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: 10369933
• 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/10369933
• 关键词: Acute Lymphocytic Leukemia; 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; JAK1 gene; Knowledge; LIM Domain; LMO2 gene; LYL1 gene; Lentivirus Vector; Macromolecular Complexes; Malignant Neoplasms; Modeling; Oncogenes; Oncogenic; Pathway interactions; Patients; Pattern; Population; Prognosis; Property; Protein Binding Domain; Proteins; Proteomics; RNA analysis; Relapse; Remission Induction; Resistance; Risk; 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）是一种侵袭性癌症。成人T-ALL是常见的