Targeting the long isoform of the prolactin receptor to treat autoimmune diseases and B-cell malignancies

靶向催乳素受体的长亚型来治疗自身免疫性疾病和 B 细胞恶性肿瘤

基本信息

批准号：
10735148
负责人：
Srividya Swaminathan
金额：
$ 43.82万
依托单位：
BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-15 至 2028-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10735148
关键词：
Adult Precursor B Lymphoblastic Leukemia Affect Alternative Splicing Apoptotic Autoimmune Autoimmune Diseases B lymphoid malignancy B-Cell Acute Lymphoblastic Leukemia B-Cell Neoplasm B-Lymphocyte Subsets B-Lymphocytes BCL2 gene Biological Burkitt Lymphoma Cell Count Cell Proliferation Cell Survival Cells Cessation of life Childhood Chronic Lymphocytic Leukemia Clinical Clone Cells Cytokine Receptors DNA Development Disease model Early Intervention Enzymes Equilibrium Evolution Growth Hormones Human Immune Immunologic Surveillance In Vitro Incidence Indolent Induction of Apoptosis Intervention Investigation Left Legal patent Lymphoid Cell Lymphoid Tissue Lymphoproliferative Disorders MYC gene Malignant - descriptor Malignant Neoplasms Measures Mediating Modeling Molecular Mus Neoplasms Outcome Pathogenicity Pathologic Pathway interactions Patients Persons Phenotype Production Prolactin Prolactin Receptor Proliferating Protein Isoforms Proto-Oncogenes RNA Splicing Refractory Research Risk Role STAT3 gene Signal Transduction Subgroup Symptoms Systemic Lupus Erythematosus Testing Therapeutic Therapeutic Intervention Vulnerable Populations activation-induced cytidine deaminase autocrine cancer cell cell killing cell transformation clinically relevant high risk in vivo innovation knock-down large cell Diffuse non-Hodgkin&apos s lymphoma mouse model novel overexpression premalignant prevent

项目摘要

PROJECT SUMMARY Early interventions for high-risk B-cell malignancies, including diffuse large B cell lymphoma (DLBCL), Burkitt's Lymphoma (BL), and B-cell acute lymphoblastic leukemia (B-ALL), remain an urgent clinical need. Development of such interventions requires a deep understanding of the molecular mechanisms underlying the evolution, i.e., initiation, establishment, and sustenance, of these malignancies. B-cell malignancies are initiated >5-fold more frequently in patients suffering from refractory autoimmune B-lymphoproliferative disorders such as systemic lupus erythematosus (SLE), making SLE a relevant disease model to study initiation of B-cell neoplasms. The hormone prolactin (PRL) is known to exacerbate the symptoms of SLE, enhance survival of lymphoid cells, and promote the expression of the protooncogenes MYC and BCL2 in these cells. Whether PRL contributes to evolution of B-cell malignancies was unknown. PRL receptors (PRLRs) are type I cytokine receptors that have long (LF), intermediate (IF, only in humans) and short (SF) isoforms generated by alternative splicing. Increased expression of the LF/IF relative to the SF PRLRs on cells leads to cell proliferation and survival, whereas increased expression of SFs relative to LF/IF inhibits proliferation, promotes differentiation, and induces apoptosis. We hypothesized that PRL, by signaling specifically through the pro-proliferative and anti-apoptotic LF/IFPRLR, promotes the malignant transformation of B cells, and establishes and sustains the growth of overt B-cell malignancies. To test our hypothesis, we measured changes in B cells in vivo in SLE- and DLBCL/BL- prone mouse models and in vitro in human B-cell malignancies after specifically knocking down expression of the LF/IFPRLR using a non-toxic splice modulating oligomer (SMO). The LFPRLR SMO prevents the synthesis of the LFPRLR in mice and the LF/IFPRLR in humans without affecting the SFPRLRs. Knockdown of LFPRLR reduced the numbers of pathogenic B-cell subsets in SLE- and DLBCL/BL-prone mice and lowered the risk of B-cell transformation in SLE-prone mice by downregulating expression of the activation-induced cytidine deaminase (AID) enzyme, whose overexpression we previously showed, drives the evolution of B-cell neoplasms. We found that overt human B-cell neoplasms aberrantly express autocrine PRL and sometimes only the LF/IFPRLR. Knockdown of LF/IFPRLR in overt B-cell malignancies reduced cell viability, downstream STAT3 activation, and expression of MYC and BCL2. Our preliminary findings warrant detailed studies of molecular pathways underlying the disturbances in B cells downstream of LF/IFPRLR in SLE-prone mice that are vulnerable to transformation (Aim 1), in mice with pre-malignant B-cell clones prone to overt B-cell malignancies (Aim 2), and in overt human B-cell neoplasms (Aim 3). Our research will solidify isoform-specific suppression of the production of LF/IFPRLR as a therapeutic strategy in SLE that concurrently lowers the incidence of B- cell malignancies in these patients (Aim 1), in people with pre-malignant and indolent B cells who are vulnerable to developing aggressive B-cell malignancies (Aim 2), and in overt B-cell neoplasms (Aim 3).

项目概要高风险 B 细胞恶性肿瘤的早期干预，包括弥漫性大 B 细胞淋巴瘤 (DLBCL)、伯基特氏淋巴瘤淋巴瘤 (BL) 和 B 细胞急性淋巴细胞白血病 (B-ALL) 仍然是临床的迫切需求。发展此类干预措施需要深入了解进化背后的分子机制，即这些恶性肿瘤的发生、形成和维持。 B 细胞恶性肿瘤的发生率是原来的 5 倍以上经常发生在患有难治性自身免疫性 B 淋巴细胞增殖性疾病（例如全身性疾病）的患者中红斑狼疮 (SLE)，使 SLE 成为研究 B 细胞肿瘤起始的相关疾病模型。这众所周知，催乳素 (PRL) 会加剧系统性红斑狼疮的症状，增强淋巴细胞的存活率，并且促进这些细胞中原癌基因 MYC 和 BCL2 的表达。 PRL 是否有助于 B 细胞恶性肿瘤的进化尚不清楚。 PRL 受体 (PRLR) 是 I 型细胞因子受体，具有由选择性剪接产生的长（LF）、中间（IF，仅在人类）和短（SF）亚型。细胞上 LF/IF 相对于 SF PRLR 的表达增加导致细胞增殖和存活，而相对于 LF/IF 而言，SF 的表达增加会抑制增殖、促进分化并诱导细胞凋亡。我们假设 PRL 通过促增殖和抗凋亡特异性信号传导 LF/IFPRLR，促进B细胞的恶性转化，并建立和维持明显的生长 B 细胞恶性肿瘤。为了验证我们的假设，我们测量了 SLE 和 DLBCL/BL 体内 B 细胞的变化在特异性敲除以下基因的表达后，在易感小鼠模型和体外人类 B 细胞恶性肿瘤中 LF/IFPRLR 使用无毒剪接调节寡聚物 (SMO)。 LFPRLR SMO 阻止合成小鼠中的 LFPRLR 和人类中的 LF/IFPRLR，而不影响 SFPRLR。击倒 LFPRLR 减少了 SLE 和 DLBCL/BL 易感小鼠中致病性 B 细胞亚群的数量，并降低了通过下调激活诱导的胞苷的表达来降低易患 SLE 的小鼠 B 细胞转化的风险脱氨酶 (AID) 酶（我们之前已证明其过度表达）可驱动 B 细胞的进化肿瘤。我们发现明显的人类 B 细胞肿瘤异常表达自分泌 PRL，有时仅表达 LF/IFPRLR。明显 B 细胞恶性肿瘤中 LF/IFPRLR 的敲低会降低下游 STAT3 的细胞活力 MYC 和 BCL2 的激活和表达。我们的初步发现需要对分子进行详细研究系统性红斑狼疮易感小鼠中 LF/IFPRLR 下游 B 细胞紊乱的潜在途径具有易发生明显 B 细胞恶性肿瘤的癌前 B 细胞克隆的小鼠容易发生转化（目标 1）（目标 2），以及明显的人类 B 细胞肿瘤（目标 3）。我们的研究将巩固异构体特异性抑制 LF/IFPRLR 的产生作为 SLE 的治疗策略，同时降低 B- 的发生率这些患者中的细胞恶性肿瘤（目标 1），以及具有癌前和惰性 B 细胞且易受影响的人群发展为侵袭性 B 细胞恶性肿瘤（目标 2），以及明显的 B 细胞肿瘤（目标 3）。