Pathophysiology of Adult T-cell leukemia/lymphoma

成人 T 细胞白血病/淋巴瘤的病理生理学

• 批准号: 10609828
• 负责人: Utpal P Dave
• 金额: --
• 依托单位: RLR VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10609828
• 关键词: Acute T Cell Leukemia; Address; Adult; Adult Precursor T Lymphoblastic Leukemia; Adult T-Cell Leukemia/Lymphoma; Affect; Apoptosis; BHLH Protein; Binding; Binding Proteins; Biochemical; Biological Models; Caring; Cells; Characteristics; Child; Clinical; Complex; Cytotoxic Chemotherapy; Data; Diagnosis; Disease remission; Epidemiology; Functional disorder; GATA1 gene; Grant; Growth; Hematopoietic stem cells; Human; Immunoblot Analysis; Immunophenotyping; JAK1 gene; Knowledge; LIM Domain; LMO2 gene; LYL1 gene; Learning; Lentivirus Vector; Macromolecular Complexes; Malignant Neoplasms; Modeling; Oncogenes; Oncogenic; Pathway interactions; Patients; Pattern; Population; Prognosis; Proliferating; Property; Protein Binding Domain; Proteins; Proteomics; Relapse; Remission Induction; Resistance; Role; Structure; T-Lymphocyte; TAL1 gene; Technology; Testing; Therapeutic; Translating; Veterans; aged; chemotherapy; drug candidate; high risk; human model; leukemia; leukemia initiating cell; leukemia/lymphoma; male; military veteran; mouse model; mutant; novel; relapse patients; relapse risk; response; selective expression; small molecule; stem cells; stem-like cell; targeted treatment; therapy resistant; transcriptome sequencing; transcriptomics; Acute T Cell Leukemia; Address; Adult; Adult Precursor T Lymphoblastic Leukemia; Adult T-Cell Leukemia/Lymphoma; Affect; Apoptosis; BHLH Protein; Binding; Binding Proteins; Biochemical; Biological Models; Caring; Cells; Characteristics; Child; Clinical; Complex; Cytotoxic Chemotherapy; Data; Diagnosis; Disease remission; Epidemiology; Functional disorder; GATA1 gene; Grant; Growth; Hematopoietic stem cells; Human; Immunoblot Analysis; Immunophenotyping; JAK1 gene; Knowledge; LIM Domain; LMO2 gene; LYL1 gene; Learning; Lentivirus Vector; Macromolecular Complexes; Malignant Neoplasms; Modeling; Oncogenes; Oncogenic; Pathway interactions; Patients; Pattern; Population; Prognosis; Proliferating; Property; Protein Binding Domain; Proteins; Proteomics; Relapse; Remission Induction; Resistance; Role; Structure; T-Lymphocyte; TAL1 gene; Technology; Testing; Therapeutic; Translating; Veterans; aged; chemotherapy; drug candidate; high risk; human model; leukemia; leukemia initiating cell; leukemia/lymphoma; male; military veteran; mouse model; mutant; novel; relapse patients; relapse risk; response; selective expression; small molecule; stem cells; stem-like cell; targeted treatment; therapy resistant; transcriptome sequencing; transcriptomics

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive cancer in adult patients. Adult T-ALL is frequently the Early T-cell Precursor (ETP-ALL) subtype that manifests with treatment-resistance and high risk of relapse. The demographic of adult T-ALL matches that of young Veterans so this grant has the potential to impact the diagnosis and care of this Veteran population. Like many aggressive human leukemias and lymphomas, T-ALL can be put into remission by cytotoxic chemotherapy yet the majority of patients relapse. We have learned from our studies that targeted therapies against mutant oncogenes stimulating proliferation, like JAK1/3, also induce responses that are short lived. In these cancers, the high rate of complete remission followed by the high rate of relapse is explained by the presence of treatment-resistant leukemia-initiating cells (LIC) that have hematopoietic stem cell-like features. The LIC lie dormant and survive during chemotherapy and then expand after remission- induction. Hence, targeting this LIC population is crucial to achieving cures. LIM domain Only-2 (LMO2) is a major driver oncogene in T-ALL, where it confers stem cell characteristics upon normal T-cell progenitor cells. Targeting LMO2-induced T-ALL LIC will involve targeting the LMO2 complex. Towards this end, we have biochemically characterized the LMO2 complex to understand its structure and function. In preliminary data, we show that LMO2’s oncogenic function requires it to act as part of a multisubunit macromolecular complex. LMO2’s direct binding partners include the basic helix-loop-helix proteins, TAL1 or LYL1, and the GATA motif binding proteins GATA1, 2, and 3. We discovered that LMO2’s ability to induce T-ALL is exquisitely dependent upon another protein, LIM domain binding 1 (LDB1), to which LMO2 is constitutively bound. LDB1 has its own interaction partners, namely the Single Stranded Binding Proteins SSBP1-4. Importantly, LMO2 complex formation confers protein stability. In the course of our studies, we made observations that could hold the key to better understanding LMO2’s induction of the LIC and to better targeting of the LMO2 complex. Although LMO2’s induction of the LIC in mouse models has been extensively studied, this has not been translated to human cells. We hypothesize that LIC properties are conferred by the LMO2 complex upon T-cell progenitor cells. Furthermore, our proteomic studies reveal a panoply of paralogous proteins in the LMO2 complex but we do not believe they are functionally equivalent. We hypothesize unique functional roles for the various paralogues of the LMO2 complex, TAL1 v. LYL1, GATA factors 1-3, and SSBP factors 2 v. 3. We will investigate this in a novel human modeling system. Lastly, we hypothesize that targeted therapy against LMO2 will involve perturbation of the LMO2 complex. The Specific Aims of this grant will advance our understanding of how LMO2 functions and how it may be targeted in these aggressive leukemias.

T细胞急性淋巴细胞白血病（T-All）是成年患者的侵略性癌症。成人T-ALL经常 早期的T细胞前体（ETP-ALL）亚型表现出耐药性和高风险退休风险。 成人T-All的人群与年轻退伍军人的人口相匹配，因此该赠款有可能影响 诊断和护理这一老兵。像许多侵略性的人类白血病和淋巴瘤一样，T-All 可以通过细胞毒性化学疗法来缓解，但大多数患者中继。我们从 我们针对抗突变癌基因的疗法刺激加剧的研究，例如JAK1/3 短暂的回答。在这些癌症中，完全缓解的高率，然后是高率 继电器的存在是通过造血性的抗治疗性白血病发射细胞（LIC）来解释的 干细胞状特征。 LIT在化疗期间处于休眠状态并存活，然后在缓解后扩展 就职。因此，针对这种LIC人群对于实现治疗至关重要。 lim域仅2（LMO2）是 T-All的主要驱动器癌基因在正常T细胞祖细胞上承认干细胞特征。 靶向LMO2诱导的T-ALL LIC将涉及针对LMO2复合物。为此，我们有 生化的LMO2复合物以了解其结构和功能。在初步数据中，我们 证明LMO2的致癌功能要求它充当多基因大分子复合物的一部分。 LMO2的直接结合伙伴包括基本的螺旋 - 环螺旋蛋白，TAL1或LYL1，以及GATA主题 结合蛋白GATA1、2和3。我们发现LMO2诱导T-ALL的能力完全取决于 在另一种蛋白质上，LIM结构域结合1（LDB1），LMO2与该结合构成结合。 LDB1有自己的 相互作用伙伴，即单链结合蛋白SSBP1-4。重要的是，LMO2复合物 形成贡献蛋白质稳定性。在学习过程中，我们进行了观察，可以保留 更好地了解LMO2对LIC的诱导并更好地靶向LMO2复合体。虽然LMO2 小鼠模型中LIC的诱导已被广泛研究，这尚未转换为人类细胞。 我们假设LMO2复合物在T细胞祖细胞上赋予LIC特性。 此外，我们的蛋白质组学研究揭示了LMO2复合物中的副蛋白的泛蛋白，但我们没有 认为它们在功能上是等效的。我们假设为各种副产品的独特功能作用 LMO2复合物，TAL1v。Lyl1，GATA因子1-3和SSBP因子2v。3。 人类建模系统。最后，我们假设针对LMO2的靶向治疗将涉及 LMO2复合物。这笔赠款的具体目的将促进我们对LMO2运作方式和 在这些积极的白血病中，它如何针对。