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Andrew L. Folpe - One of the best experts on this subject based on the ideXlab platform.
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cd1a immunopositivity in perivascular epithelioid cell Neoplasms true expression or technical artifact a streptavidin biotin and polymer based detection system immunohistochemical study of perivascular epithelioid cell Neoplasms and their morphologic
Human Pathology, 2011Co-Authors: William A Ahrens, Andrew L. FolpeAbstract:Summary Perivascular epithelioid cell Neoplasms comprise a family of rare Neoplasms composed of morphologically distinctive perivascular epithelioid Cells exhibiting a “myomelanocytic” immunophenotype. The distinction of perivascular epithelioid cell Neoplasms from other tumors with melanocytic and smooth muscle differentiation can be difficult. A recent study has suggested that perivascular epithelioid cell Neoplasms routinely express CD1a, a Langerhans cell–associated transmembrane glycoprotein involved in antigen presentation and that expression of this marker may be helpful in the distinction of perivascular epithelioid cell Neoplasms from various mimics. We evaluated a series of perivascular epithelioid cell Neoplasms and potential mimics for CD1a expression. A total of 54 cases (27 perivascular epithelioid cell Neoplasms, 11 leiomyosarcomas, 10 melanomas, 6 clear cell sarcomas) were evaluated in 2 laboratories (Mayo Clinic Rochester: 31 cases, Carolinas Medical Center: 23 cases). Selected positive cases were retested at Carolinas Medical Center (11 cases) and Mayo Clinic Rochester (10 cases). Mayo Clinic Rochester methods were as follows: MTB1 clone (1:20, Novocastra, Newcastle-upon-Tyne, UK), heat-induced epitope retrieval in EDTA (pH 8.0), and Dako Advance detection system (Dako Corp, Carpinteria, CA) with background-reducing diluent. Carolinas Medical Center methods were as follows: MTB1 clone (1:30; CellMarque, Rocklin, CA), heat-induced epitope retrieval in Medium Cell Conditioner #1 (pH 8.0-9.0), and streptavidin-biotin detection system with diaminobenzidine chromogen, with and without biotin blocking. Scores were as follows: 1+, 5% to 25%; 2+, 26% to 50%; and 3+, more than 51%. Langerhans Cells served as a positive internal control in all tested cases. All Mayo Clinic Rochester cases were negative. Sixteen Carolinas Medical Center perivascular epithelioid cell Neoplasms (14 renal angiomyolipomas, 1 soft tissue perivascular epithelioid cell Neoplasm, 1 pulmonary clear cell “sugar” tumor) showed CD1a immunopositivity (1+: 7 cases; 2+: 7 cases; 3+: 2 cases) when tested without biotin blocking, 11 of these cases were retested with biotin blocking and were negative. All non–perivascular epithelioid cell Neoplasms were negative. All positive perivascular epithelioid cell Neoplasms showed cytoplasmic staining only, without membranous staining. Ten Carolinas Medical Center positive perivascular epithelioid cell Neoplasms were negative when retested a Mayo Clinic Rochester, using a polymer-based detection system. We conclude that perivascular epithelioid cell Neoplasms do not truly express CD1a in a biologically plausible membranous pattern, but may instead show aberrant cytoplasmic immunopositivity in some laboratories. Close inspection of published photomicrographs of previously reported CD1a-positive perivascular epithelioid cell Neoplasms shows an identical pattern of cytoplasmic positivity, likely reflecting abundant endogenous biotin within perivascular epithelioid cell Neoplasm Cells. We do not believe that there is a role for CD1a immunohistochemistry in the differential diagnosis of perivascular epithelioid cell Neoplasms.
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cd1a immunopositivity in perivascular epithelioid cell Neoplasms true expression or technical artifact a streptavidin biotin and polymer based detection system immunohistochemical study of perivascular epithelioid cell Neoplasms and their morphologic
Human Pathology, 2011Co-Authors: William A Ahrens, Andrew L. FolpeAbstract:Summary Perivascular epithelioid cell Neoplasms comprise a family of rare Neoplasms composed of morphologically distinctive perivascular epithelioid Cells exhibiting a “myomelanocytic” immunophenotype. The distinction of perivascular epithelioid cell Neoplasms from other tumors with melanocytic and smooth muscle differentiation can be difficult. A recent study has suggested that perivascular epithelioid cell Neoplasms routinely express CD1a, a Langerhans cell–associated transmembrane glycoprotein involved in antigen presentation and that expression of this marker may be helpful in the distinction of perivascular epithelioid cell Neoplasms from various mimics. We evaluated a series of perivascular epithelioid cell Neoplasms and potential mimics for CD1a expression. A total of 54 cases (27 perivascular epithelioid cell Neoplasms, 11 leiomyosarcomas, 10 melanomas, 6 clear cell sarcomas) were evaluated in 2 laboratories (Mayo Clinic Rochester: 31 cases, Carolinas Medical Center: 23 cases). Selected positive cases were retested at Carolinas Medical Center (11 cases) and Mayo Clinic Rochester (10 cases). Mayo Clinic Rochester methods were as follows: MTB1 clone (1:20, Novocastra, Newcastle-upon-Tyne, UK), heat-induced epitope retrieval in EDTA (pH 8.0), and Dako Advance detection system (Dako Corp, Carpinteria, CA) with background-reducing diluent. Carolinas Medical Center methods were as follows: MTB1 clone (1:30; CellMarque, Rocklin, CA), heat-induced epitope retrieval in Medium Cell Conditioner #1 (pH 8.0-9.0), and streptavidin-biotin detection system with diaminobenzidine chromogen, with and without biotin blocking. Scores were as follows: 1+, 5% to 25%; 2+, 26% to 50%; and 3+, more than 51%. Langerhans Cells served as a positive internal control in all tested cases. All Mayo Clinic Rochester cases were negative. Sixteen Carolinas Medical Center perivascular epithelioid cell Neoplasms (14 renal angiomyolipomas, 1 soft tissue perivascular epithelioid cell Neoplasm, 1 pulmonary clear cell “sugar” tumor) showed CD1a immunopositivity (1+: 7 cases; 2+: 7 cases; 3+: 2 cases) when tested without biotin blocking, 11 of these cases were retested with biotin blocking and were negative. All non–perivascular epithelioid cell Neoplasms were negative. All positive perivascular epithelioid cell Neoplasms showed cytoplasmic staining only, without membranous staining. Ten Carolinas Medical Center positive perivascular epithelioid cell Neoplasms were negative when retested a Mayo Clinic Rochester, using a polymer-based detection system. We conclude that perivascular epithelioid cell Neoplasms do not truly express CD1a in a biologically plausible membranous pattern, but may instead show aberrant cytoplasmic immunopositivity in some laboratories. Close inspection of published photomicrographs of previously reported CD1a-positive perivascular epithelioid cell Neoplasms shows an identical pattern of cytoplasmic positivity, likely reflecting abundant endogenous biotin within perivascular epithelioid cell Neoplasm Cells. We do not believe that there is a role for CD1a immunohistochemistry in the differential diagnosis of perivascular epithelioid cell Neoplasms.
William A Ahrens - One of the best experts on this subject based on the ideXlab platform.
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cd1a immunopositivity in perivascular epithelioid cell Neoplasms true expression or technical artifact a streptavidin biotin and polymer based detection system immunohistochemical study of perivascular epithelioid cell Neoplasms and their morphologic
Human Pathology, 2011Co-Authors: William A Ahrens, Andrew L. FolpeAbstract:Summary Perivascular epithelioid cell Neoplasms comprise a family of rare Neoplasms composed of morphologically distinctive perivascular epithelioid Cells exhibiting a “myomelanocytic” immunophenotype. The distinction of perivascular epithelioid cell Neoplasms from other tumors with melanocytic and smooth muscle differentiation can be difficult. A recent study has suggested that perivascular epithelioid cell Neoplasms routinely express CD1a, a Langerhans cell–associated transmembrane glycoprotein involved in antigen presentation and that expression of this marker may be helpful in the distinction of perivascular epithelioid cell Neoplasms from various mimics. We evaluated a series of perivascular epithelioid cell Neoplasms and potential mimics for CD1a expression. A total of 54 cases (27 perivascular epithelioid cell Neoplasms, 11 leiomyosarcomas, 10 melanomas, 6 clear cell sarcomas) were evaluated in 2 laboratories (Mayo Clinic Rochester: 31 cases, Carolinas Medical Center: 23 cases). Selected positive cases were retested at Carolinas Medical Center (11 cases) and Mayo Clinic Rochester (10 cases). Mayo Clinic Rochester methods were as follows: MTB1 clone (1:20, Novocastra, Newcastle-upon-Tyne, UK), heat-induced epitope retrieval in EDTA (pH 8.0), and Dako Advance detection system (Dako Corp, Carpinteria, CA) with background-reducing diluent. Carolinas Medical Center methods were as follows: MTB1 clone (1:30; CellMarque, Rocklin, CA), heat-induced epitope retrieval in Medium Cell Conditioner #1 (pH 8.0-9.0), and streptavidin-biotin detection system with diaminobenzidine chromogen, with and without biotin blocking. Scores were as follows: 1+, 5% to 25%; 2+, 26% to 50%; and 3+, more than 51%. Langerhans Cells served as a positive internal control in all tested cases. All Mayo Clinic Rochester cases were negative. Sixteen Carolinas Medical Center perivascular epithelioid cell Neoplasms (14 renal angiomyolipomas, 1 soft tissue perivascular epithelioid cell Neoplasm, 1 pulmonary clear cell “sugar” tumor) showed CD1a immunopositivity (1+: 7 cases; 2+: 7 cases; 3+: 2 cases) when tested without biotin blocking, 11 of these cases were retested with biotin blocking and were negative. All non–perivascular epithelioid cell Neoplasms were negative. All positive perivascular epithelioid cell Neoplasms showed cytoplasmic staining only, without membranous staining. Ten Carolinas Medical Center positive perivascular epithelioid cell Neoplasms were negative when retested a Mayo Clinic Rochester, using a polymer-based detection system. We conclude that perivascular epithelioid cell Neoplasms do not truly express CD1a in a biologically plausible membranous pattern, but may instead show aberrant cytoplasmic immunopositivity in some laboratories. Close inspection of published photomicrographs of previously reported CD1a-positive perivascular epithelioid cell Neoplasms shows an identical pattern of cytoplasmic positivity, likely reflecting abundant endogenous biotin within perivascular epithelioid cell Neoplasm Cells. We do not believe that there is a role for CD1a immunohistochemistry in the differential diagnosis of perivascular epithelioid cell Neoplasms.
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cd1a immunopositivity in perivascular epithelioid cell Neoplasms true expression or technical artifact a streptavidin biotin and polymer based detection system immunohistochemical study of perivascular epithelioid cell Neoplasms and their morphologic
Human Pathology, 2011Co-Authors: William A Ahrens, Andrew L. FolpeAbstract:Summary Perivascular epithelioid cell Neoplasms comprise a family of rare Neoplasms composed of morphologically distinctive perivascular epithelioid Cells exhibiting a “myomelanocytic” immunophenotype. The distinction of perivascular epithelioid cell Neoplasms from other tumors with melanocytic and smooth muscle differentiation can be difficult. A recent study has suggested that perivascular epithelioid cell Neoplasms routinely express CD1a, a Langerhans cell–associated transmembrane glycoprotein involved in antigen presentation and that expression of this marker may be helpful in the distinction of perivascular epithelioid cell Neoplasms from various mimics. We evaluated a series of perivascular epithelioid cell Neoplasms and potential mimics for CD1a expression. A total of 54 cases (27 perivascular epithelioid cell Neoplasms, 11 leiomyosarcomas, 10 melanomas, 6 clear cell sarcomas) were evaluated in 2 laboratories (Mayo Clinic Rochester: 31 cases, Carolinas Medical Center: 23 cases). Selected positive cases were retested at Carolinas Medical Center (11 cases) and Mayo Clinic Rochester (10 cases). Mayo Clinic Rochester methods were as follows: MTB1 clone (1:20, Novocastra, Newcastle-upon-Tyne, UK), heat-induced epitope retrieval in EDTA (pH 8.0), and Dako Advance detection system (Dako Corp, Carpinteria, CA) with background-reducing diluent. Carolinas Medical Center methods were as follows: MTB1 clone (1:30; CellMarque, Rocklin, CA), heat-induced epitope retrieval in Medium Cell Conditioner #1 (pH 8.0-9.0), and streptavidin-biotin detection system with diaminobenzidine chromogen, with and without biotin blocking. Scores were as follows: 1+, 5% to 25%; 2+, 26% to 50%; and 3+, more than 51%. Langerhans Cells served as a positive internal control in all tested cases. All Mayo Clinic Rochester cases were negative. Sixteen Carolinas Medical Center perivascular epithelioid cell Neoplasms (14 renal angiomyolipomas, 1 soft tissue perivascular epithelioid cell Neoplasm, 1 pulmonary clear cell “sugar” tumor) showed CD1a immunopositivity (1+: 7 cases; 2+: 7 cases; 3+: 2 cases) when tested without biotin blocking, 11 of these cases were retested with biotin blocking and were negative. All non–perivascular epithelioid cell Neoplasms were negative. All positive perivascular epithelioid cell Neoplasms showed cytoplasmic staining only, without membranous staining. Ten Carolinas Medical Center positive perivascular epithelioid cell Neoplasms were negative when retested a Mayo Clinic Rochester, using a polymer-based detection system. We conclude that perivascular epithelioid cell Neoplasms do not truly express CD1a in a biologically plausible membranous pattern, but may instead show aberrant cytoplasmic immunopositivity in some laboratories. Close inspection of published photomicrographs of previously reported CD1a-positive perivascular epithelioid cell Neoplasms shows an identical pattern of cytoplasmic positivity, likely reflecting abundant endogenous biotin within perivascular epithelioid cell Neoplasm Cells. We do not believe that there is a role for CD1a immunohistochemistry in the differential diagnosis of perivascular epithelioid cell Neoplasms.
Warren Fiskus - One of the best experts on this subject based on the ideXlab platform.
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dual pi3k akt mtor inhibitor bez235 synergistically enhances the activity of jak2 inhibitor against cultured and primary human myeloproliferative Neoplasm Cells
Molecular Cancer Therapeutics, 2013Co-Authors: Warren Fiskus, Srdan Verstovsek, Taghi Manshouri, Jacqueline E Smith, Sunil Abhyankar, Karissa Peth, Joseph Mcguirk, Kapil N BhallaAbstract:Hemopoietic progenitor Cells (HPC) from myeloproliferative Neoplasms (MPN) such as myelofibrosis commonly express mutant JAK2-V617F or other mutations that are associated with increased activities of JAK-STAT5/3, RAS/RAF/MAPK, and PI3K/AKT/mTOR pathways. This confers proliferative and survival advantage on the MPN HPCs. Treatment with JAK tyrosine kinase inhibitor (TKI), for example, TG101209, TG101348 (SAR302503), or INCB018424 (ruxolitinib), inhibits mutant JAK2-mediated signaling. Although effective in reducing constitutional symptoms and splenomegaly, treatment with JAK-TKI does not ameliorate myelofibrosis or significantly improve survival of patients with advanced myelofibrosis. Here, we show that treatment with the dual phosphoinositide-3-kinase (PI3K)/AKT and mTOR inhibitor BEZ235 attenuated PI3K/AKT and mTOR signaling, as well as induced cell-cycle growth arrest and apoptosis of the cultured human JAK2-V617F-expressing HEL92.1.7 (HEL), UKE1 Cells, and primary CD34+ myelofibrosis (MF)-MPN Cells. Treatment with BEZ235 also induced significant apoptosis of the JAK2-TKI resistant HEL/TGR Cells that were selected for resistance against JAK-TKI. Cotreatment with BEZ235 and JAK2-TKI (TG101209 and SAR302503) synergistically induced lethal activity against the cultured and primary CD34+ MPN Cells while relatively sparing the normal CD34+ HPCs. These findings create a compelling rationale to determine the in vivo activity of dual PI3K/mTOR inhibitors in combination with JAK inhibitors against myelofibrosis HPCs.
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heat shock protein 90 inhibitor is synergistic with jak2 inhibitor and overcomes resistance to jak2 tki in human myeloproliferative Neoplasm Cells
Clinical Cancer Research, 2011Co-Authors: Warren Fiskus, Srdan Verstovsek, Taghi Manshouri, Rekha Rao, Ramesh Balusu, Sreedhar Venkannagari, Nalabothula Narasimha Rao, Jacqueline E Smith, Stacey Hembruff, Sunil AbhyankarAbstract:Purpose: We determined the activity of hsp90 inhibitor, and/or Janus-activated kinase 2 (JAK2) tyrosine kinase inhibitor (TKI), against JAK2-V617F–expressing cultured mouse (Ba/F3-JAK2-V617F) and human (HEL92.1.7 and UKE-1) or primary human CD34 + myeloproliferative Neoplasm (MPN) Cells. Experimental Design: Following exposure to the hsp90 inhibitor AUY922 and/or JAK2-TKI TG101209, the levels of JAK2-V617F, its downstream signaling proteins, as well as apoptosis were determined. Results: Treatment with AUY922 induced proteasomal degradation and depletion of JAK2-V617F as well as attenuated the signaling proteins downstream of JAK2-V617F, that is, phospho (p)-STAT5, p-AKT, and p-ERK1/2. AUY922 treatment also induced apoptosis of HEL92.1.7, UKE-1, and Ba/F3-hJAK2-V617F Cells. Combined treatment with AUY922 and TG101209 caused greater depletion of the signaling proteins than either agent alone and synergistically induced apoptosis of HEL92.1.7 and UKE-1 Cells. Cotreatment with AUY922 and TG101209 also induced significantly more apoptosis of human CD34 + MPN than normal hematopoietic progenitor Cells. As compared with the sensitive controls, JAK2-TKI–resistant HEL/TGR and UKE-1/TGR Cells exhibited significantly higher IC 50 values for JAK2-TKI ( P Conclusions: Findings presented here show that cotreatment with hsp90 inhibitor and JAK2-TKI exerts synergistic activity against cultured and primary MPN Cells. In addition, treatment with hsp90 inhibitor may overcome resistance to JAK2-TKI in human MPN Cells. Clin Cancer Res; 17(23); 7347–58. ©2011 AACR .
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synergistic activity of combinations of jak2 kinase inhibitor with pi3k mtor mek or pim kinase inhibitor against human myeloproliferative Neoplasm Cells expressing jak2v617f
Blood, 2010Co-Authors: Warren Fiskus, Ramesh Balusu, Rekha Rao Manepalli, Kapil N BhallaAbstract:Abstract 798 The mutant JAK2-V617F tyrosine kinase (TK) is present in the majority of patients with BCR-ABL negative myeloproliferative Neoplasms (MPNs). JAK2-V617F activates downstream signaling through the STAT, RAS/MAPK and PI3/AKT pathways, conferring proliferative and survival advantages in the MPN hematopoietic progenitor Cells (HPCs). We have previously reported that pan-histone deacetylase (HDAC) inhibitors e.g. panobinostat (PS) (Novartis Pharmaceuticals), depleted mRNA expression of JAK2-V617F, and disrupted the chaperone association of with hsp90 with JAK2-V617F, thereby promoting the degradation of JAK2-V617F by the proteasome. This led to attenuation of the levels and downstream transcriptional activity of STAT3 and STAT5, resulting in growth arrest and apoptosis of MPN HPCs. Additionally, co-treatment with PS and a JAK2 kinase inhibitor, TG101209, further depleted JAK/STAT signaling and synergistically induced apoptosis of JAK2-V617F expressing HEL92.1.7 and Ba/F3-JAK2V617F Cells, as well as exerted greater lethality against primary CD34+CD38-Lin- MPN versus normal CD34+ HPCs. In the present studies, we determined the cytotoxic effects of inhibiting JAK2-STAT3/5 in conjunction with pharmacologic targeting of the collateral, pro-growth and pro-survival signaling through PI3K/AKT, RAF-MEK or PIM1 kinases in MPN Cells. For this, the cytotoxic effects of co-treatment with TG101209 and the MEK inhibitor (AZD6244, AstraZenaca), dual PI3K/mTOR inhibitor (BEZ235, Novartis) or the PIM1 kinase inhibitor (SGI-1776, SuperGen) were evaluated in HEL92.1.7, Ba/F3-JAK2V617 and primary human MPN Cells. Treatment with BEZ235 dose-dependently attenuated the levels of p-JAK2, p-STAT5, p-STAT3, p-AKT, p-ERK1/2 and p-4EBP1. Co-treatment with BEZ235 and TG101209 was synergistically lethal against the cultured MPN and primary CD34+ MF-MPN Cells (combination indices Disclosures: No relevant conflicts of interest to declare.
Sunil Abhyankar - One of the best experts on this subject based on the ideXlab platform.
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dual pi3k akt mtor inhibitor bez235 synergistically enhances the activity of jak2 inhibitor against cultured and primary human myeloproliferative Neoplasm Cells
Molecular Cancer Therapeutics, 2013Co-Authors: Warren Fiskus, Srdan Verstovsek, Taghi Manshouri, Jacqueline E Smith, Sunil Abhyankar, Karissa Peth, Joseph Mcguirk, Kapil N BhallaAbstract:Hemopoietic progenitor Cells (HPC) from myeloproliferative Neoplasms (MPN) such as myelofibrosis commonly express mutant JAK2-V617F or other mutations that are associated with increased activities of JAK-STAT5/3, RAS/RAF/MAPK, and PI3K/AKT/mTOR pathways. This confers proliferative and survival advantage on the MPN HPCs. Treatment with JAK tyrosine kinase inhibitor (TKI), for example, TG101209, TG101348 (SAR302503), or INCB018424 (ruxolitinib), inhibits mutant JAK2-mediated signaling. Although effective in reducing constitutional symptoms and splenomegaly, treatment with JAK-TKI does not ameliorate myelofibrosis or significantly improve survival of patients with advanced myelofibrosis. Here, we show that treatment with the dual phosphoinositide-3-kinase (PI3K)/AKT and mTOR inhibitor BEZ235 attenuated PI3K/AKT and mTOR signaling, as well as induced cell-cycle growth arrest and apoptosis of the cultured human JAK2-V617F-expressing HEL92.1.7 (HEL), UKE1 Cells, and primary CD34+ myelofibrosis (MF)-MPN Cells. Treatment with BEZ235 also induced significant apoptosis of the JAK2-TKI resistant HEL/TGR Cells that were selected for resistance against JAK-TKI. Cotreatment with BEZ235 and JAK2-TKI (TG101209 and SAR302503) synergistically induced lethal activity against the cultured and primary CD34+ MPN Cells while relatively sparing the normal CD34+ HPCs. These findings create a compelling rationale to determine the in vivo activity of dual PI3K/mTOR inhibitors in combination with JAK inhibitors against myelofibrosis HPCs.
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heat shock protein 90 inhibitor is synergistic with jak2 inhibitor and overcomes resistance to jak2 tki in human myeloproliferative Neoplasm Cells
Clinical Cancer Research, 2011Co-Authors: Warren Fiskus, Srdan Verstovsek, Taghi Manshouri, Rekha Rao, Ramesh Balusu, Sreedhar Venkannagari, Nalabothula Narasimha Rao, Jacqueline E Smith, Stacey Hembruff, Sunil AbhyankarAbstract:Purpose: We determined the activity of hsp90 inhibitor, and/or Janus-activated kinase 2 (JAK2) tyrosine kinase inhibitor (TKI), against JAK2-V617F–expressing cultured mouse (Ba/F3-JAK2-V617F) and human (HEL92.1.7 and UKE-1) or primary human CD34 + myeloproliferative Neoplasm (MPN) Cells. Experimental Design: Following exposure to the hsp90 inhibitor AUY922 and/or JAK2-TKI TG101209, the levels of JAK2-V617F, its downstream signaling proteins, as well as apoptosis were determined. Results: Treatment with AUY922 induced proteasomal degradation and depletion of JAK2-V617F as well as attenuated the signaling proteins downstream of JAK2-V617F, that is, phospho (p)-STAT5, p-AKT, and p-ERK1/2. AUY922 treatment also induced apoptosis of HEL92.1.7, UKE-1, and Ba/F3-hJAK2-V617F Cells. Combined treatment with AUY922 and TG101209 caused greater depletion of the signaling proteins than either agent alone and synergistically induced apoptosis of HEL92.1.7 and UKE-1 Cells. Cotreatment with AUY922 and TG101209 also induced significantly more apoptosis of human CD34 + MPN than normal hematopoietic progenitor Cells. As compared with the sensitive controls, JAK2-TKI–resistant HEL/TGR and UKE-1/TGR Cells exhibited significantly higher IC 50 values for JAK2-TKI ( P Conclusions: Findings presented here show that cotreatment with hsp90 inhibitor and JAK2-TKI exerts synergistic activity against cultured and primary MPN Cells. In addition, treatment with hsp90 inhibitor may overcome resistance to JAK2-TKI in human MPN Cells. Clin Cancer Res; 17(23); 7347–58. ©2011 AACR .
Kapil N Bhalla - One of the best experts on this subject based on the ideXlab platform.
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dual pi3k akt mtor inhibitor bez235 synergistically enhances the activity of jak2 inhibitor against cultured and primary human myeloproliferative Neoplasm Cells
Molecular Cancer Therapeutics, 2013Co-Authors: Warren Fiskus, Srdan Verstovsek, Taghi Manshouri, Jacqueline E Smith, Sunil Abhyankar, Karissa Peth, Joseph Mcguirk, Kapil N BhallaAbstract:Hemopoietic progenitor Cells (HPC) from myeloproliferative Neoplasms (MPN) such as myelofibrosis commonly express mutant JAK2-V617F or other mutations that are associated with increased activities of JAK-STAT5/3, RAS/RAF/MAPK, and PI3K/AKT/mTOR pathways. This confers proliferative and survival advantage on the MPN HPCs. Treatment with JAK tyrosine kinase inhibitor (TKI), for example, TG101209, TG101348 (SAR302503), or INCB018424 (ruxolitinib), inhibits mutant JAK2-mediated signaling. Although effective in reducing constitutional symptoms and splenomegaly, treatment with JAK-TKI does not ameliorate myelofibrosis or significantly improve survival of patients with advanced myelofibrosis. Here, we show that treatment with the dual phosphoinositide-3-kinase (PI3K)/AKT and mTOR inhibitor BEZ235 attenuated PI3K/AKT and mTOR signaling, as well as induced cell-cycle growth arrest and apoptosis of the cultured human JAK2-V617F-expressing HEL92.1.7 (HEL), UKE1 Cells, and primary CD34+ myelofibrosis (MF)-MPN Cells. Treatment with BEZ235 also induced significant apoptosis of the JAK2-TKI resistant HEL/TGR Cells that were selected for resistance against JAK-TKI. Cotreatment with BEZ235 and JAK2-TKI (TG101209 and SAR302503) synergistically induced lethal activity against the cultured and primary CD34+ MPN Cells while relatively sparing the normal CD34+ HPCs. These findings create a compelling rationale to determine the in vivo activity of dual PI3K/mTOR inhibitors in combination with JAK inhibitors against myelofibrosis HPCs.
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synergistic activity of combinations of jak2 kinase inhibitor with pi3k mtor mek or pim kinase inhibitor against human myeloproliferative Neoplasm Cells expressing jak2v617f
Blood, 2010Co-Authors: Warren Fiskus, Ramesh Balusu, Rekha Rao Manepalli, Kapil N BhallaAbstract:Abstract 798 The mutant JAK2-V617F tyrosine kinase (TK) is present in the majority of patients with BCR-ABL negative myeloproliferative Neoplasms (MPNs). JAK2-V617F activates downstream signaling through the STAT, RAS/MAPK and PI3/AKT pathways, conferring proliferative and survival advantages in the MPN hematopoietic progenitor Cells (HPCs). We have previously reported that pan-histone deacetylase (HDAC) inhibitors e.g. panobinostat (PS) (Novartis Pharmaceuticals), depleted mRNA expression of JAK2-V617F, and disrupted the chaperone association of with hsp90 with JAK2-V617F, thereby promoting the degradation of JAK2-V617F by the proteasome. This led to attenuation of the levels and downstream transcriptional activity of STAT3 and STAT5, resulting in growth arrest and apoptosis of MPN HPCs. Additionally, co-treatment with PS and a JAK2 kinase inhibitor, TG101209, further depleted JAK/STAT signaling and synergistically induced apoptosis of JAK2-V617F expressing HEL92.1.7 and Ba/F3-JAK2V617F Cells, as well as exerted greater lethality against primary CD34+CD38-Lin- MPN versus normal CD34+ HPCs. In the present studies, we determined the cytotoxic effects of inhibiting JAK2-STAT3/5 in conjunction with pharmacologic targeting of the collateral, pro-growth and pro-survival signaling through PI3K/AKT, RAF-MEK or PIM1 kinases in MPN Cells. For this, the cytotoxic effects of co-treatment with TG101209 and the MEK inhibitor (AZD6244, AstraZenaca), dual PI3K/mTOR inhibitor (BEZ235, Novartis) or the PIM1 kinase inhibitor (SGI-1776, SuperGen) were evaluated in HEL92.1.7, Ba/F3-JAK2V617 and primary human MPN Cells. Treatment with BEZ235 dose-dependently attenuated the levels of p-JAK2, p-STAT5, p-STAT3, p-AKT, p-ERK1/2 and p-4EBP1. Co-treatment with BEZ235 and TG101209 was synergistically lethal against the cultured MPN and primary CD34+ MF-MPN Cells (combination indices Disclosures: No relevant conflicts of interest to declare.