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

• 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
• 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' s lymphoma; mouse model; novel; overexpression; premalignant; prevent

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 高危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（Burkitt's） 淋巴瘤（BL）和B细胞急性淋巴细胞白血病（B-ALL）仍然是迫切的临床需求。发展 这种干预需要深入了解进化背后的分子机制，即， 这些恶性肿瘤的开始、建立和维持。B细胞恶性肿瘤的发生率>5倍 在患有难治性自身免疫性B淋巴细胞增生性疾病的患者中， 红斑狼疮（SLE），使得SLE成为研究B细胞肿瘤起始的相关疾病模型。的 已知激素催乳素（PRL）会加重SLE的症状，增强淋巴细胞的存活， 促进这些细胞中原癌基因MYC和BCL 2的表达。PRL是否有助于 B细胞恶性肿瘤的演变是未知的。PRL受体（PRLR）是I型细胞因子受体， 具有通过选择性剪接产生的长（LF）、中间（IF，仅在人类中）和短（SF）同种型。 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，SF表达增加可抑制增殖、促进分化并诱导 凋亡我们假设，PRL通过特异性地通过促增殖和抗凋亡信号传导， LF/IFPRLR，促进B细胞恶性转化，并建立和维持明显的B细胞生长。 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-患者体内B细胞的变化。 易感小鼠模型和体外人B细胞恶性肿瘤中特异性敲低 LF/IFPRLR使用无毒剪接调节寡聚体（SMO）。LFPRLR SMO阻止合成 的LFPRLR在小鼠和LF/IFPRLR在人类不影响SFPRLR。敲低 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表达降低狼疮易感小鼠B细胞转化的风险 脱氨酶（AID）酶，其过度表达，我们以前显示，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 LF/IFPRLR。在明显的B细胞恶性肿瘤中LF/IFPRLR的敲低降低了细胞活力，下游STAT 3 MYC和BCL 2的活化和表达。我们的初步研究结果保证了分子的详细研究。 SLE易感小鼠LF/IFPRLR下游B细胞紊乱的潜在途径， 易转化（目的1），在具有易发生明显B细胞恶性肿瘤的癌前B细胞克隆的小鼠中 (Aim 2），并在明显的人类B细胞肿瘤（目的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- 这些患者（目标1）中的恶性细胞肿瘤，在具有癌前病变和惰性B细胞的人群中， 发展为侵袭性B细胞恶性肿瘤（目标2）和明显的B细胞肿瘤（目标3）。