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Gautam Borthakur - One of the best experts on this subject based on the ideXlab platform.
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clinical outcomes of patients with chronic myeloid leukemia with concurrent Core Binding Factor rearrangement and philadelphia chromosome
Clinical Lymphoma Myeloma & Leukemia, 2021Co-Authors: Kiyomi Morita, Guillermo Garciamanero, Elias Jabbour, Gautam Borthakur, Farhad Ravandi, Naval Daver, Ghayas C Issa, Joseph D Khoury, William G Wierda, Naveen PemmarajuAbstract:Abstract Background Acquisition of additional cytogenetic abnormalities (ACAs) in addition to Philadelphia chromosome is frequently observed in patients with chronic myeloid leukemia (CML) in advanced phase. The presence of Core Binding Factor (CBF) translocations determines the diagnosis of acute myeloid leukemia regardless of blast percentage, and CBF rearrangements are rarely identified as ACAs. Patients and Methods A retrospective chart review of patients with CML who had CBF rearrangement, t(8;21) or inv(16), in Philadelphia chromosome-positive clones was conducted. Additional cases of CML with CBF rearrangements were identified through literature review. Results Between August 1997 and December 2014, we identified 11 patients who had Philadelphia chromosome and CBF rearrangement in the same clones: 1 (9%) with t(8;21) and 10 (91%) with inv(16). Nine (82%) patients were in blast phase, and 2 (18%) in second chronic phase. Four (36%) patients received tyrosine kinase inhibitor monotherapy, 2 (18%) received tyrosine kinase inhibitor and chemotherapy, and 5 (45%) received chemotherapy only. Three (27%) patients achieved complete remission with incomplete count recovery, and 4 (36%) had no response after the initial therapy. Three (27%) patients underwent allogeneic stem cell transplantation. The median event-free survival and overall survival for the 11 patients were 2 months and 6 months, respectively. Literature review identified 14 patients with CML with CBF rearrangement with a median overall survival of 14 months. Conclusion Acquisition of CBF rearrangement in addition to Philadelphia chromosome is a rare phenomenon associated with poor prognosis. CBF rearrangements as ACAs in patients with CML can be considered high-risk features.
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Core Binding Factor acute myelogenous leukemia-2021 treatment algorithm
'Springer Science and Business Media LLC', 2021Co-Authors: Gautam Borthakur, Hagop KantarjianAbstract:Abstract Core Binding Factor acute myelogenous leukemia (CBF-AML), characterized by the presence of either t(8;21) (q22;q22) or inv(16) (p13q22)/t(16;16), is considered good-risk AML in the context of cytarabine based intensive chemotherapy. Still, outcome can be improved significantly through the effective implementation of available therapeutic measures and appropriate disease monitoring. The incorporation of gemtuzumab ozogamicin into frontline therapy should be standard. Cytarabine based induction/consolidation regimen may be combined with anthracycline (3 + 7 standard) or antimetabolite, fludarabine. Serial quantitative polymerase chain reaction (QPCR) monitoring of unique fusion transcripts allows monitoring for measurable residual disease clearance; this allows for better prognostication and well as treatment modifications
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comparison of therapy related and de novo Core Binding Factor acute myeloid leukemia a bone marrow pathology group study
American Journal of Hematology, 2020Co-Authors: Heesun J Rogers, Gautam Borthakur, Xiaoqiong Wang, Adam R Davis, Beenu Thakral, Sa A Wang, Miguel Dario Cantu, Elizabeth Margolskee, John Philip, Madina SukhanovaAbstract:: This multi-institutional study retrospectively evaluated clinicopathologic and genetic characteristics in 351 patients with Core-Binding-Factor acute myeloid leukemia (CBF-AML), comprising 69 therapy-related (t-CBF-AML) and 282 de novo cases. T-CBF-AML patients were older, had lower WBC counts, and slightly higher hemoglobin than patients with de novo disease. Secondary cytogenetic abnormalities were more frequent in patients with de novo disease than t-CBF-AML (57.1% vs 41.1%, p=0.026). Patients with secondary cytogenetic abnormalities had longer overall survival (OS) than those without abnormalities (median 190 vs 87 months, p=0.021); trisomy 8, trisomy 22, and loss of the X or Y chromosome were associated with longer OS. In the 165 cases performed targeted gene sequencing, pathogenic mutations were detected in 75.7% of cases and were more frequent in de novo than in therapy-related disease (p=0.013). Mutations were found in N/KRAS (37.0%), FLT3 (27.8%), KIT (17.2%), TET2 (4.9%), and ASXL1 (3.9%). TET2 mutations were associated with shorter OS (p=0.012) while N/KRAS mutation was associated with longer OS in t(8;21) AML patients (p=0.001). KIT mutation did not show prognostic significance in this cohort. Although they received similar therapy, t-CBF-AML patients had shorter OS than de novo patients (median 69 vs 190 months, p=0.038). In multivariate analysis of all patients, older age and absence of any secondary cytogenetic abnormalities were significant predictors of shorter OS. Among the t-CBF-AML subset, age and hemoglobin were significant on multivariate analysis. This study demonstrated that although de novo and t-CBF-AML patients share many features, t-CBF-AML patients have worse clinical outcome than de novo patients. This article is protected by copyright. All rights reserved.
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comparison of therapy related and de novo Core Binding Factor acute myeloid leukemia a bone marrow pathology group study
American Journal of Hematology, 2020Co-Authors: Heesun J Rogers, Gautam Borthakur, Xiaoqiong Wang, Adam R Davis, Beenu Thakral, Sa A Wang, Miguel Dario Cantu, Elizabeth Margolskee, Yan Xie, John PhilipAbstract:This multi-institutional study retrospectively evaluated clinicopathologic and genetic characteristics in 351 patients with Core-Binding-Factor acute myeloid leukemia (CBF-AML), comprising 69 therapy-related (t-CBF-AML) and 282 de novo cases. The T-CBF-AML patients were older, had lower WBC counts, and slightly higher hemoglobin than patients with de novo disease. Secondary cytogenetic abnormalities were more frequent in patients with de novo disease than t-CBF-AML (57.1% vs 41.1%, P = .026). Patients with secondary cytogenetic abnormalities had longer overall survival (OS) than those without abnormalities (median 190 vs 87 months, P = .021); trisomy 8, trisomy 22, and loss of the X or Y chromosome were associated with longer OS. In the 165 cases performed of targeted gene sequencing, pathogenic mutations were detected in 75.7% of cases, and were more frequent in de novo than in therapy-related disease (P = .013). Mutations were found in N/KRAS (37.0%), FLT3 (27.8%), KIT (17.2%), TET2 (4.9%), and ASXL1 (3.9%). The TET2 mutations were associated with shorter OS (P = .012) while N/KRAS mutation was associated with longer OS in t(8;21) AML patients (P = .001). The KIT mutation did not show prognostic significance in this cohort. Although they received similar therapy, t-CBF-AML patients had shorter OS than de novo patients (median 69 vs 190 months, P = .038). In multivariate analysis of all patients, older age and absence of any secondary cytogenetic abnormalities were significant predictors of shorter OS. Among the t-CBF-AML subset, age and hemoglobin were significant on multivariate analysis. This study demonstrated that although de novo and t-CBF-AML patients share many features, t-CBF-AML patients have worse clinical outcome than de novo patients.
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outcomes of patients with relapsed Core Binding Factor positive acute myeloid leukemia
Clinical Lymphoma Myeloma & Leukemia, 2018Co-Authors: Maliha Khan, Jorge E. Cortes, Hagop M. Kantarjian, Farhad Ravandi, Sherry Pierce, Wei Qiao, Mohanad Alzubaidi, Gautam BorthakurAbstract:Abstract Purpose To determine the Factors associated with outcomes in patients with Core Binding Factor acute myeloid leukemia (CBF-AML) in first relapse. Material and Methods We conducted a retrospective analysis of 92 patients with CBF-AML in first relapse who presented to our institution from 1990-2014. Clinical and demographic parameters were included in univariate and multivariate Cox proportional hazards regression model to predict overall survival. Results Among the 92 relapsed patients, 60 (65%) patients had inv (16) and 32 (35%) had t (8;21). The median survival for patients with inv(16) cytogenetic group was 15.6 months (range 10.32 to 20.88 months) while for the t(8;21) group was 9 months (range 3.68 to 14.32) ( P = .004). Univariate Cox model analysis showed that increased age, high white blood cell count, t (8;21) cytogenetic group, and high bone marrow blast percentage were associated with poor overall outcome, while stem cell transplant intervention was associated with better survival. Additional cytogenetic aberrations at relapse were not associated with survival outcomes ( P = .4). Multivariate Cox model analysis showed that t(8;21) cytogenetic group has more hazard of death after adjusting, age, marrow blast percentage, blood cell count, and stem cell transplant(hazard ratio 1.802; P = .02). Conclusion Among patients with relapsed CBF-AML, median survival was less than a year and half and the outcome was worse in patients with t (8;21). Despite the relatively better outcomes, dedicated clinical trials are needed to improve the outcome in all patients with relapsed CBF-AML.
Alan D Friedman - One of the best experts on this subject based on the ideXlab platform.
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the Core Binding Factor cbf alpha interaction domain and the smooth muscle myosin heavy chain smmhc segment of cbfbeta smmhc are both required to slow cell proliferation
Journal of Biological Chemistry, 1998Co-Authors: Wangsen Cao, Neeraj Adya, Martin Britosbray, Pu Paul Liu, Alan D FriedmanAbstract:We have expressed several variants of Core Binding Factor beta (CBFbeta)-smooth muscle myosin heavy chain (SMMHC) from the metallothionein promoter in Ba/F3 cells. Deletion of amino acids 2-11 from the CBFbeta segment, required for interaction with CBFalpha, prevented CBFbeta-SMMHC from inhibiting CBF DNA Binding and cell cycle progression. Deletion of 283 carboxyl-terminal residues from the SMMHC domain, required for multimerization, also inactivated CBFbeta-SMMHC. Nuclear expression of CBFbeta(Delta2-11)-SMMHC was decreased relative to CBFbeta-SMMHC. CBFbeta(Delta2-11)-SMMHC linked to a nuclear localization signal still did not slow cell growth. The ability of each CBFbeta-SMMHC variant to inhibit CBF DNA Binding and cell proliferation correlated with its ability to inhibit transactivation by an AML1-VP16 fusion protein. Thus, CBFbeta-SMMHC slows cell cycle progression from G1 to S phase by inhibiting CBF DNA Binding and transactivation.
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the Core Binding Factor cbf α interaction domain and the smooth muscle myosin heavy chain smmhc segment of cbfβ smmhc are both required to slow cell proliferation
Journal of Biological Chemistry, 1998Co-Authors: Wangsen Cao, Neeraj Adya, Martin Britosbray, Pu Paul Liu, Alan D FriedmanAbstract:We have expressed several variants of Core Binding Factor beta (CBFbeta)-smooth muscle myosin heavy chain (SMMHC) from the metallothionein promoter in Ba/F3 cells. Deletion of amino acids 2-11 from the CBFbeta segment, required for interaction with CBFalpha, prevented CBFbeta-SMMHC from inhibiting CBF DNA Binding and cell cycle progression. Deletion of 283 carboxyl-terminal residues from the SMMHC domain, required for multimerization, also inactivated CBFbeta-SMMHC. Nuclear expression of CBFbeta(Delta2-11)-SMMHC was decreased relative to CBFbeta-SMMHC. CBFbeta(Delta2-11)-SMMHC linked to a nuclear localization signal still did not slow cell growth. The ability of each CBFbeta-SMMHC variant to inhibit CBF DNA Binding and cell proliferation correlated with its ability to inhibit transactivation by an AML1-VP16 fusion protein. Thus, CBFbeta-SMMHC slows cell cycle progression from G1 to S phase by inhibiting CBF DNA Binding and transactivation.
Nancy A. Speck - One of the best experts on this subject based on the ideXlab platform.
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a tool compound targeting the Core Binding Factor runt domain to disrupt Binding to cbfβ in leukemic cells
Leukemia & Lymphoma, 2018Co-Authors: Anuradha Illendula, Jolanta Grembecka, Charles Schmidt, Yunpeng Zhou, Virginie Esain, Wanda Kwan, Isaura M Frost, Trista E North, Roger A Rajewski, Nancy A. SpeckAbstract:The Core Binding Factor (CBF) gene RUNX1 is a target of chromosomal translocations in leukemia, including t(8;21) in acute myeloid leukemia (AML). Normal CBF function is essential for activity of AML1-ETO, product of the t(8;21), and for survival of several leukemias lacking RUNX1 mutations. Using virtual screening and optimization, we developed Runt domain inhibitors which bind to the Runt domain and disrupt its interaction with CBFβ. On-target activity was demonstrated by the Runt domain inhibitors' ability to depress hematopoietic cell formation in zebrafish embryos, reduce growth and induce apoptosis of t(8;21) AML cell lines, and reduce progenitor activity of mouse and human leukemia cells harboring the t(8;21), but not normal bone marrow cells. Runt domain inhibitors had similar effects on murine and human T cell acute lymphocytic leukemia (T-ALL) cell lines. Our results confirmed that Runt domain inhibitors might prove efficacious in various AMLs and in T-ALL.
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the Core Binding Factor beta subunit is required for bone formation and hematopoietic maturation
Nature Genetics, 2002Co-Authors: Janelle Miller, Alan Horner, Terryl Stacy, Christopher H Lowrey, Jane B Lian, Gary S Stein, Glen H Nuckolls, Nancy A. SpeckAbstract:Core-Binding Factor β (Cbfβ) is the common non-DNA-Binding subunit of the Cbf family of heterodimeric transcription Factors. Mice deficient in Cbfβ have a severe block in fetal liver hematopoiesis at the stage of hematopoietic stem cell (HSC) emergence1,2. Here we show that by providing Cbfβ function in endothelial cells and hematopoietic progenitors we can rescue fetal liver hematopoiesis in Cbfβ-deficient embryos. The rescued mice die at birth, however, with severe defects in skeletal development, though intramembranous ossification occurs to some extent. Fetal liver hematopoiesis is restored at embryonic day (E) 12.5, but by E17.5 significant impairments in lymphopoiesis and myelopoiesis are observed. Thus, we conclude that the Cbfβ subunit is required for HSC emergence, bone formation and normal differentiation of lymphoid and myeloid lineage cells.
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the leukemic protein Core Binding Factor beta cbfbeta smooth muscle myosin heavy chain sequesters cbfalpha2 into cytoskeletal filaments and aggregates
Molecular and Cellular Biology, 1998Co-Authors: Neeraj Adya, Nancy A. Speck, Terryl Stacy, Pengfei LiuAbstract:The fusion gene CBFB-MYH11 is generated by the chromosome 16 inversion associated with acute myeloid leukemias. This gene encodes a chimeric protein involving the Core Binding Factor beta (CBFbeta) and the smooth-muscle myosin heavy chain (SMMHC). Mouse model studies suggest that this chimeric protein CBFbeta-SMMHC dominantly suppresses the function of CBF, a heterodimeric transcription Factor composed of DNA Binding subunits (CBFalpha1 to 3) and a non-DNA Binding subunit (CBFbeta). This dominant suppression results in the blockage of hematopoiesis in mice and presumably contributes to leukemogenesis. We used transient-transfection assays, in combination with immunofluorescence and green fluorescent protein-tagged proteins, to monitor subcellular localization of CBFbeta-SMMHC, CBFbeta, and CBFalpha2 (also known as AML1 or PEBP2alphaB). When expressed individually, CBFalpha2 was located in the nuclei of transfected cells, whereas CBFbeta was distributed throughout the cell. On the other hand, CBFbeta-SMMHC formed filament-like structures that colocalized with actin filaments. Upon cotransfection, CBFalpha2 was able to drive localization of CBFbeta into the nucleus in a dose-dependent manner. In contrast, CBFalpha2 colocalized with CBFbeta-SMMHC along the filaments instead of localizing to the nucleus. Deletion of the CBFalpha-interacting domain within CBFbeta-SMMHC abolished this CBFalpha2 sequestration, whereas truncation of the C-terminal-end SMMHC domain led to nuclear localization of CBFbeta-SMMHC when coexpressed with CBFalpha2. CBFalpha2 sequestration by CBFbeta-SMMHC was further confirmed in vivo in a knock-in mouse model. These observations suggest that CBFbeta-SMMHC plays a dominant negative role by sequestering CBFalpha2 into cytoskeletal filaments and aggregates, thereby disrupting CBFalpha2-mediated regulation of gene expression.
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cooperative Binding of ets 1 and Core Binding Factor to dna
Molecular and Cellular Biology, 1994Co-Authors: David Wotton, Nancy A. Speck, Jacques Ghysdael, Shuwen Wang, Michael John OwenAbstract:Two phorbol ester-inducible elements (beta E2 and beta E3) within the human T-cell receptor beta gene enhancer each contain consensus Binding sites for the Ets and Core Binding Factor (CBF) transcription Factor families. Recombinant Ets-1 and purified CBF bound individually to beta E2 and beta E3, in which the Ets and Core sites are directly adjacent. In this report, we show that CBF and Ets-1 bind together to beta E2 and beta E3 and that Ets-1-CBF-DNA complexes are favored over the Binding of either protein alone to beta E2. Formation of Ets-1-CBF-DNA complexes increased the affinity of Ets-1-DNA interactions and decreased the rate of dissociation of CBF from DNA. Ets-1-CBF-DNA complexes were not observed when either the Ets or Core site was mutated. The spatial requirements for the cooperative interaction of Ets-1 and CBF were analyzed by oligonucleotide mutagenesis and Binding site selection experiments. Core and Ets sites were coselected, and there appeared to be little constraint on the relative orientation and spacing of the two sites. These results demonstrate that CBF and Ets-1 form a high-affinity DNA-Binding complex when both of their cognate sites are present and that the relative spacing and orientation of the two sites are unimportant. Ets and Core sites are found in several T-cell-specific enhancers, suggesting that this interaction is of general importance in T-cell-specific transcription.
Neeraj Adya - One of the best experts on this subject based on the ideXlab platform.
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the leukemic protein Core Binding Factor beta cbfbeta smooth muscle myosin heavy chain sequesters cbfalpha2 into cytoskeletal filaments and aggregates
Molecular and Cellular Biology, 1998Co-Authors: Neeraj Adya, Nancy A. Speck, Terryl Stacy, Pengfei LiuAbstract:The fusion gene CBFB-MYH11 is generated by the chromosome 16 inversion associated with acute myeloid leukemias. This gene encodes a chimeric protein involving the Core Binding Factor beta (CBFbeta) and the smooth-muscle myosin heavy chain (SMMHC). Mouse model studies suggest that this chimeric protein CBFbeta-SMMHC dominantly suppresses the function of CBF, a heterodimeric transcription Factor composed of DNA Binding subunits (CBFalpha1 to 3) and a non-DNA Binding subunit (CBFbeta). This dominant suppression results in the blockage of hematopoiesis in mice and presumably contributes to leukemogenesis. We used transient-transfection assays, in combination with immunofluorescence and green fluorescent protein-tagged proteins, to monitor subcellular localization of CBFbeta-SMMHC, CBFbeta, and CBFalpha2 (also known as AML1 or PEBP2alphaB). When expressed individually, CBFalpha2 was located in the nuclei of transfected cells, whereas CBFbeta was distributed throughout the cell. On the other hand, CBFbeta-SMMHC formed filament-like structures that colocalized with actin filaments. Upon cotransfection, CBFalpha2 was able to drive localization of CBFbeta into the nucleus in a dose-dependent manner. In contrast, CBFalpha2 colocalized with CBFbeta-SMMHC along the filaments instead of localizing to the nucleus. Deletion of the CBFalpha-interacting domain within CBFbeta-SMMHC abolished this CBFalpha2 sequestration, whereas truncation of the C-terminal-end SMMHC domain led to nuclear localization of CBFbeta-SMMHC when coexpressed with CBFalpha2. CBFalpha2 sequestration by CBFbeta-SMMHC was further confirmed in vivo in a knock-in mouse model. These observations suggest that CBFbeta-SMMHC plays a dominant negative role by sequestering CBFalpha2 into cytoskeletal filaments and aggregates, thereby disrupting CBFalpha2-mediated regulation of gene expression.
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the Core Binding Factor cbf alpha interaction domain and the smooth muscle myosin heavy chain smmhc segment of cbfbeta smmhc are both required to slow cell proliferation
Journal of Biological Chemistry, 1998Co-Authors: Wangsen Cao, Neeraj Adya, Martin Britosbray, Pu Paul Liu, Alan D FriedmanAbstract:We have expressed several variants of Core Binding Factor beta (CBFbeta)-smooth muscle myosin heavy chain (SMMHC) from the metallothionein promoter in Ba/F3 cells. Deletion of amino acids 2-11 from the CBFbeta segment, required for interaction with CBFalpha, prevented CBFbeta-SMMHC from inhibiting CBF DNA Binding and cell cycle progression. Deletion of 283 carboxyl-terminal residues from the SMMHC domain, required for multimerization, also inactivated CBFbeta-SMMHC. Nuclear expression of CBFbeta(Delta2-11)-SMMHC was decreased relative to CBFbeta-SMMHC. CBFbeta(Delta2-11)-SMMHC linked to a nuclear localization signal still did not slow cell growth. The ability of each CBFbeta-SMMHC variant to inhibit CBF DNA Binding and cell proliferation correlated with its ability to inhibit transactivation by an AML1-VP16 fusion protein. Thus, CBFbeta-SMMHC slows cell cycle progression from G1 to S phase by inhibiting CBF DNA Binding and transactivation.
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the Core Binding Factor cbf α interaction domain and the smooth muscle myosin heavy chain smmhc segment of cbfβ smmhc are both required to slow cell proliferation
Journal of Biological Chemistry, 1998Co-Authors: Wangsen Cao, Neeraj Adya, Martin Britosbray, Pu Paul Liu, Alan D FriedmanAbstract:We have expressed several variants of Core Binding Factor beta (CBFbeta)-smooth muscle myosin heavy chain (SMMHC) from the metallothionein promoter in Ba/F3 cells. Deletion of amino acids 2-11 from the CBFbeta segment, required for interaction with CBFalpha, prevented CBFbeta-SMMHC from inhibiting CBF DNA Binding and cell cycle progression. Deletion of 283 carboxyl-terminal residues from the SMMHC domain, required for multimerization, also inactivated CBFbeta-SMMHC. Nuclear expression of CBFbeta(Delta2-11)-SMMHC was decreased relative to CBFbeta-SMMHC. CBFbeta(Delta2-11)-SMMHC linked to a nuclear localization signal still did not slow cell growth. The ability of each CBFbeta-SMMHC variant to inhibit CBF DNA Binding and cell proliferation correlated with its ability to inhibit transactivation by an AML1-VP16 fusion protein. Thus, CBFbeta-SMMHC slows cell cycle progression from G1 to S phase by inhibiting CBF DNA Binding and transactivation.
Toshihisa Komori - One of the best experts on this subject based on the ideXlab platform.
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Core Binding Factor beta interacts with runx2 and is required for skeletal development
Nature Genetics, 2002Co-Authors: Carolina A Yoshida, Masanobu Satake, Tatsuya Furuichi, Ryo Fukuyama, Kenji Takada, Shinji Kobayashi, Naoko Kanatani, Toshihisa KomoriAbstract:Core-Binding Factor β (CBFβ, also called polyomavirus enhancer Binding protein 2β (PEBP2B)) is associated with an inversion of chromosome 16 and is associated with acute myeloid leukemia in humans1. CBFβ forms a heterodimer with RUNX1 (runt-related transcription Factor 1), which has a DNA Binding domain homologous to the pair-rule protein runt in Drosophila melanogaster. Both RUNX1 and CBFβ are essential for hematopoiesis2,3,4,5,6. Haploinsufficiency of another runt-related protein, RUNX2 (also called CBFA1), causes cleidocranial dysplasia in humans7 and is essential in skeletal development by regulating osteoblast differentiation and chondrocyte maturation8,9,10,11,12,13,14,15. Mice deficient in Cbfb (Cbfb−/−) die at midgestation4,5,6, so the function of Cbfβ in skeletal development has yet to be ascertained. To investigate this issue, we rescued hematopoiesis of Cbfb−/− mice by introducing Cbfb using the Gata1 promoter. The rescued Cbfb−/− mice recapitulated fetal liver hematopoiesis in erythroid and megakaryocytic lineages and survived until birth, but showed severely delayed bone formation. Although mesenchymal cells differentiated into immature osteoblasts, intramembranous bones were poorly formed. The maturation of chondrocytes into hypertrophic cells was markedly delayed, and no endochondral bones were formed. Electrophoretic mobility shift assays and reporter assays showed that Cbfβ was necessary for the efficient DNA Binding of Runx2 and for Runx2-dependent transcriptional activation. These findings indicate that Cbfβ is required for the function of Runx2 in skeletal development.
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Core-Binding Factor beta interacts with Runx2 and is required for skeletal development.
Nature Genetics, 2002Co-Authors: Carolina A Yoshida, Masanobu Satake, Tatsuya Furuichi, Ryo Fukuyama, Kenji Takada, Shinji Kobayashi, Naoko Kanatani, Toshihisa KomoriAbstract:Core-Binding Factor beta (CBFbeta, also called polyomavirus enhancer Binding protein 2beta (PEBP2B)) is associated with an inversion of chromosome 16 and is associated with acute myeloid leukemia in humans. CBFbeta forms a heterodimer with RUNX1 (runt-related transcription Factor 1), which has a DNA Binding domain homologous to the pair-rule protein runt in Drosophila melanogaster. Both RUNX1 and CBFbeta are essential for hematopoiesis. Haploinsufficiency of another runt-related protein, RUNX2 (also called CBFA1), causes cleidocranial dysplasia in humans and is essential in skeletal development by regulating osteoblast differentiation and chondrocyte maturation. Mice deficient in Cbfb (Cbfb(-/-)) die at midgestation, so the function of Cbfbeta in skeletal development has yet to be ascertained. To investigate this issue, we rescued hematopoiesis of Cbfb(-/-) mice by introducing Cbfb using the Gata1 promoter. The rescued Cbfb(-/-) mice recapitulated fetal liver hematopoiesis in erythroid and megakaryocytic lineages and survived until birth, but showed severely delayed bone formation. Although mesenchymal cells differentiated into immature osteoblasts, intramembranous bones were poorly formed. The maturation of chondrocytes into hypertrophic cells was markedly delayed, and no endochondral bones were formed. Electrophoretic mobility shift assays and reporter assays showed that Cbfbeta was necessary for the efficient DNA Binding of Runx2 and for Runx2-dependent transcriptional activation. These findings indicate that Cbfbeta is required for the function of Runx2 in skeletal development.
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absence of fetal liver hematopoiesis in mice deficient in transcriptional coactivator Core Binding Factor beta
Proceedings of the National Academy of Sciences of the United States of America, 1996Co-Authors: Koichi Sasaki, Hideshi Yagi, Roderick T Bronson, Kumi Tominaga, Tatsuro Matsunashi, Kenji Deguchi, Yoshihiko Tani, Tadamitsu Kishimoto, Toshihisa KomoriAbstract:Core Binding Factor beta (CBF beta) is considered to be a transcriptional coactivator that dimerizes with transcription Factors Core Binding Factor alpha 1 (CBFA1), -2, and -3, and enhances DNA Binding capacity of these transcription Factors. CBF beta and CBFA2, which is also called acute myeloid leukemia 1 gene, are frequently involved in chromosomal translocations in human leukemia. To elucidate the function of CBF beta, mice carrying a mutation in the Cbfb locus were generated. Homozygous mutant embryos died between embryonic days 11.5-13.5 due to hemorrhage in the central nervous system. Mutant embryos had primitive erythropoiesis in yolk sac but lacked definitive hematopoiesis in fetal liver. In the yolk sac of mutant embryos, no erythroid or myeloid progenitors of definitive hematopoietic origin were detected, and the expression of flk-2/flt-3, the marker gene for early precursor cells of definitive hematopoiesis, was absent. These data suggest that Cbfb is essential for definitive hematopoiesis in liver, especially for the commitment to early hematopoietic precursor cells.