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: 8876933
• 负责人: ANDREI L GARTEL
• 金额: $ 20.85万
• 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 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8876933
• 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; Gene Expression Profiling; Genes; Goals; Grant; HL-60 Cells; HL60; 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; Phenotype; Prognostic Factor; Prognostic Marker; Property; Proteins; RNA Interference; Recurrence; Relapse; Resistance; Risk; Role; Sampling; Stratification; Subgroup; Testing; Time; Tissues; Transplantation; U937 Cells; Vertebral column; Xenograft procedure; biobank; cancer cell; chemotherapy; clinically significant; cohort; imaging modality; imaging system; improved; in vivo; leukemia; liquid crystal polymer; mouse model; mutant; novel; novel strategies; novel therapeutics; nucleophosmin; outcome forecast; overexpression; prognostic; public health relevance; 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（由申请人提供）：过去 30 年来，急性髓系白血病 (AML) 的治疗结果一直很糟糕，20-40% 的患者未能通过诱导化疗获得缓解，50-70% 的患者获得完全缓解。虽然细胞遗传学是风险分层的支柱，但近 50% 的 AML 病例细胞遗传学正常 (CN-AML)。在生物学和临床上，最异质的群体是核-细胞质穿梭蛋白核磷蛋白 (NPM1)，在 50% 的 CN-AML 病例中发生突变，导致该蛋白出现核输出。此类患者的预后良好，无需进行骨髓移植，这一亚型已在 WHO 2008 年分类中被认定为独特的诊断类别。突变的 NPM1 (NPM1mut) 在 CN-AML 中赋予这种优势的机制尚不清楚，此前我们已经证明，NPM1mut 会将其他蛋白伴侣移位到细胞质中，从而影响它们的功能。致癌转录因子与 NPM1 共定位于癌细胞中。在本提案中，我们将使用一种新型多光谱成像方式研究 FOXM1 和 NPM1 的细胞相互作用。 NPM1 在 AML 原代母细胞中的作用我们打算证明 FOXM1 是决定 AML 预后的致癌驱动因素，导致其核输出。将 FOXM1 错误定位到细胞质中，使其作为转录因子失活，这可能是这一相当大的 AML 患者亚群结果改善的原因，我们将在几种 AML 细胞系中测试 FOXM1 敲低或 FOXM1 过度表达将如何影响化疗药物的敏感性。我们将确定 FOXM1 核定位的 AML 细胞系中的 FOXM1 敲除是否会使它们对化疗更加敏感。具有稳定的 FOXM1 敲低的 AML 细胞系或具有稳定的 FOXM1 敲低或 FOXM1 过表达的 OCI-AML3 细胞系，以及与对照细胞系建立异种移植肿瘤，我们预计 U937 和 HL60 AML 细胞系中的 FOXM1 敲低将增加对治疗的敏感性。与此相反，在 OCI-AML3 细胞中，这些 AML 细胞系诱导的异种移植肿瘤位于细胞质中的 FOXM1 受到抑制。细胞系不会影响该细胞系诱导的异种移植肿瘤对化疗的敏感性。我们提案中描述的实验将揭示细胞质 FOXM1 是否是 AML 的新预后因素，以及 FOXM1 的核表达是否决定了 AML 细胞诱导的异种移植肿瘤的耐药性。化疗线。