Targeting the CaM Kinases in Treating Myeloid Leukemia

靶向 CaM 激酶治疗髓系白血病

• 批准号: 7626246
• 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 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7626246
• 关键词: Acute Myelocytic Leukemia; Acute Promyelocytic Leukemia; Calmodulin; Cell Culture Techniques; Cell Differentiation process; Cell Line; Cells; Clinical; Exhibits; Family; Gene Targeting; Goals; Human; In Vitro; Knowledge; Lentivirus Vector; 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）：急性髓性白血病（AML）是由于正常骨髓前体细胞/干细胞的终末分化受阻导致未成熟成粒细胞潜在致命的积累而引起的。诸如视黄酸（RA）之类的药物可以增强某些髓系白血病细胞的终末分化，并且在治疗髓系白血病的急性早幼粒细胞白血病（APL）子集方面具有重大的治疗作用。然而，尽管 RA 治疗，20-30% 的 APL 患者仍然会复发，而大多数其他类型的 AML 对 RA 根本没有反应。定义调节 RA 受体活性的因素将有助于深入了解为什么这些不同的 AML 细胞对 RA 的反应不同。我们观察到 Ca++ 调节蛋白激酶（CaM 激酶）是 RA 受体活性和骨髓性白血病细胞分化的关键调节因子。事实上，KN62 是 CaM 激酶的小分子抑制剂，可在体外触发某些 AML 细胞的终末分化。我们的长期目标是确定 CaM 激酶在调节 RA 受体活性和骨髓分化中先前未探索的作用的分子基础，我们希望将这一知识转化为针对某些人类髓系白血病的新型靶向治疗。在特定目标 I 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 诱导的分化敏感的髓系白血病细胞的分化中的作用。在特定目标 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，以便从生化和分子水平上区分这些不敏感的 AML 细胞与特定目标 I 中分析的敏感细胞系。最后，在特定目标 III 中，我们将评估短期培养中的原代 AML 样本对 RA 和 KN62 的分化反应，并确定它们的反应与特定目标是否存在任何相关性。 这些不同的原发性 AML 细胞表现出的临床病理学或分子参数。 关联。这些研究将剖析 CaM 激酶在调节髓系白血病细胞分化中的一种新的、先前未探索的作用，并且与确定人类髓系白血病临床治疗的新分子靶点直接相关。