Survival Mechanisms of Cancer-initiating (Stem) Cells in Ph+ Leukemia

Ph 白血病中癌症起始（干）细胞的生存机制

• 批准号: 7741092
• 负责人: Shaoguang Li
• 金额: $ 31.07万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-25 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7741092
• 关键词: Acute; Address; Adoptive Transfer; Affect; Age; Allogeneic Bone Marrow Transplantation; Appearance; B-Cell Acute Lymphoblastic Leukemia; B-Lymphocytes; BMS-214662; Bcr-Abl tyrosine kinase; Blast Phase; Bone Marrow; Bone Marrow Cells; Cell Lineage; Cell Proliferation; Cell Survival; Cells; Chemical Agents; Chemotherapy-Oncologic Procedure; Chronic; Chronic Lymphocytic Leukemia; Chronic Myeloid Leukemia; Chronic Phase; Chronic-Phase Myeloid Leukemia; Clinical; Combined Modality Therapy; Data; Disease; Disease Progression; Disease remission; Foundations; Functional disorder; Gleevec; Goals; Hematologic Neoplasms; Hematopoietic; Hematopoietic stem cells; Human; Imatinib; Imatinib mesylate; Knockout Mice; Large Intestine Carcinoma; Lead; Leukemic Cell; Link; Lymphoblastic Leukemia; Lymphoid Cell; Malignant - descriptor; Malignant Epithelial Cell; Malignant Neoplasms; Marrow; Mediating; Molecular; Mus; Myelogenous; Myeloid Leukemia; Myeloproliferative disease; Oncogenes; Pathway interactions; Patients; Phase; Philadelphia Chromosome; Play; Proliferating; Public Health; Recurrence; Relapse; Resistance; Role; STI571; Secondary to; Signal Transduction; Sorting - Cell Movement; Stem cells; Testing; Therapeutic; Therapeutic Effect; Transplantation; Tumor Stem Cells; Tyrosine Kinase Inhibitor; bcr-abl Fusion Proteins; chemotherapy; human disease; improved; in vivo; killings; kinase inhibitor; leukemia; leukemogenesis; metaplastic cell transformation; mouse model; novel therapeutics; pre-clinical; prevent; self-renewal; src-Family Kinases; tyrosine kinase ABL1; v-src Oncogenes

DESCRIPTION (provided by applicant): The overall goal of this project is to identify molecular mechanisms for self-renewal and survival of leukemic initiating (stem) cells that may be targets for curative therapy of human Philadelphia chromosome-positive (Ph+) leukemias. Ph+ leukemias induced by the BCR-ABL oncogene, including chronic myeloid leukemia (CML) and the B-cell acute lymphoblastic leukemia (B-ALL), are among the most common myeloproliferative malignancies. Allogeneic bone marrow transplantation, the only established curative therapy for CML, is not feasible for most patients. The BCR-ABL tyrosine kinase inhibitors including imatinib mesylate (Gleevec) are highly effective in treating chronic phase CML patients, but not more advanced CML blast crisis and Ph+ B-ALL patients. Moreover, clinical resistance to imatinib develops and imatinib does not completely eradicate leukemic stem cells, suggesting that use of a BCR-ABL kinase inhibitor such as imatinib as a single agent will not prevent eventual disease progression or cure CML. New therapeutic strategies are needed, especially for older CML patients. Our overall hypothesis is that self-renewal and survival of these leukemic stem cells are mediated by different molecular pathways than those that stimulate leukemic cell proliferation, and targeting leukemic stem cells is essential to curative therapy of Ph+ leukemias. This project uses the efficient, accurate mouse models for Ph+ leukemias to identify and characterize leukemic stem cells by focusing on three specific aims: 1) To determine which hematopoietic lineages of BCR-ABL-transduced bone marrow cells transfer Ph+ leukemias, affect leukemic stem cell function, and are sensitive to BCR-ABL kinase inhibitors. Leukemic mice will be treated with a BCR-ABL kinase inhibitor imatinib or BMS-354825, followed by the analysis of leukemic stem cells using multicolor FACS to identify and sort different cell lineages for adoptive transfer of the diseases and for examination of survival/self-renewal of the stem cells. 2) To determine the hematopoietic lineages in which 2-catenin is activated by BCR-ABL, to test whether Src kinases are involved in 2-catenin activation in these lineages and have a positive effect on survival of these cells, and to establish the role of 2-catenin in BCR-ABL leukemogenesis. Src kinase-deficient mice and Src kinase inhibitors, and 2-catenin conditional knockout mouse will be used to address the role of 2-catenin in BCR-ABL leukemogenesis. 3) To determine the inhibitory mechanism of a novel anti-stem cell agent BMS-214662 on survival of BCR-ABL-expressing HSCs and to test whether this compound in combination with a BCR-ABL kinase inhibitor provides a curative therapy for Ph+ leukemias. Leukemic mice will be treated with BMS-214662 alone or together with a dual BCR- ABL/Src kinase inhibitor BMS-254825, followed by the analysis of survival/self-renewal of leukemic stem cells in mice. This study will help to understand the biology of leukemia stem cells and develop novel anti-stem cell strategies for Ph+ leukemias.

描述（由申请人提供）：该项目的总体目标是确定可能是治疗人类费城染色体染色体阳性（pH+）白血病的靶标的白血病启动（STEM）细胞自我更新和生存的分子机制。由BCR-ABL癌基因诱导的pH+白血病，包括慢性髓样白血病（CML）和B细胞急性淋巴细胞白血病（B-ALL），是最常见的骨髓增生性恶性肿瘤之一。对于大多数患者而言，同种异体骨髓移植是CML的唯一已建立的治疗疗法。包括伊马替尼甲酸酯（Gleevec）在内的BCR-Abl酪氨酸激酶抑制剂在治疗慢性期CML患者方面非常有效，但不再先进的CML爆炸危机和PH+ B-ALL患者。此外，对伊马替尼的临床抗性发展，伊马替尼不能完全消除白血病干细胞，这表明使用BCR-ABL激酶抑制剂（如伊马替尼）作为单一药物不会防止最终的疾病进展或治愈CML。需要新的治疗策略，尤其是对于老年CML患者。我们的总体假设是，这些白血病干细胞的自我更新和存活与刺激白血病细胞增殖的分子途径不同，靶向白血病干细胞对于治愈pH+白血病的治疗至关重要。该项目使用有效，准确的小鼠模型用于PH+白血病，通过重点关注三个特定目的来识别和表征白血病干细胞：1）确定BCR-ABL-ABL-ALB-ABL转导的骨髓细胞的造血谱系传递pH+白血病，影响白血病细胞的功能，并对BCR-ABL-ABL KINase Indimanase Indimanase Indimanse Indibitors敏感。白血病小鼠将用BCR-ABL激酶抑制剂伊马替尼或BMS-354825进行治疗，然后使用多色FACS分析白血病干细胞，以识别和对不同的细胞谱系进行疾病的过继转移和对干细胞生存/自我恢复的疾病的过继转移。 2）确定通过BCR-ABL激活2-catenin的造血谱系，以测试SRC激酶在这些谱系中是否参与了2-catenin激活，并对这些细胞的存活产生积极作用，并确定2-catenin在BCR-ABL白细胞生生成中的作用。 SRC激酶缺陷型小鼠和SRC激酶抑制剂和2-catenin条件基因敲除小鼠将用于解决2-catenin在BCR-ABL白血病发生中的作用。 3）确定新型抗茎细胞剂BMS-214662对表达BCR-ABL的HSC存活的抑制作用机制，并测试该化合物是否与BCR-ABL激酶抑制剂结合使用，为pH+白血病提供了一种治疗疗法。白血病小鼠将单独或与双BCR-ABL/SRC激酶抑制剂BMS-254825一起使用BMS-214662处理，然后分析小鼠白血病干细胞的生存/自我更新。这项研究将有助于理解白血病干细胞的生物学，并开发出新的pH+白血病抗茎细胞策略。