Targeting the CaM Kinases in Treating Myeloid Leukemia

靶向 CaM 激酶治疗髓系白血病

• 批准号: 7146498
• 负责人: STEVEN Collins COLLINS
• 金额: $ 27.64万
• 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/7146498
• 关键词: cell differentiation; receptor; role

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）是由正常骨髓前体细胞/干细胞终末分化受阻导致未成熟成髓细胞潜在致死性蓄积引起的。诸如视黄酸（RA）的药剂可以增强某些髓性白血病细胞的终末分化，并且在髓性白血病的急性早幼粒细胞白血病（APL）子集的治疗中具有主要的治疗影响。尽管如此，20-30%的APL患者在接受RA治疗后仍会复发，而大多数其他类型的AML对RA完全没有反应。确定调节RA受体活性的因素将有助于了解为什么这些不同的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受体活性和髓系白血病细胞分化的关键调节剂。事实上，KN 62，一种CaM激酶的小分子抑制剂，触发某些AML细胞的体外终末分化。我们的长期目标是确定以前未探索的钙调素激酶在调节RA受体活性和髓系分化中的作用的分子基础，我们希望将这些知识转化为某些人类髓系白血病的新靶向治疗。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KN 62诱导分化敏感的髓性白血病细胞分化中的作用。在Specific Aim II中，我们将探索对RA/KN 62不敏感的AML细胞系中的CaM激酶表达、定位和活性，以在生物化学和分子上区分这些不敏感的AML细胞与Specific Aim 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的原发性AML样本对RA和KN 62的分化反应，并确定其反应是否与这些不同原发性AML细胞表现出的特定临床病理学或分子参数相关。 本案无关这些研究将剖析一个新的，以前未探索的作用，钙调素激酶在调节髓性白血病细胞的分化，并直接相关的识别新的分子靶点的临床治疗的人髓性白血病。