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

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) 是成人患者中的一种侵袭性癌症。成人 T-ALL 常见 早期 T 细胞前体 (ETP-ALL) 亚型，表现为治疗耐药和高复发风险。 成年 T-ALL 的人口结构与年轻退伍军人的人口结构相匹配，因此这笔赠款有可能影响 对退伍军人群体进行诊断和护理。与许多侵袭性人类白血病和淋巴瘤一样，T-ALL 可以通过细胞毒性化疗缓解，但大多数患者会复发。我们从中学到了 我们的研究针对刺激增殖的突变癌基因（如 JAK1/3）进行靶向治疗，也诱导 短暂的反应。在这些癌症中，完全缓解率很高，随后的复发率也很高。 复发的原因是存在具有造血功能的耐药性白血病起始细胞 (LIC) 干细胞样特征。 LIC 处于休眠状态并在化疗期间存活，然后在缓解后扩展 - 就职。因此，针对低收入人群对于实现治愈至关重要。 LIM 域 Only-2 (LMO2) 是 T-ALL 中的主要驱动癌基因，它赋予正常 T 细胞祖细胞干细胞特征。 靶向 LMO2 诱导的 T-ALL LIC 将涉及靶向 LMO2 复合物。为此，我们有 对 LMO2 复合物进行生化表征，以了解其结构和功能。在初步数据中，我们 研究表明，LMO2 的致癌功能要求它作为多亚基大分子复合物的一部分。 LMO2 的直接结合伙伴包括基本螺旋-环-螺旋蛋白、TAL1 或 LYL1 以及 GATA 基序 结合蛋白 GATA1、2 和 3。我们发现 LMO2 诱导 T-ALL 的能力高度依赖 LMO2 与另一种蛋白质 LIM 结构域结合 1 (LDB1) 组成型结合。 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 形成赋予蛋白质稳定性。在我们的研究过程中，我们进行了一些观察，这些观察可能是解决问题的关键 更好地了解 LMO2 对 LIC 的诱导并更好地靶向 LMO2 复合物。虽然LMO2的 小鼠模型中 LIC 的诱导已被广泛研究，但尚未转化为人类细胞。 我们假设 LIC 特性是由 LMO2 复合物赋予 T 细胞祖细胞的。 此外，我们的蛋白质组学研究揭示了 LMO2 复合物中的一系列旁系同源蛋白质，但我们没有 相信它们在功能上是等效的。我们假设各种旁系同源物具有独特的功能作用 LMO2 复合物、TAL1 与 LYL1、GATA 因子 1-3 和 SSBP 因子 2 v. 3。我们将在小说中对此进行研究 人体建模系统。最后，我们假设针对 LMO2 的靶向治疗将涉及扰动 LMO2复合体。这笔赠款的具体目标将加深我们对 LMO2 功能和功能的理解 如何针对这些侵袭性白血病进行靶向治疗。

项目成果

Regulation of cellular sterol homeostasis by the oxygen responsive noncoding RNA lincNORS.

• DOI: 10.1038/s41467-020-18411-x
• 发表时间: 2020-09-21
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Wu X;Niculite CM;Preda MB;Rossi A;Tebaldi T;Butoi E;White MK;Tudoran OM;Petrusca DN;Jannasch AS;Bone WP;Zong X;Fang F;Burlacu A;Paulsen MT;Hancock BA;Sandusky GE;Mitra S;Fishel ML;Buechlein A;Ivan C;Oikonomopoulos S;Gorospe M;Mosley A;Radovich M;Davé UP;Ragoussis J;Nephew KP;Mari B;McIntyre A;Konig H;Ljungman M;Cousminer DL;Macchi P;Ivan M
• 通讯作者: Ivan M

Epigenetic Aberrations and Targets in Peripheral T-Cell Lymphoma.

• DOI: 10.1016/j.clml.2022.04.015
• 发表时间: 2022-04
• 期刊: Clinical lymphoma, myeloma & leukemia
• 作者: Suheil Albert Atallah-Yunes;M. Robertson;Utpal P. Davé

Primary cutaneous peripheral T-cell lymphoma, not otherwise specified with mammalian target of rapamycin mutation: A novel finding for targeted treatment.

• DOI: 10.1016/j.jdcr.2020.08.041
• 发表时间: 2020-12
• 期刊: JAAD case reports
• 作者: De la Sancha C;Burgin C;Warren S;Hoffmann K;Davé U;Nassiri M
• 通讯作者: Nassiri M

Loss of Dnmt3a impairs hematopoietic homeostasis and myeloid cell skewing via the PI3Kinase pathway.

• DOI: 10.1172/jci.insight.163864
• 发表时间: 2023-05-08
• 期刊: JCI INSIGHT
• 影响因子: 8
• 作者: Palam, Lakshmi Reddy;Ramdas, Baskar;Pickerell, Katelyn;Pasupuleti, Santhosh Kumar;Kanumuri, Rahul;Cesarano, Annamaria;Szymanski, Megan;Selman, Bryce;Dave, Utpal P.;Sandusky, George;Perna, Fabiana;Paczesny, Sophie;Kapur, Reuben
• 通讯作者: Kapur, Reuben

PI3Kγ/δ and NOTCH1 Cross-Regulate Pathways That Define the T-cell Acute Lymphoblastic Leukemia Disease Signature.

• DOI: 10.1158/1535-7163.mct-17-0141
• 发表时间: 2017-10
• 期刊: Molecular cancer therapeutics
• 影响因子: 5.7
• 作者: Efimenko E;Davé UP;Lebedeva IV;Shen Y;Sanchez-Quintero MJ;Diolaiti D;Kung A;Lannutti BJ;Chen J;Realubit R;Niatsetskaya Z;Ten V;Karan C;Chen X;Califano A;Diacovo TG
• 通讯作者: Diacovo TG