diseases characterized by amyloid formation. Mutations associated with frontotemporal dementia increase tau aggregation propensity and disrupt its endogenous microtubule-binding activity. The structural relationship between aggregation propensity and biological activity remains unclear. We employed a multi-disciplinary approach, including computational modeling, NMR, cross-linking mass spectrometry, and cell models to design tau sequences that stabilize its structural ensemble. Our findings reveal that substitutions near the conserved 'PGGG' beta-turn motif can modulate local conformation, more stably engaging in interactions with the
Language	English
Publishing date	2024-01-16
Publishing country	United States
Document type	Preprint
DOI	10.21203/rs.3.rs-3796916/v1
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Article: Ensemble-based design of tau to inhibit aggregation while preserving biological activity.

Bali, Sofia / Singh, Ruhar / Wydorski, Pawel M / Wosztyl, Aleksandra / Perez, Valerie A / Chen, Dailu / Rizo, Josep / Joachimiak, Lukasz A

bioRxiv : the preprint server for biology

2023

Abstract	The microtubule-associated protein tau is implicated in neurodegenerative diseases characterized by amyloid formation. Mutations associated with frontotemporal dementia increase tau aggregation propensity and disrupt its endogenous microtubule-binding activity. The structural relationship between aggregation propensity and biological activity remains unclear. We employed a multi-disciplinary approach, including computational modeling, NMR, cross-linking mass spectrometry, and cell models to design tau sequences that stabilize its structural ensemble. Our findings reveal that substitutions near the conserved 'PGGG' beta-turn motif can modulate local conformation, more stably engaging in interactions with the
Language	English
Publishing date	2023-12-14
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.12.13.571598
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Article ; Online: Imetelstat in intermediate-2 or high-risk myelofibrosis refractory to JAK inhibitor: IMpactMF phase III study design.

Mascarenhas, John / Harrison, Claire N / Kiladjian, Jean-Jacques / Komrokji, Rami S / Koschmieder, Steffen / Vannucchi, Alessandro M / Berry, Tymara / Redding, Denise / Sherman, Laurie / Dougherty, Souria / Peng, Lixian / Sun, Libo / Huang, Fei / Wan, Ying / Feller, Faye M / Rizo, Aleksandra / Verstovsek, Srdan

Future oncology (London, England)

2022 Volume 18, Issue 22, Page(s) 2393–2402

Abstract: Imetelstat, a first-in-class telomerase inhibitor, demonstrated meaningful clinical benefit including a robust symptom response rate and potential overall survival benefit in IMbark, a phase II study in intermediate-2 or high-risk myelofibrosis (MF) ... ...

Abstract	Imetelstat, a first-in-class telomerase inhibitor, demonstrated meaningful clinical benefit including a robust symptom response rate and potential overall survival benefit in IMbark, a phase II study in intermediate-2 or high-risk myelofibrosis (MF) patients who have relapsed after or are refractory to JAK inhibitors. We describe the rationale and design for the phase III trial, IMpactMF (NCT04576156), an open-label evaluation of imetelstat versus best available therapy, excluding JAK inhibitors, in MF patients refractory to JAK inhibitor. Imetelstat 9.4 mg/kg is administered as an intravenous infusion every 21 days. Primary objective is to assess overall survival. Secondary objectives include symptom and spleen responses, progression-free survival, clinical response assessment, bone marrow fibrosis reduction, safety and pharmacokinetics. Biomarker, cytogenetics and mutation analyses will be performed.
MeSH term(s)	Clinical Trials, Phase II as Topic ; Clinical Trials, Phase III as Topic ; Humans ; Janus Kinase Inhibitors ; Nitriles/therapeutic use ; Oligonucleotides ; Primary Myelofibrosis/diagnosis ; Primary Myelofibrosis/drug therapy ; Pyrazoles/therapeutic use ; Pyrimidines/adverse effects
Chemical Substances	Janus Kinase Inhibitors ; Nitriles ; Oligonucleotides ; Pyrazoles ; Pyrimidines ; imetelstat (F60NE4XB53)
Language	English
Publishing date	2022-05-05
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	2274956-1
ISSN	1744-8301 ; 1479-6694
ISSN (online)	1744-8301
ISSN	1479-6694
DOI	10.2217/fon-2022-0235
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Article ; Online: Favorable overall survival with imetelstat in relapsed/refractory myelofibrosis patients compared with real-world data.

Kuykendall, Andrew T / Sun, Libo / Mascarenhas, John / Kiladjian, Jean-Jacques / Vannucchi, Alessandro M / Wang, Julia / Xia, Qi / Zhu, Eugene / Feller, Faye / Rizo, Aleksandra / Bussolari, Jacqueline / Wan, Ying / Komrokji, Rami

Annals of hematology

2021 Volume 101, Issue 1, Page(s) 139–146

Abstract: In the MYF2001 trial, treatment of Janus kinase (JAK) inhibitor-relapsed/refractory intermediate-2 or high-risk myelofibrosis (MF) with imetelstat 9.4 mg/kg every 3 weeks demonstrated encouraging median overall survival of 29.9 months. To provide ... ...

Abstract	In the MYF2001 trial, treatment of Janus kinase (JAK) inhibitor-relapsed/refractory intermediate-2 or high-risk myelofibrosis (MF) with imetelstat 9.4 mg/kg every 3 weeks demonstrated encouraging median overall survival of 29.9 months. To provide historical context, external real-world data (RWD) were collected from a study of 96 patients who had discontinued ruxolitinib and were subsequently treated with best available therapy (BAT) at Moffitt Cancer Center. A closely matched cohort was identified using the MYF2001 eligibility criteria, including patients with MF who had discontinued ruxolitinib due to lack or loss of response. Overall survival was measured from time of JAK inhibitor discontinuation to death or censored at last follow-up. To improve comparability, propensity score weighting approaches using average treatment effect for overlap population (ATO) and stabilized inverse probability treatment weighting (sIPTW) were used for 10 critical baseline covariates. Fifty-seven patients treated with imetelstat 9.4 mg/kg from MYF2001 and 38 patients treated with BAT from RWD were analyzed with improved balanced baseline covariates after propensity score adjustment, showing significantly lower risk of death with imetelstat compared with BAT (hazard ratio: 0.35; p = 0.0019). With sIPTW, results were similar. Results of sensitivity analyses were consistent with the primary analysis. In conclusion, treatment with imetelstat was associated with longer overall survival compared to BAT (30 vs 12 months, respectively) in closely matched patients with MF after JAK inhibitor failure, warranting further evaluation of imetelstat in this poor-prognosis patient population.
MeSH term(s)	Aged ; Female ; Humans ; Janus Kinases/antagonists & inhibitors ; Male ; Middle Aged ; Nitriles/adverse effects ; Nitriles/therapeutic use ; Oligonucleotides/adverse effects ; Oligonucleotides/therapeutic use ; Primary Myelofibrosis/drug therapy ; Primary Myelofibrosis/epidemiology ; Propensity Score ; Protein Kinase Inhibitors/adverse effects ; Protein Kinase Inhibitors/therapeutic use ; Pyrazoles/adverse effects ; Pyrazoles/therapeutic use ; Pyrimidines/adverse effects ; Pyrimidines/therapeutic use ; Secondary Prevention ; Survival Analysis
Chemical Substances	Nitriles ; Oligonucleotides ; Protein Kinase Inhibitors ; Pyrazoles ; Pyrimidines ; ruxolitinib (82S8X8XX8H) ; Janus Kinases (EC 2.7.10.2) ; imetelstat (F60NE4XB53)
Language	English
Publishing date	2021-10-08
Publishing country	Germany
Document type	Clinical Trial ; Comparative Study ; Journal Article
ZDB-ID	1064950-5
ISSN	1432-0584 ; 0939-5555 ; 0945-8077
ISSN (online)	1432-0584
ISSN	0939-5555 ; 0945-8077
DOI	10.1007/s00277-021-04683-w
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Article ; Online: Randomized, Single-Blind, Multicenter Phase II Study of Two Doses of Imetelstat in Relapsed or Refractory Myelofibrosis.

Journal of clinical oncology : official journal of the American Society of Clinical Oncology

2021 Volume 39, Issue 26, Page(s) 2881–2892

Abstract: Purpose: Patients with myelofibrosis who are relapsed or refractory (R/R) to Janus-associated kinase inhibitors (JAKis) have poor clinical outcomes including dismal overall survival (OS) that ranges between 13 and 16 months. Imetelstat, a telomerase ... ...

Abstract	Purpose: Patients with myelofibrosis who are relapsed or refractory (R/R) to Janus-associated kinase inhibitors (JAKis) have poor clinical outcomes including dismal overall survival (OS) that ranges between 13 and 16 months. Imetelstat, a telomerase inhibitor, was evaluated in patients with intermediate-2 or high-risk myelofibrosis R/R to JAKi in a phase II multicenter study (ClinicalTrials.gov identifier: NCT02426086). Patients and methods: Patients were randomly assigned to receive either imetelstat 9.4 mg/kg or 4.7 mg/kg intravenous once every 3 weeks. Spleen response (≥ 35% spleen volume reduction) and symptom response (≥ 50% reduction in total symptom score) rates at week 24 were coprimary end points. Secondary end points included OS and safety. Results: Study enrollment was closed early, and patients treated with 4.7 mg/kg were permitted to continue treatment with 9.4 mg/kg. At week 24, spleen and symptom response rates were 10.2% and 32.2% in the 9.4-mg/kg arm and 0% and 6.3% in the 4.7-mg/kg arm. Treatment with imetelstat 9.4 mg/kg led to a median OS of 29.9 months and bone marrow fibrosis improvement in 40.5% and variant allele frequency reduction of driver mutations in 42.1% of evaluable patients. Fibrosis improvement and variant allele frequency reduction correlated with OS. Target inhibition was demonstrated by reduction of telomerase activity and human telomerase reverse transcriptase level and correlated with spleen response, symptom response, and OS. Most common adverse events on both arms were grade 3 or 4 reversible cytopenias. Conclusion: In this phase II study of two imetelstat doses, 9.4 mg/kg once every 3 weeks demonstrated clinical benefits in symptom response rate, with an acceptable safety profile for this poor-risk JAKi R/R population. Biomarker and bone marrow fibrosis assessments suggested selective effects on the malignant clone. A confirmatory phase III study is currently underway.
MeSH term(s)	Aged ; Enzyme Inhibitors/administration & dosage ; Enzyme Inhibitors/adverse effects ; Europe ; Female ; Humans ; Male ; Middle Aged ; Oligonucleotides/administration & dosage ; Oligonucleotides/adverse effects ; Primary Myelofibrosis/drug therapy ; Primary Myelofibrosis/enzymology ; Primary Myelofibrosis/mortality ; Primary Myelofibrosis/pathology ; Recurrence ; Single-Blind Method ; Telomerase/antagonists & inhibitors ; Time Factors ; Treatment Outcome ; United States
Chemical Substances	Enzyme Inhibitors ; Oligonucleotides ; Telomerase (EC 2.7.7.49) ; imetelstat (F60NE4XB53)
Language	English
Publishing date	2021-06-17
Publishing country	United States
Document type	Clinical Trial, Phase II ; Comparative Study ; Journal Article ; Multicenter Study ; Randomized Controlled Trial ; Research Support, Non-U.S. Gov't
ZDB-ID	604914-x
ISSN	1527-7755 ; 0732-183X
ISSN (online)	1527-7755
ISSN	0732-183X
DOI	10.1200/JCO.20.02864
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Zs.A 1847: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Imetelstat Achieves Meaningful and Durable Transfusion Independence in High Transfusion-Burden Patients With Lower-Risk Myelodysplastic Syndromes in a Phase II Study.

Journal of clinical oncology : official journal of the American Society of Clinical Oncology

2020 Volume 39, Issue 1, Page(s) 48–56

Abstract: Purpose: Patients with lower-risk (LR) myelodysplastic syndromes (MDS) who are RBC transfusion dependent and have experienced relapse after or are refractory to erythropoiesis-stimulating agent (ESA) have limited treatment options. High telomerase ... ...

Abstract	Purpose: Patients with lower-risk (LR) myelodysplastic syndromes (MDS) who are RBC transfusion dependent and have experienced relapse after or are refractory to erythropoiesis-stimulating agent (ESA) have limited treatment options. High telomerase activity and human telomerase reverse-transcription expression in clonal hematopoietic cells have been reported in patients with MDS. Imetelstat, a first-in-class competitive inhibitor of telomerase enzymatic activity, targets cells with active telomerase. We report efficacy, safety, and biomarker data for patients with LR MDS who are RBC transfusion dependent and who were relapsed/refractory to ESAs. Patients and methods: In this two-part phase II/III study (MDS3001), the primary end point was 8-week RBC transfusion independence (TI) rate, with key secondary end points of 24-week RBC TI rate, TI duration, and hematologic improvement-erythroid. Results: Data from the phase II part of the study are reported. Of 57 patients enrolled and treated (overall population), 38 were non-del(5q) and hypomethylating agent and lenalidomide naïve (subset population). The 8- and 24-week RBC TI rates in the overall population were 37% and 23%, respectively, with a median TI duration of 65 weeks. In the subset population, 8- and 24-week RBC TI rates were 42% and 29%, respectively, with a median TI duration of 86 weeks. Eight-week TI rate was observed across all subgroups evaluated. Cytogenetic and mutational data revealed a reduction of the malignant clones, suggesting disease modification activity. The most common adverse events were cytopenias, typically reversible within 4 weeks. Conclusion: Imetelstat treatment results in a meaningful, durable TI rate across a broad range of heavily transfused patients with LR MDS who are ineligible for or relapsed/refractory to ESAs. Biomarker analyses indicated effects on the mutant malignant clone.
MeSH term(s)	Aged ; Aged, 80 and over ; Biomarkers, Tumor/blood ; Enzyme Inhibitors/therapeutic use ; Erythrocyte Transfusion/statistics & numerical data ; Female ; Hematinics/therapeutic use ; Humans ; Male ; Middle Aged ; Myelodysplastic Syndromes/drug therapy ; Oligonucleotides/therapeutic use
Chemical Substances	Biomarkers, Tumor ; Enzyme Inhibitors ; Hematinics ; Oligonucleotides ; imetelstat (F60NE4XB53)
Language	English
Publishing date	2020-10-27
Publishing country	United States
Document type	Clinical Trial, Phase II ; Journal Article ; Multicenter Study ; Research Support, Non-U.S. Gov't
ZDB-ID	604914-x
ISSN	1527-7755 ; 0732-183X
ISSN (online)	1527-7755
ISSN	0732-183X
DOI	10.1200/JCO.20.01895
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Zs.A 1847: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
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Article: Signaling pathways in self-renewing hematopoietic and leukemic stem cells: do all stem cells need a niche?

Rizo, Aleksandra / Vellenga, Edo / de Haan, Gerald / Schuringa, Jan Jacob

Human molecular genetics

2006 Volume 15 Spec No 2, Page(s) R210–9

Abstract: Many adult tissue stem cells, such as the cells of the hematopoietic system, gastrointestinal epithelium, brain, epidermis, mammary gland and lung have now been identified, all of them fulfilling a crucial role in supplying organisms with mature cells ... ...

Abstract	Many adult tissue stem cells, such as the cells of the hematopoietic system, gastrointestinal epithelium, brain, epidermis, mammary gland and lung have now been identified, all of them fulfilling a crucial role in supplying organisms with mature cells during normal homeostasis as well as in times of tissue generation or repair. Two unique features characterize adult stem cells: the ability to generate new pluripotent stem cells (to self-renew) and the ability to give rise to differentiated progeny that has lost its self-renewal capacity. Our understanding of the mechanisms that determine whether, where and when a stem cell will self-renew or differentiate is still limited, but recent advances have indicated that the stem cell microenvironment, or niche, provides essential cues that direct these cell fate decisions. Moreover, loss of control over these cell fate decisions might lead to cellular transformation and cancer. This review addresses the current understandings of the molecular mechanisms that regulate hematopoietic stem cell self-renewal in the niche and how leukemic transformation might change the dependency of leukemic stem cells on their microenvironment for self-renewal and survival.
MeSH term(s)	Animals ; Catechin/analogs & derivatives ; Cell Differentiation ; Cell Transformation, Neoplastic ; Cytokines/metabolism ; Epigenesis, Genetic ; Glycosides ; Growth Substances/metabolism ; Hematopoietic Stem Cells/cytology ; Hematopoietic Stem Cells/metabolism ; Humans ; Leukemia/metabolism ; Leukemia/pathology ; Mice ; Models, Biological ; Neoplastic Stem Cells/metabolism ; Neoplastic Stem Cells/pathology ; Pluripotent Stem Cells/cytology ; Pluripotent Stem Cells/metabolism ; Signal Transduction
Chemical Substances	Cytokines ; Glycosides ; Growth Substances ; epigeoside (134515-72-3) ; Catechin (8R1V1STN48)
Language	English
Publishing date	2006-10-15
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1108742-0
ISSN	1460-2083 ; 0964-6906
ISSN (online)	1460-2083
ISSN	0964-6906
DOI	10.1093/hmg/ddl175
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Zs.A 3469: Show issues

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Article ; Online: Repression of BMI1 in normal and leukemic human CD34(+) cells impairs self-renewal and induces apoptosis.

Rizo, Aleksandra / Olthof, Sandra / Han, Lina / Vellenga, Edo / de Haan, Gerald / Schuringa, Jan Jacob

Blood

2009 Volume 114, Issue 8, Page(s) 1498–1505

Abstract: High expression of BMI1 in acute myeloid leukemia (AML) cells is associated with an unfavorable prognosis. Therefore, the effects of down-modulation of BMI1 in normal and leukemic CD34(+) AML cells were studied using a lentiviral RNA interference ... ...

Abstract	High expression of BMI1 in acute myeloid leukemia (AML) cells is associated with an unfavorable prognosis. Therefore, the effects of down-modulation of BMI1 in normal and leukemic CD34(+) AML cells were studied using a lentiviral RNA interference approach. We demonstrate that down-modulation of BMI1 in cord blood CD34(+) cells impaired long-term expansion and progenitor-forming capacity, both in cytokine-driven liquid cultures as well as in bone marrow stromal cocultures. In addition, long-term culture-initiating cell frequencies were dramatically decreased upon knockdown of BMI1, indicating an impaired maintenance of stem and progenitor cells. The reduced progenitor and stem cell frequencies were associated with increased expression of p14ARF and p16INK4A and enhanced apoptosis, which coincided with increased levels of intracellular reactive oxygen species and reduced FOXO3A expression. In AML CD34(+) cells, down-modulation of BMI1 impaired long-term expansion, whereby self-renewal capacity was lost, as determined by the loss of replating capacity of the cultures. These phenotypes were also associated with increased expression levels of p14ARF and p16INK4A. Together our data indicate that BMI1 expression is required for maintenance and self-renewal of normal and leukemic stem and progenitor cells, and that expression of BMI1 protects cells against oxidative stress.
MeSH term(s)	Antigens, CD34/metabolism ; Apoptosis/genetics ; Blood Cell Count ; Blood Cells/drug effects ; Blood Cells/metabolism ; Cell Proliferation ; Cells, Cultured ; Fetal Blood/cytology ; Hematopoietic Stem Cells/cytology ; Hematopoietic Stem Cells/drug effects ; Hematopoietic Stem Cells/metabolism ; Hematopoietic Stem Cells/pathology ; Humans ; Infant, Newborn ; Leukemia, Myeloid, Acute/genetics ; Leukemia, Myeloid, Acute/metabolism ; Leukemia, Myeloid, Acute/pathology ; Nuclear Proteins/antagonists & inhibitors ; Nuclear Proteins/genetics ; Nuclear Proteins/metabolism ; Oxidative Stress/drug effects ; Oxidative Stress/genetics ; Polycomb Repressive Complex 1 ; Proto-Oncogene Proteins/antagonists & inhibitors ; Proto-Oncogene Proteins/genetics ; Proto-Oncogene Proteins/metabolism ; RNA Interference/physiology ; RNA, Small Interfering/pharmacology ; Reactive Oxygen Species/metabolism ; Repressor Proteins/antagonists & inhibitors ; Repressor Proteins/genetics ; Repressor Proteins/metabolism
Chemical Substances	Antigens, CD34 ; BMI1 protein, human ; Nuclear Proteins ; Proto-Oncogene Proteins ; RNA, Small Interfering ; Reactive Oxygen Species ; Repressor Proteins ; Polycomb Repressive Complex 1 (EC 2.3.2.27)
Language	English
Publishing date	2009-06-25
Publishing country	United States
Document type	Comparative Study ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80069-7
ISSN	1528-0020 ; 0006-4971
ISSN (online)	1528-0020
ISSN	0006-4971
DOI	10.1182/blood-2009-03-209734
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Article ; Online: Frontline rituximab, cyclophosphamide, doxorubicin, and prednisone with bortezomib (VR-CAP) or vincristine (R-CHOP) for non-GCB DLBCL.

Offner, Fritz / Samoilova, Olga / Osmanov, Evgenii / Eom, Hyeon-Seok / Topp, Max S / Raposo, João / Pavlov, Viacheslav / Ricci, Deborah / Chaturvedi, Shalini / Zhu, Eugene / van de Velde, Helgi / Enny, Christopher / Rizo, Aleksandra / Ferhanoglu, Burhan

Blood

2015 Volume 126, Issue 16, Page(s) 1893–1901

Abstract: This phase 2 study evaluated whether substituting bortezomib for vincristine in frontline rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) therapy could improve efficacy in non-germinal center B-cell-like diffuse large B- ...

Abstract	This phase 2 study evaluated whether substituting bortezomib for vincristine in frontline rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) therapy could improve efficacy in non-germinal center B-cell-like diffuse large B-cell lymphoma (non-GCB DLBCL), centrally confirmed by immunohistochemistry (Hans method). In total, 164 patients were randomized 1:1 to receive six 21-day cycles of rituximab 375 mg/m(2), cyclophosphamide 750 mg/m(2), and doxorubicin 50 mg/m(2), all IV day 1, prednisone 100 mg/m(2) orally days 1-5, plus either bortezomib 1.3 mg/m(2) IV days 1, 4, 8, 11 (rituximab, cyclophosphamide, doxorubicin, and prednisone with bortezomib [VR-CAP]; n = 84) or vincristine 1.4 mg/m(2) (maximum 2 mg) IV day 1 (R-CHOP; n = 80). There were no significant differences between VR-CAP and R-CHOP in complete response rate (64.5%, 66.2%; odds ratio [OR], 0.91; P = .80), overall response rate (93.4%, 98.6%; OR, 0.21; P = .11), progression-free survival (hazard ratio [HR], 1.12; P = .76), or overall survival (HR, 0.89; P = .75). Rates of grade ≥3 adverse events (AEs; 88%, 89%), serious AEs (38%, 34%), discontinuations due to AEs (7%, 3%), and deaths due to AEs (2%, 5%) were similar with VR-CAP and R-CHOP. Grade ≥3 peripheral neuropathy rates were 6% and 3%, respectively. VR-CAP did not improve efficacy vs R-CHOP in non-GCB DLBCL. This trial was registered at www.clinicaltrials.gov as #NCT01040871.
MeSH term(s)	Adult ; Aged ; Aged, 80 and over ; Antibodies, Monoclonal, Murine-Derived/administration & dosage ; Antineoplastic Combined Chemotherapy Protocols/administration & dosage ; Bortezomib/administration & dosage ; Cyclophosphamide/administration & dosage ; Disease-Free Survival ; Doxorubicin/administration & dosage ; Female ; Humans ; Lymphoma, Large B-Cell, Diffuse/drug therapy ; Lymphoma, Large B-Cell, Diffuse/mortality ; Male ; Middle Aged ; Prednisone/administration & dosage ; Rituximab/administration & dosage ; Survival Rate ; Vincristine/administration & dosage
Chemical Substances	Antibodies, Monoclonal, Murine-Derived ; R-CHOP protocol ; Rituximab (4F4X42SYQ6) ; Vincristine (5J49Q6B70F) ; Bortezomib (69G8BD63PP) ; Doxorubicin (80168379AG) ; Cyclophosphamide (8N3DW7272P) ; Prednisone (VB0R961HZT)
Language	English
Publishing date	2015-07-31
Publishing country	United States
Document type	Clinical Trial, Phase II ; Journal Article ; Multicenter Study ; Randomized Controlled Trial ; Research Support, Non-U.S. Gov't
ZDB-ID	80069-7
ISSN	1528-0020 ; 0006-4971
ISSN (online)	1528-0020
ISSN	0006-4971
DOI	10.1182/blood-2015-03-632430
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Article: Long-term maintenance of human hematopoietic stem/progenitor cells by expression of BMI1.

Rizo, Aleksandra / Dontje, Bert / Vellenga, Edo / de Haan, Gerald / Schuringa, Jan Jacob

Blood

2007 Volume 111, Issue 5, Page(s) 2621–2630

Abstract: The polycomb group (PcG) gene BMI1 has been identified as one of the key epigenetic regulators of cell fates during different stages of development in multiple murine tissues. In a clinically relevant model, we demonstrate that enforced expression of ... ...

Abstract	The polycomb group (PcG) gene BMI1 has been identified as one of the key epigenetic regulators of cell fates during different stages of development in multiple murine tissues. In a clinically relevant model, we demonstrate that enforced expression of BMI1 in cord blood CD34(+) cells results in long-term maintenance and self-renewal of human hematopoietic stem and progenitor cells. Long-term culture-initiating cell frequencies were increased upon stable expression of BMI1 and these cells engrafted more efficiently in NOD-SCID mice. Week 5 cobblestone area-forming cells (CAFCs) were replated to give rise to secondary CAFCs. Serial transplantation studies in NOD-SCID mice revealed that secondary engraftment was only achieved with cells overexpressing BMI1. Importantly, BMI1-transduced cells proliferated in stroma-free cytokine-dependent cultures for more than 20 weeks, while a stable population of approximately 1% to 5% of CD34(+) cells was preserved that retained colony-forming capacity. Whereas control cells lost most of their NOD-SCID engraftment potential after 10 days of ex vivo culturing in absence of stroma, NOD-SCID multilineage engraftment was retained by overexpression of BMI1. Thus, our data indicate that self-renewal of human hematopoietic stem cells is enhanced by BMI1, and we classify BMI1 as an intrinsic regulator of human stem/progenitor cell self-renewal.
MeSH term(s)	ADP-ribosyl Cyclase 1/metabolism ; Animals ; Antigens, CD34/metabolism ; Apoptosis ; Cell Proliferation ; Cells, Cultured ; Chimerism ; Female ; Fetal Blood/cytology ; Hematopoietic Stem Cell Transplantation ; Hematopoietic Stem Cells/cytology ; Hematopoietic Stem Cells/metabolism ; Humans ; Mice ; Mice, SCID ; Nuclear Proteins/metabolism ; Polycomb Repressive Complex 1 ; Proto-Oncogene Proteins/metabolism ; Repressor Proteins/metabolism ; Retroviridae ; Stromal Cells/cytology ; Time Factors
Chemical Substances	Antigens, CD34 ; BMI1 protein, human ; Nuclear Proteins ; Proto-Oncogene Proteins ; Repressor Proteins ; Polycomb Repressive Complex 1 (EC 2.3.2.27) ; ADP-ribosyl Cyclase 1 (EC 3.2.2.6)
Language	English
Publishing date	2007-12-21
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80069-7
ISSN	1528-0020 ; 0006-4971
ISSN (online)	1528-0020
ISSN	0006-4971
DOI	10.1182/blood-2007-08-106666
Database	MEDical Literature Analysis and Retrieval System OnLINE

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