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    Gene defects and mutant ALK kinase in human solid tumors
    2.
    发明授权
    Gene defects and mutant ALK kinase in human solid tumors 有权
    人类实体瘤中的基因缺陷和突变ALK激酶

    公开(公告)号：US08486645B2

    公开(公告)日：2013-07-16

    申请号：US13438218

    申请日：2012-04-03

    Applicant: Klarisa Rikova ,  Herbert Haack ,  Laura Sullivan ,  Ailan Guo ,  Anthony Possemato ,  Joan MacNeill ,  Ting-Lei Gu ,  Jian Yu

    Inventor： Klarisa Rikova ,  Herbert Haack ,  Laura Sullivan ,  Ailan Guo ,  Anthony Possemato ,  Joan MacNeill ,  Ting-Lei Gu ,  Jian Yu

    IPC: G01N33/53 ,  G01N33/563 ,  C12Q1/48 ,  C12N9/12 ,  G01N35/08

    CPC classification number: G01N33/574 ,  A61K38/00 ,  C07K2319/00 ,  C12N9/1205 ,  C12Q1/6886 ,  C12Q2600/136 ,  C12Q2600/156 ,  G01N33/57484 ,  G01N2333/9121 ,  Y10T436/117497

    Abstract: Novel gene deletions and translocations involving chromosome 2 resulting in fusion proteins combining part of Anaplastic Lymphoma Kinase (ALK) kinase with part of a secondary protein have now been identified in human solid tumors, e.g. non-small cell lung carcinoma (NSCLC). Secondary proteins include Echinoderm Microtubule-Associated Protein-Like 4 (EML-4) and TRK-Fusion Gene (TFG). The EML4-ALK fusion protein, which retains ALK tyrosine kinase activity, was confirmed to drive the proliferation and survival of NSCLC characterized by this mutation. The invention therefore provides, in part, isolated polynucleotides and vectors encoding the disclosed mutant polypeptides, probes for detecting it, isolated mutant polypeptides, and reagents for detecting the fusion and truncated polypeptides. The invention also provides methods for determining the presence of these mutant polypeptides in a biological sample, methods for screening for compounds that inhibit the proteins, and methods for inhibiting the progression of a cancer characterized by the mutant polynucleotides or polypeptides.

    Abstract translation: 涉及染色体2的新型基因缺失和易位导致融合蛋白的结合，其部分的间变型淋巴瘤激酶（ALK）激酶与部分二级蛋白结合，已经在人类实体瘤中被鉴定。 非小细胞肺癌（NSCLC）。 次级蛋白包括棘皮动物微管相关蛋白样4（EML-4）和TRK-融合基因（TFG）。 确认了保留ALK酪氨酸激酶活性的EML4-ALK融合蛋白，以驱动以这种突变为特征的NSCLC的增殖和存活。 因此，本发明部分地提供分离的多核苷酸和编码所公开的突变多肽的载体，用于检测其的探针，分离的突变多肽和用于检测融合和截短的多肽的试剂。 本发明还提供了用于确定生物样品中这些突变体多肽的存在的方法，用于筛选抑制蛋白质的化合物的方法，以及用于突变多核苷酸或多肽特征的癌症进展抑制方法。

    GENE DEFECTS AND MUTANT ALK KINASE IN HUMAN SOLID TUMORS
    3.
    发明申请
    GENE DEFECTS AND MUTANT ALK KINASE IN HUMAN SOLID TUMORS 有权
    人类固体肿瘤中的基因缺陷和突变碱性激酶

    公开(公告)号：US20120288872A1

    公开(公告)日：2012-11-15

    申请号：US13438218

    申请日：2012-04-03

    Applicant: Klarisa Rikova ,  Herbert Haack ,  Laura Sullivan ,  Ailan Guo ,  Anthony Possemato ,  Joan MacNeill ,  Ting-Lei Gu ,  Jian Yu

    Inventor： Klarisa Rikova ,  Herbert Haack ,  Laura Sullivan ,  Ailan Guo ,  Anthony Possemato ,  Joan MacNeill ,  Ting-Lei Gu ,  Jian Yu

    IPC: G01N33/574

    CPC classification number: G01N33/574 ,  A61K38/00 ,  C07K2319/00 ,  C12N9/1205 ,  C12Q1/6886 ,  C12Q2600/136 ,  C12Q2600/156 ,  G01N33/57484 ,  G01N2333/9121 ,  Y10T436/117497

    Abstract: Novel gene deletions and translocations involving chromosome 2 resulting in fusion proteins combining part of Anaplastic Lymphoma Kinase (ALK) kinase with part of a secondary protein have now been identified in human solid tumors, e.g. non-small cell lung carcinoma (NSCLC). Secondary proteins include Echinoderm Microtubule-Associated Protein-Like 4 (EML-4) and TRK-Fusion Gene (TFG). The EML4-ALK fusion protein, which retains ALK tyrosine kinase activity, was confirmed to drive the proliferation and survival of NSCLC characterized by this mutation. The invention therefore provides, in part, isolated polynucleotides and vectors encoding the disclosed mutant polypeptides, probes for detecting it, isolated mutant polypeptides, and reagents for detecting the fusion and truncated polypeptides. The invention also provides methods for determining the presence of these mutant polypeptides in a biological sample, methods for screening for compounds that inhibit the proteins, and methods for inhibiting the progression of a cancer characterized by the mutant polynucleotides or polypeptides.

    Abstract translation: 涉及染色体2的新型基因缺失和易位导致融合蛋白的结合，其部分的间变型淋巴瘤激酶（ALK）激酶与部分二级蛋白结合，已经在人类实体瘤中被鉴定。 非小细胞肺癌（NSCLC）。 次级蛋白包括棘皮动物微管相关蛋白样4（EML-4）和TRK-融合基因（TFG）。 确认了保留ALK酪氨酸激酶活性的EML4-ALK融合蛋白，以驱动以这种突变为特征的NSCLC的增殖和存活。 因此，本发明部分地提供分离的多核苷酸和编码所公开的突变多肽的载体，用于检测其的探针，分离的突变多肽和用于检测融合和截短的多肽的试剂。 本发明还提供了用于确定生物样品中这些突变体多肽的存在的方法，用于筛选抑制蛋白质的化合物的方法，以及用于突变多核苷酸或多肽特征的癌症进展抑制方法。

    Reagents for the detection of protein phosphorylation in leukemia signaling pathways
    4.
    发明授权
    Reagents for the detection of protein phosphorylation in leukemia signaling pathways 有权
    用于检测白血病信号通路中蛋白质磷酸化的试剂

    公开(公告)号：US07888480B2

    公开(公告)日：2011-02-15

    申请号：US12074224

    申请日：2008-02-29

    Applicant: Roberto Polakiewicz ,  Valerie Goss ,  Albrecht Moritz ,  Ting-Lei Gu ,  Kimberly Lee

    Inventor： Roberto Polakiewicz ,  Valerie Goss ,  Albrecht Moritz ,  Ting-Lei Gu ,  Kimberly Lee

    IPC: C07K16/00

    CPC classification number: G01N33/6842 ,  C07K16/3061 ,  C07K16/44 ,  C07K2317/34 ,  G01N33/57426 ,  G01N2458/15

    Abstract: The invention discloses nearly 288 novel phosphorylation sites identified in signal transduction proteins and pathways underlying human Leukemia, and provides phosphorylation-site specific antibodies and heavy-isotope labeled peptides (AQUA peptides) for the selective detection and quantification of these phosphorylated sites/proteins, as well as methods of using the reagents for such purpose. Among the phosphorylation sites identified are sites occurring in the following protein types: Adaptor/Scaffold proteins, Cytoskeletal proteins, Cellular Metabolism enzymes, G Protein/GTPase Activating/Guanine Nucleotide Exchange Factor proteins, Immunoglobulin Superfamily proteins, Inhibitor proteins, Lipid Kinases, Nuclear DNA Repair/RNA Binding/Transcription proteins, Serine/Threonine Protein Kinases, Tyrosine Kinases, Protein Phosphatases, and Translation/Transporter proteins.

    Abstract translation: 本发明公开了在信号转导蛋白中鉴定的近288个新的磷酸化位点和人类白血病潜在的途径，并提供磷酸化位点特异性抗体和重同位素标记肽（AQUA肽），用于选择性检测和定量这些磷酸化位点/蛋白质，如 以及使用试剂用于此目的的方法。 所鉴定的磷酸化位点是以下蛋白质类型的位点：适配器/支架蛋白，细胞骨架蛋白，细胞代谢酶，G蛋白/ GTP酶激活/鸟嘌呤核苷酸交换因子蛋白，免疫球蛋白超家族蛋白，抑制蛋白，脂质激酶，核DNA 修复/ RNA结合/转录蛋白，丝氨酸/苏氨酸蛋白激酶，酪氨酸激酶，蛋白磷酸酶和翻译/转运蛋白。

    TRANSLOCATION AND MUTANT TNK1 KINASE IN HUMAN LYMPHOMA
    5.
    发明申请
    TRANSLOCATION AND MUTANT TNK1 KINASE IN HUMAN LYMPHOMA 审中-公开
    人淋巴瘤转移和突变TNK1激酶

    公开(公告)号：US20100266580A1

    公开(公告)日：2010-10-21

    申请号：US12746713

    申请日：2008-12-08

    Applicant: Ting-Lei Gu

    Inventor： Ting-Lei Gu

    IPC: C12N9/12 ,  C12N15/54 ,  C12N15/11 ,  C07K16/18 ,  C12Q1/68 ,  C12Q1/48 ,  A61K39/395 ,  A61K31/436 ,  A61K31/7088

    CPC classification number: C12N9/12

    Abstract: In accordance with the invention, a novel gene translocation in human Hodgkin's lymphoma (HL) that results in a fusion protein combining part of C17ORF61 with Thirty-eight-negative kinase 1 (Tnk1) kinase has now been identified. The TNK1-C17ORF61 fusion protein, which retains TNK1 tyrosine kinase activity, was confirmed to drive the proliferation and survival of Hodgkin's lymphoma (HL) cell line, L-540. The invention therefore provides, in part, isolated polynucleotides and vectors encoding the disclosed mutant TNK1 kinase polypeptides, probes for detecting it, isolated mutant polypeptides, recombinant polypeptides, and reagents for detecting the fusion and truncated polypeptides. The disclosed identification of this new fusion protein and truncated kinase enables new methods for determining the presence of these mutant TNK1 kinase polypeptides in a biological sample, methods for screening for compounds that inhibit the proteins, and methods for inhibiting the progression of a cancer characterized by the mutant polynucleotides or polypeptides, which are also provided by the invention.

    Abstract translation: 根据本发明，现在已经鉴定出导致融合蛋白质结合C17ORF61与三十八阴性激酶1（Tnk1）激酶的融合蛋白的人类霍奇金淋巴瘤（HL）中的新基因易位。 确认保留TNK1酪氨酸激酶活性的TNK1-C17ORF61融合蛋白驱动Hodgkin淋巴瘤（HL）细胞系L-540的增殖和存活。 因此，本发明部分地提供了分离的多核苷酸和编码所公开的突变型TNK1激酶多肽的载体，用于检测其的探针，分离的突变多肽，重组多肽和用于检测融合和截短的多肽的试剂。 所公开的这种新的融合蛋白和截短的激酶的鉴定使得能够确定生物样品中这些突变型TNK1激酶多肽的存在的新方法，用于筛选抑制蛋白质的化合物的方法，以及抑制癌症进展的方法 突变体多核苷酸或多肽，其也由本发明提供。

    PHOSPHO-SPECIFIC ANTIBODIES TO FLT3 (TYR969) AND USES THEREOF
    6.
    发明申请
    PHOSPHO-SPECIFIC ANTIBODIES TO FLT3 (TYR969) AND USES THEREOF 审中-公开
    FLT3（TYR969）的磷酸特异性抗体及其用途

    公开(公告)号：US20100093008A1

    公开(公告)日：2010-04-15

    申请号：US11681521

    申请日：2007-03-02

    Applicant: Valerie GOSS ,  Roberto Polakiewicz ,  Kimberly Lee ,  Ting-Lei Gu ,  Albrecht Moritz ,  Jiong Wu

    Inventor： Valerie GOSS ,  Roberto Polakiewicz ,  Kimberly Lee ,  Ting-Lei Gu ,  Albrecht Moritz ,  Jiong Wu

    IPC: C12Q1/48 ,  C07K16/40 ,  C12N5/12

    CPC classification number: G01N33/573 ,  C07K16/2863 ,  C07K16/44 ,  C07K2317/34 ,  G01N33/57426 ,  G01N2333/9121 ,  G01N2800/52

    Abstract: The invention discloses a newly discovered Flt3 phosphorylation site, tyrosine 969 (Tyr969) in the intracellular domain, and provides reagents, including polyclonal and monoclonal antibodies, that selectively bind to Flt3 when phosphorylated at this site. Also provided are assays utilizing this reagent, including methods for determining the phosphorylation of Flt3 in a biological sample, selecting a patient suitable for Flt3 inhibitor therapy, profiling Flt3 activation in a test tissue, and identifying a compound that modulates phosphorylation of Flt3 in a test tissue, by using a detectable reagent, such as the disclosed antibody, that binds to Flt3 only when phosphorylated at Tyr969. The sample or test tissue may be taken from a subject suspected of having cancer, such as acute myelogenous leukemia (AML).

    Abstract translation: 本发明公开了新发现的Flt3磷酸化位点，细胞内结构域中的酪氨酸969（Tyr969），并提供了在该位点磷酸化时选择性结合Flt3的试剂，包括多克隆和单克隆抗体。 还提供了使用该试剂的测定法，包括用于测定生物样品中Flt3的磷酸化的方法，选择适合Flt3抑制剂治疗的患者，在测试组织中分析Flt3活化，以及鉴定在测试中调节Flt3的磷酸化的化合物 通过使用仅在Tyr969磷酸化时与Flt3结合的可检测试剂，例如所公开的抗体。 样品或测试组织可以从疑似患有癌症的受试者中获取，例如急性骨髓性白血病（AML）。

    MUTANT JAK3 KINASE IN HUMAN LEUKEMIA
    7.
    发明申请
    MUTANT JAK3 KINASE IN HUMAN LEUKEMIA 审中-公开
    MUTANT JAK3激活人类LEUKEMIA

    公开(公告)号：US20090285796A1

    公开(公告)日：2009-11-19

    申请号：US12161512

    申请日：2007-01-19

    Applicant: Valerie Goss ,  Ting-lei Gu ,  Roberto Polakiewicz ,  Brian Druker ,  Denise Walters

    Inventor： Valerie Goss ,  Ting-lei Gu ,  Roberto Polakiewicz ,  Brian Druker ,  Denise Walters

    IPC: A61K39/395 ,  C07H21/04 ,  C07K14/00 ,  C12N15/63 ,  C12N5/10 ,  C12N9/12 ,  C07K16/00 ,  C12Q1/68 ,  G01N33/53 ,  A61K31/7088 ,  A61P35/02

    CPC classification number: C12N9/1205 ,  C12Q1/6886 ,  C12Q2600/106 ,  C12Q2600/136

    Abstract: In accordance with the invention, a novel activating mutation (alanine 572 to valine) in JAK3 kinase has been discovered in human acute myelogenous leukemia (AML). The mutant JAK3 kinase was confirmed to drive the proliferation and survival of acute megakaryoblastic leukemia (AML-M7). The invention therefore provides, in part, isolated polynucleotides and vectors encoding the disclosed mutant JAK3 kinase polypeptides, probes for detecting it, isolated mutant polypeptides, recombinant polypeptides, and reagents for detecting the mutant polypeptides. The disclosed identification of this new mutant protein and enables new methods for determining the presence of mutant JAK3 kinase polypeptides in a biological sample, methods for screening for compounds that inhibit the mutant proteins, and methods for inhibiting the progression of a cancer characterized by the mutant polynucleotides or polypeptides, which are also provided by the invention.

    Abstract translation: 根据本发明，已经在人类急性骨髓性白血病（AML）中发现JAK3激酶中的新的活化突变（丙氨酸572至缬氨酸）。 证实突变型JAK3激酶能够驱动急性巨核细胞白血病（AML-M7）的增殖和存活。 因此，本发明部分地提供分离的多核苷酸和编码所公开的突变体JAK3激酶多肽的载体，用于检测其的探针，分离的突变多肽，重组多肽和用于检测突变体多肽的试剂。 所公开的这种新的突变蛋白的鉴定并且使得能够确定生物样品中突变体JAK3激酶多肽的存在的新方法，用于筛选抑制突变蛋白质的化合物的方法，以及用于抑制突变体特征的癌症进展的方法 多核苷酸或多肽，其也由本发明提供。

    Reagents for the detection of protein phosphorylation in leukemia signaling pathways
    8.
    发明申请
    Reagents for the detection of protein phosphorylation in leukemia signaling pathways 审中-公开
    用于检测白血病信号通路中蛋白质磷酸化的试剂

    公开(公告)号：US20090220991A1

    公开(公告)日：2009-09-03

    申请号：US12074214

    申请日：2008-02-29

    Applicant: Roberto Polakiewicz ,  Valerie Goss ,  Albrecht Moritz ,  Ting-Lei Gu ,  Kimberly Lee

    Inventor： Roberto Polakiewicz ,  Valerie Goss ,  Albrecht Moritz ,  Ting-Lei Gu ,  Kimberly Lee

    IPC: G01N33/53 ,  G01N33/536 ,  C07K16/18 ,  C12N5/18

    CPC classification number: C07K16/40 ,  C07K16/18 ,  C07K16/2803 ,  C07K16/2896 ,  C07K16/3061 ,  C07K2317/34 ,  G01N33/57426 ,  G01N33/6854

    Abstract: The invention discloses nearly 480 novel phosphorylation sites identified in signal transduction proteins and pathways underlying human Leukemia, and provides phosphorylation site specific antibodies and heavy-isotope labeled peptides (AQUA peptides) for the selective detection and quantification of these phosphorylated sites/proteins, as well as methods of using the reagents for such purpose. Among the phosphorylation sites identified are sites occurring in the following protein types: adaptor/scaffold proteins, acetyltransferases, actin binding proteins, adhesion proteins, apoptosis proteins, calcium-binding proteins, cell cycle regulation proteins, cell surface proteins, channel proteins, chaperone proteins, contractile proteins, cytokine proteins, cytoskeletal proteins, G protein regulators and GTPase activating proteins, guanine nucleotide exchange factors, helicase proteins, immunoglobulin superfamily proteins, inhibitor proteins, protein kinases, lipid kinases, ligases, lipid binding proteins, methytransferases, motor proteins, oxidoreductases, phosphotases, phosphodiesterases, phospholipases, proteases, receptor proteins, trascription factors, transferases, translation/transporter proteins, and ubiquitin conjugating system proteins.

    Abstract translation: 本发明公开了在信号转导蛋白中识别的近480个新的磷酸化位点和人类白血病下游的途径，并提供磷酸化位点特异性抗体和重同位素标记肽（AQUA肽），用于选择性检测和定量这些磷酸化位点/蛋白质 作为使用试剂用于此目的的方法。 鉴定的磷酸化位点是发生在以下蛋白质类型中的位点：衔接子/支架蛋白，乙酰转移酶，肌动蛋白结合蛋白，粘附蛋白，凋亡蛋白，钙结合蛋白，细胞周期调节蛋白，细胞表面蛋白，通道蛋白，伴侣蛋白 鸟嘌呤核苷酸交换因子，解旋酶蛋白，免疫球蛋白超家族蛋白，抑制蛋白，蛋白激酶，脂质激酶，连接酶，脂质结合蛋白，甲基转移酶，运动蛋白，肌动蛋白， 氧化还原酶，磷酸二酯酶，磷脂酶，蛋白酶，受体蛋白，trascription因子，转移酶，翻译/转运蛋白和泛素缀合系统蛋白。

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