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).

项目摘要高风险B细胞恶性肿瘤的早期干预措施，包括弥漫性大B细胞淋巴瘤（DLBCL），Burkitt's 淋巴瘤（BL）和B细胞急性淋巴细胞白血病（B-ALL）仍然是紧迫的临床需求。发展在这种干预措施中，需要深入了解进化进化的分子机制，即这些恶性肿瘤的启动，建立和寄托。 B细胞恶性肿瘤的开始> 5倍经常患有难治性自身免疫性B淋巴增生性疾病（例如全身性）的患者狼疮红膜（SLE），使SLE成为研究B细胞肿瘤开始的相关疾病模型。这众所周知，激素催乳素（PRL）会加剧SLE的症状，增强淋巴样细胞的存活和在这些细胞中促进原始基因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长（LF），中间（如果仅在人类中）和替代剪接产生的短（SF）同工型。 LF/如果相对于细胞上的SF PRLS的表达增加会导致细胞增殖和存活，而相对于LF/IF抑制增殖，促进分化并诱导SF的表达增加凋亡。我们假设PRL是通过促生产性和抗凋亡的特殊信号来发出的 LF/IFPRLR，促进B细胞的恶性转化，并建立和维持公开的增长 B细胞恶性肿瘤。为了检验我们的假设，我们在SLE和DLBCL/BL-中测量了B细胞的变化俯卧的小鼠模型和在人类B细胞恶性肿瘤中的体外特异性击倒表达后 LF/IFPRLR使用无毒剪接调节寡聚物（SMO）。 LFPRLR SMO阻止合成小鼠的LFPRLR和人类中的LF/IFPRLR的数量，而不会影响SFPRLR。击倒 LFPRLR减少了在SLE和DLBCL/BL-丙打小鼠中的致病性B细胞子集的数量，并降低了通过下调激活诱导的胞苷的表达，在SLE易发的小鼠中发生B细胞转化的风险脱氨酶（AID）酶，我们先前显示的过表达驱动B细胞的演变肿瘤。我们发现明显的人类B细胞肿瘤异常表达自分泌PRL，有时只是 LF/IFPRLR。公开B细胞恶性肿瘤中LF/IFPRLR的敲低可降低细胞活力，下游STAT3 MYC和BCL2的激活和表达。我们的初步发现保证了分子的详细研究 LF/IFPRLR的B细胞中的障碍的途径容易受到转化的攻击（AIM 1），在具有明显的B细胞恶性肿瘤前b-cell克隆的小鼠中（AIM 2），在公开的人类B细胞肿瘤中（AIM 3）。我们的研究将巩固同工型特异性抑制 LF/IFPRLR作为SLE的治疗策略的生产，同时降低了B-的发生率这些患者的细胞恶性肿瘤（AIM 1），具有脆弱性和懒惰的B细胞的患者发展积极的B细胞恶性肿瘤（AIM 2）和公开的B细胞肿瘤（AIM 3）。