Targeting the CaM Kinase Cascade in Treating Myeloid Leukemia

靶向 CaM 激酶级联治疗髓系白血病

• 批准号: 7246550
• 负责人: STEVEN Collins COLLINS
• 金额: $ 26.84万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7246550
• 关键词: Acute; Acute Myelocytic Leukemia; Acute Promyelocytic Leukemia; Calmodulin; Cell Differentiation process; Cell Line; Cells; Clinical; Cultured Cells; Exhibits; Family; Gene Targeting; Goals; Human; In Vitro; Knowledge; Lentivirus Vector; Localized; Maps; Mediating; Molecular; Molecular Target; Myelogenous; Myeloid Cells; Myeloid Leukemia; Neurons; Patients; Phosphorylation; Phosphorylation Site; Phosphotransferases; Protein Kinase; RNA Interference; Relapse; Resistance; Retinoic Acid Receptor; Role; Sampling; Stem cells; Testing; Therapeutic; Transduction Gene; Translating; Tretinoin; base; chromatin immunoprecipitation; immunocytochemistry; inhibitor/antagonist; insight; kinase inhibitor; member; myeloblast; novel; promoter; response; small molecule

DESCRIPTION (provided by applicant): Acute myelogenous leukemia (AML) results from a block in the terminal differentiation of normal myeloid precursors/stem cells leading to the potentially lethal accumulation of immature myeloblasts. Agents such as retinoic acid (RA) can enhance the terminal differentiation of certain myeloid leukemia cells and have had a major therapeutic impact in the treatment of the acute promyelocytic leukemia (APL) subset of myeloid leukemia. Nevertheless 20-30% of APL patients still relapse despite RA therapy, and most other types of AML fail to respond at all to RA. Defining factors which regulate RA receptor activity will provide insight into why these different AML cells respond differently to RA. We have observed that the Ca++regulated protein kinases (CaM kinases) are critical regulators of both RA receptor activity and myeloid leukemia cell differentiation. Indeed KN62, a small molecule inhibitor of the CaM kinases, triggers the in vitro terminal differentiation of certain AML cells. Our Long Term Objectives are to define the molecular basis for this previously unexplored role of the CaM kinases in regulating RA receptor activity and myeloid differentiation, and we hope to translate this knowledge into novel targeted therapy for certain human myeloid leukemias. In Specific Aim I we will determine the role of CaM kinase expression, cellular localization and enzymatic activity in regulating the differentiation of myeloid leukemia cells that are sensitive to RA and KN62 induced differentiation. In Specific Aim II we will explore CaM kinase expression, localization and activity in AML cell lines that are insensitive to RA/KN62 in an effort to biochemically and molecularly distinguish these insensitive AML cells from the sensitive cell lines analyzed in Specific Aim I. Finally in Specific Aim III we will assess the differentiative response of primary AML samples in short term culture to RA and KN62 and determine whether there is any correlation of their response with the specific clinicopathological or molecular parameters exhibited by these different primary AML cells. Relevance. These studies will dissect a new, previously unexplored role of the CaM kinases in regulating the differentiation of myeloid leukemia cells and are directly relevant for identifying new molecular targets for the clinical therapy of the human myeloid leukemias.

描述（由申请人提供）：急性髓质白血病（AML）是由正常髓样前体/干细胞末端分化的块引起的，导致可能未成熟的髓细胞的致命积累。诸如视黄酸（RA）之类的药物可以增强某些髓样白血病细胞的末端分化，并在治疗急性前临床白血病（APL）子集的治疗中具有重大治疗作用。尽管如此，尽管RA疗法，但仍有20-30％的APL患者仍会复发，而大多数其他类型的AML对RA根本没有反应。定义调节RA受体活性的因素将为为什么这些不同的AML细胞对RA的反应不同。我们已经观察到Ca ++调节的蛋白激酶（CAM激酶）是RA受体活性和髓样白血病细胞分化的关键调节剂。实际上，KN62是CAM激酶的小分子抑制剂，可触发某些AML细胞的体外末端分化。我们的长期目标是定义CAM激酶在调节RA受体活性和髓样分化中的这种先前未开发的作用的分子基础，我们希望将这些知识转化为某些人类髓样白血病的新型靶向治疗。在特定目的中，我们将确定CAM激酶表达，细胞定位和酶活性在调节对RA和KN62敏感的髓样白血病细胞分化中的作用。在特定目的II中，我们将探索对RA/KN62不敏感的AML细胞系中的CAM激酶表达，定位和活性，以便在特定目标I中分析的生化和分子分析这些不敏感的AML细胞与分析的敏感细胞系与特定目标I的敏感细胞系进行区分。最后，在特定目标中，在特定的目标III中，我们将评估IS的较短期和kn 66的较短响应，并确定RA62是否具有RA的不同响应，并确定了RA的差异响应。这些不同的原代AML细胞表现出的临床病理或分子参数。 关联。这些研究将剖析CAM激酶在调节髓样白血病细胞分化中的一种新的，以前未开发的作用，并且与鉴定人髓样白血病的临床治疗的新分子靶标直接相关。