The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Imke H Bartelink - One of the best experts on this subject based on the ideXlab platform.
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fludarabine and exposure targeted busulfan compares favorably with busulfan cyclophosphamide based regimens in pediatric hematopoietic cell transplantation maintaining efficacy with less toxicity
Biology of Blood and Marrow Transplantation, 2014Co-Authors: Imke H Bartelink, E M L Van Reij, Corinne Gerhardt, E M Van Maarseveen, A De Wildt, B Versluys, Caroline A Lindemans, Marc Bierings, Jaap Jan BoelensAbstract:Busulfan (Bu) is used as a myeloablative agent in conditioning regimens before allogeneic hematopoietic cell transplantation (allo-HCT). In line with strategies explored in adults, patient outcomes may be optimized by replacing cyclophosphamide (Cy) with or without melphalan (Mel) with fludarabine (Flu). We compared outcomes in 2 consecutive cohorts of HCT recipients with a nonmalignant HCT indication, a Myeloid Malignancy, or a lymphoid Malignancy with a contraindication for total body irradiation (TBI). Between 2009 and 2012, 64 children received Flu + Bu at a target dose of 80-95 mg·h/L, and between 2005 and 2008, 50 children received Bu targeted to 74-80 mg·h/L + Cy. In the latter group, Mel was added for patients with Myeloid Malignancy (n = 12). Possible confounding effects of calendar time were studied in 69 patients receiving a myeloablative dose of TBI between 2005 and 2012. Estimated 2-year survival and event-free survival were 82% and 78%, respectively, in the FluBu arm and 78% and 72%, respectively, in the BuCy (Mel) arm (P = not significant). Compared with the BuCy (Mel) arm, less toxicity was noted in the FluBu arm, with lower rates of acute (noninfectious) lung injury (16% versus 36%; P = .007), veno-occlusive disease (3% versus 28%; P = .003), chronic graft-versus-host disease (9% versus 26%; P = .047), adenovirus infection (3% versus 32%; P = .001), and human herpesvirus 6 infection reactivation (21% versus 44%; P = .005). Furthermore, the median duration of neutropenia was shorter in the FluBu arm (11 days versus 22 days; P < .001), and the patients in this arm required fewer transfusions. Our data indicate that Flu (160 mg/m(2)) with targeted myeloablative Bu (90 mg·h/L) is less toxic than and equally effective as BuCy (Mel) in patients with similar indications for allo-HCT.
Yuan Zhou - One of the best experts on this subject based on the ideXlab platform.
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tet2 loss dysregulates the behavior of bone marrow mesenchymal stromal cells and accelerates tet2 driven Myeloid Malignancy progression
Stem cell reports, 2018Co-Authors: Yuan Zhou, Shi Chen, Jie Bai, Weiping Yuan, Zeng Cao, Lin Liu, Jinhuan Wang, Zizhen Chen, Wen Xing, Tao ChengAbstract:TET2 is a methylcytosine dioxygenase that regulates cytosine hydroxymethylation. Although there are extensive data implicating a pivotal role of TET2 in hematopoietic stem/progenitor cells (HSPCs), the importance of TET2 in bone marrow mesenchymal stromal cells (BMSCs) remains unknown. In this study, we show that loss of TET2 in BMSCs increases cell proliferation and self-renewal and enhances osteoblast differentiation potential of BMSCs, which may in turn alter their behavior in supporting HSPC proliferation and differentiation. In addition, Tet2 loss alters BMSCs in promoting Tet2-deficiency-mediated Myeloid Malignancy progression. Tet2 loss in BMSCs also dysregulates hydroxylation of 5-methylcytosine (5mC) and the expression of genes that are key for BMSC proliferation and osteoblast differentiation, leading to alteration of biological characteristics in vivo. These results highlight the critical role of TET2 in the maintenance of BMSC functions and osteoblast differentiation and provide evidence that dysregulation of epigenetic modifiers in BMSCs contributes to the progression of Myeloid malignancies.
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tet2 loss dysregulates the behavior of mesenchymal stem cells and increases their ability to promote tet2 driven Myeloid Malignancy progression
Blood, 2016Co-Authors: Zhigang Zhao, Weiping Yuan, Feng Chun Yang, Lin Liu, Jinhuan Wang, Zizhen Chen, Wen Xing, Yuan ZhouAbstract:As a hallmark of epigenetic regulation, DNA methylation plays an important role in regulating gene expression. The TET methylcytosine dioxygenase enzymes (TET1/2/3) catalyze the conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), and can further oxidize 5hmC to 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC). Participating in the initial steps of active DNA demethylation, TETs are important regulators of cytosine methylation in the genome. Mutations and/or deletions of the TET2 gene have been reported to frequently occur in Myeloid malignancies. We and others have reported that Tet2 loss dysregulates HSC/HPC function, leading to the development of Myeloid malignancies in mice. Therefore, TET2 acts as a tumor suppressor in myelopoiesis. Although the HSC/HPC-autonomous effects of Tet2 loss on the malignant process is well established, it remains to be explored whether non-hematopoietic cells contribute to Tet2 loss mediated malignant process. Specifically, Tet2 loss may dysregulate the integrity of bone marrow niche, by which affects the malignant progression. Here, we show that while both Tet2f/f;Mx1Cre (conditional Tet2 -inactivation in hematopoietic cells) and Tet2f/f;MxfCre (germ line Tet2 -inactivation) developed Myeloid malignancies in mice, Tet2f/f;MxfCre mice had a significantly shortened survival compared to Tet2f/f;Mx1Cre mice. When WT and Tet2-/- recipient mice were transplanted with WT or Tet2-/- Lin-Sca-1+c-Kit+(LSK) cells, both genotypes of recipients receiving Tet2-/- but not WT LSK cells developed abnormal hematopoietic characteristics including monocytosis/neutrophilia and splenomegaly, resembling CMML and MPN. Interestingly, Tet2-/- recipient mice exhibited a higher incident of Myeloid malignancies and a significantly reduced survival rate compare to WT recipient mice. These data indicate that Tet2-/- bone marrow niche might promote the progression of Myeloid malignancies in Tet2-/- mice. To identify the specific niche components that are responsible for the accelerated progression of Myeloid malignancies in Tet2-/- mice, we selectively deleted Tet2 from candidate niche cell components and characterized the effects on Myeloid Malignancy development. Deletion of Tet2 in osteoblasts ( Col2.3 -cre), endothelial cells ( Ve-Cadherin -cre) and osteoclasts ( LysM -cre) have little effects on the initiation/progression of Tet2-/- -driven Myeloid malignancies. Strikingly, deletion of Tet2 in mesenchymal stem cells (MSCs) using Prx1 -cre is associated with a significantly accelerated Malignancy progression and shortened survival, suggesting that MSCs are the cell components in Tet2-/- mice play a role in the initiation/progression of Tet2-/- -driven Myeloid malignancies. Furthermore, Tet2-/- MSCs displayed a significantly increased self-renewal, proliferating and differentiation capability as assayed by the frequency of CFU-F and commitment towards osteoblasts. In addition, Tet2-/- but not WT MSCs exhibited a significantly increased supportive capacity to Tet2-/- HSC/HPC proliferation. RNA-sequencing analysis revealed that Tet2-/- MSCs exhibited a distinct gene expression profiles with 468 dysregulated genes as compared to WT MSCs. Quantitative real-time PCR confirmed that multiple genes critical for cell proliferation, osteoblast differentiation and stem cell pluripotency were down- ( Cxcl12 , Lom1, Cxcl14, Nt5e, Lfit1 and Comp ) or up- ( Sox2 , Nanog, Sp7, Bmp2, Bmp4 and Il6 ) regulated in Tet2 -/- MSCs compared to WT MSCs. Furthermore, the number of 5-hmC peaks were significantly decreased in Tet2-/- MSCs compared to WT MSCs based on whole genomic 5-hmC profiling. The majority of TET2-dependent 5hmC modifications in MSCs are located within genes. We then examined TET2 gene expression in MSCs derived from human myeloproliferative neoplasms (MPN) patients and healthy individuals and found that TET2 and 5-hmC was moderately down-regulated in MPN MSCs as compared to healthy controls. In summary, these results indicate that Tet2 loss dysregulates hydroxylation of 5-mC and gene expression in MSCs, which in turn alters their behavior and ability to promote Tet2-/- -driven Myeloid Malignancy progression. These studies could lead to the identification of additional therapeutic targets for patients with Myeloid malignancies. Disclosures No relevant conflicts of interest to declare.
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the catalytic activity of tet2 is essential for its Myeloid Malignancy suppressive function in hematopoietic stem progenitor cells
Leukemia, 2016Co-Authors: Zhigang Zhao, Shi Chen, Xingguo Zhu, Feng Pan, Yuan Zhou, Weiping Yuan, Feng Chun YangAbstract:The catalytic activity of TET2 is essential for its Myeloid Malignancy-suppressive function in hematopoietic stem/progenitor cells
Jaap Jan Boelens - One of the best experts on this subject based on the ideXlab platform.
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fludarabine and exposure targeted busulfan compares favorably with busulfan cyclophosphamide based regimens in pediatric hematopoietic cell transplantation maintaining efficacy with less toxicity
Biology of Blood and Marrow Transplantation, 2014Co-Authors: Imke H Bartelink, E M L Van Reij, Corinne Gerhardt, E M Van Maarseveen, A De Wildt, B Versluys, Caroline A Lindemans, Marc Bierings, Jaap Jan BoelensAbstract:Busulfan (Bu) is used as a myeloablative agent in conditioning regimens before allogeneic hematopoietic cell transplantation (allo-HCT). In line with strategies explored in adults, patient outcomes may be optimized by replacing cyclophosphamide (Cy) with or without melphalan (Mel) with fludarabine (Flu). We compared outcomes in 2 consecutive cohorts of HCT recipients with a nonmalignant HCT indication, a Myeloid Malignancy, or a lymphoid Malignancy with a contraindication for total body irradiation (TBI). Between 2009 and 2012, 64 children received Flu + Bu at a target dose of 80-95 mg·h/L, and between 2005 and 2008, 50 children received Bu targeted to 74-80 mg·h/L + Cy. In the latter group, Mel was added for patients with Myeloid Malignancy (n = 12). Possible confounding effects of calendar time were studied in 69 patients receiving a myeloablative dose of TBI between 2005 and 2012. Estimated 2-year survival and event-free survival were 82% and 78%, respectively, in the FluBu arm and 78% and 72%, respectively, in the BuCy (Mel) arm (P = not significant). Compared with the BuCy (Mel) arm, less toxicity was noted in the FluBu arm, with lower rates of acute (noninfectious) lung injury (16% versus 36%; P = .007), veno-occlusive disease (3% versus 28%; P = .003), chronic graft-versus-host disease (9% versus 26%; P = .047), adenovirus infection (3% versus 32%; P = .001), and human herpesvirus 6 infection reactivation (21% versus 44%; P = .005). Furthermore, the median duration of neutropenia was shorter in the FluBu arm (11 days versus 22 days; P < .001), and the patients in this arm required fewer transfusions. Our data indicate that Flu (160 mg/m(2)) with targeted myeloablative Bu (90 mg·h/L) is less toxic than and equally effective as BuCy (Mel) in patients with similar indications for allo-HCT.
Weiping Yuan - One of the best experts on this subject based on the ideXlab platform.
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tet2 loss dysregulates the behavior of bone marrow mesenchymal stromal cells and accelerates tet2 driven Myeloid Malignancy progression
Stem cell reports, 2018Co-Authors: Yuan Zhou, Shi Chen, Jie Bai, Weiping Yuan, Zeng Cao, Lin Liu, Jinhuan Wang, Zizhen Chen, Wen Xing, Tao ChengAbstract:TET2 is a methylcytosine dioxygenase that regulates cytosine hydroxymethylation. Although there are extensive data implicating a pivotal role of TET2 in hematopoietic stem/progenitor cells (HSPCs), the importance of TET2 in bone marrow mesenchymal stromal cells (BMSCs) remains unknown. In this study, we show that loss of TET2 in BMSCs increases cell proliferation and self-renewal and enhances osteoblast differentiation potential of BMSCs, which may in turn alter their behavior in supporting HSPC proliferation and differentiation. In addition, Tet2 loss alters BMSCs in promoting Tet2-deficiency-mediated Myeloid Malignancy progression. Tet2 loss in BMSCs also dysregulates hydroxylation of 5-methylcytosine (5mC) and the expression of genes that are key for BMSC proliferation and osteoblast differentiation, leading to alteration of biological characteristics in vivo. These results highlight the critical role of TET2 in the maintenance of BMSC functions and osteoblast differentiation and provide evidence that dysregulation of epigenetic modifiers in BMSCs contributes to the progression of Myeloid malignancies.
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tet2 loss dysregulates the behavior of mesenchymal stem cells and increases their ability to promote tet2 driven Myeloid Malignancy progression
Blood, 2016Co-Authors: Zhigang Zhao, Weiping Yuan, Feng Chun Yang, Lin Liu, Jinhuan Wang, Zizhen Chen, Wen Xing, Yuan ZhouAbstract:As a hallmark of epigenetic regulation, DNA methylation plays an important role in regulating gene expression. The TET methylcytosine dioxygenase enzymes (TET1/2/3) catalyze the conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), and can further oxidize 5hmC to 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC). Participating in the initial steps of active DNA demethylation, TETs are important regulators of cytosine methylation in the genome. Mutations and/or deletions of the TET2 gene have been reported to frequently occur in Myeloid malignancies. We and others have reported that Tet2 loss dysregulates HSC/HPC function, leading to the development of Myeloid malignancies in mice. Therefore, TET2 acts as a tumor suppressor in myelopoiesis. Although the HSC/HPC-autonomous effects of Tet2 loss on the malignant process is well established, it remains to be explored whether non-hematopoietic cells contribute to Tet2 loss mediated malignant process. Specifically, Tet2 loss may dysregulate the integrity of bone marrow niche, by which affects the malignant progression. Here, we show that while both Tet2f/f;Mx1Cre (conditional Tet2 -inactivation in hematopoietic cells) and Tet2f/f;MxfCre (germ line Tet2 -inactivation) developed Myeloid malignancies in mice, Tet2f/f;MxfCre mice had a significantly shortened survival compared to Tet2f/f;Mx1Cre mice. When WT and Tet2-/- recipient mice were transplanted with WT or Tet2-/- Lin-Sca-1+c-Kit+(LSK) cells, both genotypes of recipients receiving Tet2-/- but not WT LSK cells developed abnormal hematopoietic characteristics including monocytosis/neutrophilia and splenomegaly, resembling CMML and MPN. Interestingly, Tet2-/- recipient mice exhibited a higher incident of Myeloid malignancies and a significantly reduced survival rate compare to WT recipient mice. These data indicate that Tet2-/- bone marrow niche might promote the progression of Myeloid malignancies in Tet2-/- mice. To identify the specific niche components that are responsible for the accelerated progression of Myeloid malignancies in Tet2-/- mice, we selectively deleted Tet2 from candidate niche cell components and characterized the effects on Myeloid Malignancy development. Deletion of Tet2 in osteoblasts ( Col2.3 -cre), endothelial cells ( Ve-Cadherin -cre) and osteoclasts ( LysM -cre) have little effects on the initiation/progression of Tet2-/- -driven Myeloid malignancies. Strikingly, deletion of Tet2 in mesenchymal stem cells (MSCs) using Prx1 -cre is associated with a significantly accelerated Malignancy progression and shortened survival, suggesting that MSCs are the cell components in Tet2-/- mice play a role in the initiation/progression of Tet2-/- -driven Myeloid malignancies. Furthermore, Tet2-/- MSCs displayed a significantly increased self-renewal, proliferating and differentiation capability as assayed by the frequency of CFU-F and commitment towards osteoblasts. In addition, Tet2-/- but not WT MSCs exhibited a significantly increased supportive capacity to Tet2-/- HSC/HPC proliferation. RNA-sequencing analysis revealed that Tet2-/- MSCs exhibited a distinct gene expression profiles with 468 dysregulated genes as compared to WT MSCs. Quantitative real-time PCR confirmed that multiple genes critical for cell proliferation, osteoblast differentiation and stem cell pluripotency were down- ( Cxcl12 , Lom1, Cxcl14, Nt5e, Lfit1 and Comp ) or up- ( Sox2 , Nanog, Sp7, Bmp2, Bmp4 and Il6 ) regulated in Tet2 -/- MSCs compared to WT MSCs. Furthermore, the number of 5-hmC peaks were significantly decreased in Tet2-/- MSCs compared to WT MSCs based on whole genomic 5-hmC profiling. The majority of TET2-dependent 5hmC modifications in MSCs are located within genes. We then examined TET2 gene expression in MSCs derived from human myeloproliferative neoplasms (MPN) patients and healthy individuals and found that TET2 and 5-hmC was moderately down-regulated in MPN MSCs as compared to healthy controls. In summary, these results indicate that Tet2 loss dysregulates hydroxylation of 5-mC and gene expression in MSCs, which in turn alters their behavior and ability to promote Tet2-/- -driven Myeloid Malignancy progression. These studies could lead to the identification of additional therapeutic targets for patients with Myeloid malignancies. Disclosures No relevant conflicts of interest to declare.
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the catalytic activity of tet2 is essential for its Myeloid Malignancy suppressive function in hematopoietic stem progenitor cells
Leukemia, 2016Co-Authors: Zhigang Zhao, Shi Chen, Xingguo Zhu, Feng Pan, Yuan Zhou, Weiping Yuan, Feng Chun YangAbstract:The catalytic activity of TET2 is essential for its Myeloid Malignancy-suppressive function in hematopoietic stem/progenitor cells
Yoshihiro Inamoto - One of the best experts on this subject based on the ideXlab platform.
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clinical utility of wilms tumor 1 monitoring in patients with Myeloid Malignancy and prior allogeneic hematopoietic stem cell transplantation
Biology of Blood and Marrow Transplantation, 2017Co-Authors: Kazuko Ino, Shigeo Fuji, Kinuko Tajima, Takashi Tanaka, Keiji Okinaka, Yoshihiro Inamoto, Saiko Kurosawa, Sungwon Kim, Naoyuki Katayama, Takahiro FukudaAbstract:Abstract Although allogeneic hematopoietic stem cell transplantation (allo-HSCT) is 1 of the standard treatments for Myeloid Malignancy, relapse remains a major obstacle to cure. Early detection of relapse by monitoring of minimal residual disease (MRD) may enable us to intervene pre-emptively and potentially prevent overt relapse. Wilms' tumor 1 (WT1) is well known as a pan-leukemic marker. We retrospectively examined serially monitored WT1 levels of peripheral blood in 98 patients (84 with acute Myeloid leukemia and 14 with myelodysplastic syndrome). At the time of allo-HSCT, 49 patients (50%) were in complete remission. Patients were divided into 3 groups according to WT1 levels ( 500 copies/µg RNA). The cumulative incidence of relapse (CIR) and overall survival (OS) differed statistically according to the WT1 levels before allo-HSCT and at days 30 and 60 after allo-HSCT. In multivariate analysis, WT1 >500 copies/µg RNA before and at day 60 after allo-HSCT and WT1 ≥50 copies/µg RNA at day 30 were correlated with CIR. Moreover, WT1 >500 copies/µg RNA at day 60 after allo-HSCT was only correlated with worse OS. Our data suggest that serial monitoring of WT1 levels in peripheral blood may be useful for MRD monitoring and as a predictor of hematological relapse in allo-HSCT.
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phase ii study of dose modified busulfan by real time targeting in allogeneic hematopoietic stem cell transplantation for Myeloid Malignancy
Cancer Science, 2012Co-Authors: Yachiyo Kuwatsuka, Yoshihiro Inamoto, Akio Kohno, Seitaro Terakura, Shigeki Saito, Kazuyuki Shimada, Takahiko Yasuda, Koichi Miyamura, Masashi Sawa, Makoto MurataAbstract:We aimed to evaluate the efficacy and safety of allogeneic hematopoietic stem cell transplantation with targeted oral busulfan (BU) and cyclophosphamide (CY) in a phase II study. Busulfan (1.0 mg/kg) was given initially in six doses. Based on the estimated concentration at steady state after the first dose of BU, subsequent (7th–16th) doses were adjusted to obtain a targeted overall concentration at steady state of 700–900 ng/mL. The primary endpoint was 1-year overall survival (OS). Fifty patients were registered and 46 (median age, 53 years; range, 18–62 years) received planned transplant, including 24 with AML, 16 with myelodysplastic syndrome, and six with CML. Fourteen patients were categorized as standard risk. Nineteen patients received transplant from human leukocyte antigen-identical siblings, 27 from unrelated donors. The BU dose required reduction in 32 patients and escalation in six patients. One-year OS was 65% (95% confidence interval, 50–77%). Cumulative incidence of hepatic sinusoidal obstruction syndrome was 11%. One-year transplant-related mortality was 18%. Both OS and transplant-related mortality were favorable in this study, including patients of older age and with high risk diseases. Individual dose adjustment based on BU pharmacokinetics was feasible and effective in the current phase II study. This trial is registered in the University Hospital Medical Information Network Clinical Trial Registry System (UMIN-CTR, ID:C000000156).
