Cytoplasmic FOXM1 contributes to the higher complete remission and longer overall survival of AML patients after chemotherapy

细胞质 FOXM1 有助于 AML 患者化疗后更高的完全缓解率和更长的总生存期

• 批准号: 9061641
• 负责人: ANDREI L GARTEL
• 金额: $ 17.39万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-01 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9061641
• 关键词: Accounting; Acute Myelocytic Leukemia; Affect; Allogenic; Apoptosis; Archives; Biological Markers; Blast Cell; Bone Marrow; Bone Marrow Transplantation; Categories; Cell Communication; Cell Line; Cell Nucleus; Cell Proliferation; Cells; Characteristics; Chromosome abnormality; Classification; Clinical; Cytarabine; Cytogenetics; Cytoplasm; Data; Development; Diagnosis; Diagnostic; Disease; Disease remission; Doxorubicin; FOXM1 gene; Gene Expression Profiling; Genes; Goals; Grant; HL-60 Cells; HL60; Health; Hematologic Neoplasms; Human; Immunofluorescence Immunologic; In Vitro; Laboratories; Link; Malignant Neoplasms; Molecular; Molecular Profiling; Mus; Mutate; Mutation; NPM1 gene; Neoplasms; Nuclear; Nuclear Export; Nude Mice; Oncogenic; One-Step dentin bonding system; Outcome; Pathologic; Patients; Pharmaceutical Preparations; Pharmacotherapy; Phenotype; Prognostic Factor; Prognostic Marker; Property; Proteins; RNA Interference; Recurrence; Relapse; Resistance; Risk; Role; Sampling; Stratification; Subgroup; Testing; Time; Tissue imaging; Transplantation; U937 Cells; Vertebral column; Xenograft procedure; biobank; cancer cell; chemotherapy; clinically significant; cohort; imaging modality; imaging system; improved; improved outcome; in vivo; knock-down; leukemia; liquid crystal polymer; mouse model; mutant; novel; novel strategies; novel therapeutics; nucleophosmin; outcome forecast; overexpression; prognostic; research study; response; transcription factor; treatment strategy; tumor; tumor xenograft

 DESCRIPTION (provided by applicant): The outcomes for acute myeloid leukemia (AML) have remained abysmal for the past 30 years. 20- 40% of patients fail to achieve remission with induction chemotherapy, and 50-70% of patients who achieve a complete remission relapse within 3 years. While cytogenetics are the backbone of risk-stratification, nearly 50% of AML cases are cytogenetically normal (CN-AML) and, biologically and clinically, the most heterogenous group. The nucleo-cytoplasmic shuttle protein nucleophosmin (NPM1) is mutated in 50% of CN-AML cases resulting in the nuclear export of this protein. This has been shown in large clinical cohorts to confer a favorable prognosis and obviates the need for a bone marrow transplant in these patients. This subset of AML has been recognized in a unique diagnostic category in the WHO 2008 classification of hematologic malignancies. The mechanism by which mutated NPM1 (NPM1mut) confers this advantage in CN-AML is unclear. It has previously been hypothesized that NPM1mut dislocates other protein partners into the cytoplasm and consequently affecting their function. We have previously demonstrated that FOXM1, an oncogenic transcription factor, co-localizes with NPM1 in cancer cells. In this proposal, using a novel multispectral imaging modality we will study the cellular interaction of FOXM1 and NPM1 in AML primary blast cells. We will also investigate the functional significance of FOXM1 localization in this disease using AML cell lines. Importantly, we will assess the clinical correlation of mislocalized cytoplasmic FOXM1 with outcomes in AML with the goal of examining its role as a favorable prognostic marker in CN-AML. We intend to show that FOXM1 is the oncogenic driver dictating prognosis in AML. Mutations in NPM1 resulting in its nuclear export mislocalizes FOXM1 to the cytoplasm where it is inactive as a transcription factor. This may account for the improved outcome in this sizeable subset of AML patients. In several AML cell lines we will test how FOXM1 knockdown or FOXM1 overexpression will affect sensitivity to chemotherapeutic drugs in vitro and vivo. We will determine whether FOXM1 knockdown in AML cell lines with nuclear localization of FOXM1 makes them more sensitive to chemotherapy. Nude mice will be injected with AML cell lines with stable FOXM1 knockdown or OCI-AML3 cell line with stable FOXM1 knockdown or with FOXM1 overexpression, and with control cell lines to establish xenograft tumors. We expect that FOXM1 knockdown in U937 and HL60 AML cell lines will increase sensitivity to treatment in xenograft tumors induced by these AML cell lines. I contrast, suppression of FOXM1, localized in the cytoplasm, in OCI-AML3 cell line would not affect sensitivity to chemotherapy in xenograft tumors induced by this cell line. The experiments described in our proposal will reveal if cytoplasmic FOXM1 is a novel favorable prognostic factor in AML and whether nuclear expression of FOXM1 determines the resistance of xenograft tumors induced by AML cell lines to chemotherapy.

 描述（由适用提供）：在过去的30年中，急性髓细胞性白血病（AML）的结果一直保持糟糕。 20-40％的患者无法通过诱导化疗来缓解，而在3年内实现完全缓解继电器的患者中有50-70％。虽然细胞遗传学是风险分层的骨干，但几乎50％的AML病例在细胞遗传学上是正常的（CN-AML），并且在生物学上和临床上是最异性的组。在50％的CN-AML病例中，将核质梭菌蛋白核磷灰石（NPM1）突变，从而导致该蛋白的核出口。这已经在大型临床队列中显示出来，以赋予有利的预后，并消除了这些患者对骨髓移植的需求。 AML的这一子集已在WHO 2008年血液学恶性肿瘤分类中的独特诊断类别中得到认可。突变的NPM1（NPM1MUT）在CN-AML中承认这种优势的机制尚不清楚。以前已经假设NPM1MUT将其他蛋白质伴侣置入细胞质中，从而影响其功能。我们以前已经证明，一种致癌转录因子FOXM1与NPM1在癌细胞中共定位。在此提案中，使用新型的多光谱成像方式，我们将研究AML原代爆炸细胞中FOXM1和NPM1的细胞相互作用。我们还将使用AML细胞系研究该疾病中FOXM1定位的功能意义。重要的是，我们将评估错误定位的细胞质FOXM1与AML结果的临床相关性，目的是研究其作为CN-AML中有利的预后标记的作用。我们打算表明，FOXM1是肿瘤驱动器，在AML中指示预后。 NPM1中的突变导致其核出口将FOXM1错误定位到细胞质中，在该细胞质中它是不活跃的转录因子。这可能是AML患者的大量子集的结果改善。在几种AML细胞系中，我们将测试FOXM1敲低或FOXM1过表达如何影响对体外和体内化学治疗药物的敏感性。我们将确定FOXM1在AML细胞系中是否具有FOXM1的核定位置使它们对化学疗法更敏感。裸鼠将用稳定的FOXM1敲低或OCI-AML3细胞系注射AML细胞系，具有稳定的FOXM1敲低或FOXM1的过表达，并具有控制细胞系以建立Xenographic肿瘤。我们预计U937和HL60 AML细胞系中的FOXM1敲低将增加对这些AML细胞系诱导的元素肿瘤治疗的敏感性。 I对比了，在OCI-AML3细胞系中定位于细胞质中的FOXM1的抑制不会影响该细胞系诱导的异种移植肿瘤化学疗法的敏感性。我们的提案中描述的实验将揭示细胞质FOXM1是否是AML中的一个新颖的预后因素，以及FOXM1的核表达是否确定AML细胞系对化学疗法诱导的异种移植肿瘤的抗性。