Role of SETBP1 in adult Ph+ acute lymphoblastic leukemia

酪氨酸激酶抑制剂联合化疗显著改善了费城- 染色体阳性（Ph+）B细胞急性淋巴细胞白血病（B-ALL）。然而，由于高复发率， TKI耐药性的发展或化疗诱导的不良反应仍然是主要的治疗方法 挑战此外，并非所有TKI均对Ph+白血病起始细胞（LIC）有效。肿瘤 抑制蛋白磷酸酶2A（PP 2A）在几乎所有实体瘤和造血系统肿瘤中无活性。PP2A 抑制与不良结果和疾病进展相关，并且在很大程度上依赖于异常表达 CIP 2A、SET和/或SETBP 1。SETBP 1被发现是一种SET相互作用蛋白，最近被描述为 在几种骨髓恶性肿瘤中突变或过表达，在这些肿瘤中作为独立的阴性 预后因子和作为PP 2A的抑制剂。因此，SETBP 1可能调节生存和自我调节。 通过抑制PP 2A更新Ph+ B-ALL LIC。已发表的工作和初步数据表明： Ph+（CML和B-ALL）祖细胞和静止期TKI耐药CML中依赖性PP 2A抑制增加 分别为LIC; SET下调或药理学（即SET相互作用PP 2A激活药物; PAD） PP 2A活性的恢复强烈损害恶性造血，但不损害正常造血; 伊马替尼（IM）不敏感，对Ph+ B-ALL的PP 2A抑制和克隆形成潜力至关重要 Ph+细胞中可能存在SETBP 1-SET/CIP 2A复合物，这表明SETBP 1可能用于 募集SET和CIP 2A以抑制PP 2A活性。基于这些考虑以及SETBP 1 稳定SET并增强PP 2A抑制，并且异位SETBP 1表达赋予小鼠自我更新 骨髓祖细胞，并与BCR-ABL 1合作，以诱导小鼠的CML急变样疾病， 驱动这一提议的假设是异常的SETBP 1表达显著地有助于持续的 TKI耐药Ph+ B-ALL LIC。因此，本提案的总体目标有两个方面： Ph+ B-ALL LIC自我更新/存活的SETBP 1-PP 2A相互作用的要求，和B）评估 SETBP 1下调和PP 2A抗TKI活性的药理学恢复的治疗相关性- 耐药LIC。具体而言，我们将：1）确定PP 2A是否在Ph+ B-ALL LIC中受到抑制，如果是， 评估SETBP 1是否是PP 2A抑制复合物的一部分;和2）研究SETBP 1的作用 下调和PAD（例如OSU 2S、FTY 720）治疗对Ph+ B-ALL LIC存活/自我更新的影响（按集落）- 形成细胞/再铺板和系列BM移植测定。我们有信心， 这项工作不仅将推进我们对SETBP 1在白血病中作用的认识， 我们在过去几年中的发现，也将促进Ph+ B-ALL领域的新观察， 其中一些将揭示新的基于PAD的治疗干预策略。因此，强者 这项工作对基础和转化癌症研究的重要性和高度相关性。

Tyrosine kinase inhibitors combined with chemotherapy significantly improved outcomes in adult Philadelphia- chromosome-positive (Ph+) B-cell Acute Lymphoblastic Leukemia (B-ALL). However, high relapse rate due development of TKI resistance or chemotherapy-induced adverse effects remain the major therapeutic challenges. Furthermore, all TKIs are not effective against Ph+ leukemia-initiating cells (LICs). The tumor suppressor protein phosphatase 2A (PP2A) is inactive in almost all solid and hematopoietic tumors. PP2A inhibition correlates with poor outcome and disease progression, and largely relies on the aberrant expression of CIP2A, SET and/or SETBP1. SETBP1 was discovered as a SET-interacting protein, and recently described as mutated or overexpressed in several myeloid malignancies where it acts as an independent negative prognostic factor and as an inhibitor of PP2A. Thus it is possible that SETBP1 regulates survival and self- renewal of Ph+ B-ALL LICs through inhibition of PP2A. Published work and preliminary data indicate that: SET- dependent PP2A inhibition increases in Ph+ (CML and B-ALL) progenitors and quiescent TKI-resistant CML LICs, respectively; SET downregulation or pharmacologic (i.e. SET-interacting PP2A-activating drugs; PADs) restoration of PP2A activity strongly impaired malignant but not normal hematopoiesis; SETBP1 is induced in an imatinib (IM)-insensitive manner and essential for PP2A inhibition and clonogenic potential of Ph+ B-ALL cells; and a SETBP1-SET/CIP2A complex may exist in Ph+ cells, suggesting that SETBP1 might serve to recruit SET and CIP2A to suppress PP2A activity. Based on these considerations and on the fact that SETBP1 stabilizes SET and augments PP2A inhibition, and ectopic SETBP1 expression confers self-renewal to mouse myeloid progenitors and cooperates with BCR-ABL1 to induce a CML blast crisis-like disease in mice, the hypothesis driving this proposal is that aberrant SETBP1 expression significantly contributes to persistence of TKI-resistant Ph+ B-ALL LICs. Thus, the overall objective of this proposal is two-fold: a) understand the requirement of the SETBP1-PP2A interplay for Ph+ B-ALL LIC self-renewal/survival, and b) assess the therapeutic relevance of SETBP1 downregulation and pharmacologic restoration of PP2A activity against TKI- resistant LICs. Specifically, we will: 1) determine whether PP2A is inhibited in Ph+ B-ALL LICs and, if so, assess whether SETBP1 is part of the PP2A inhibitory complex; and 2) investigate the effects of SETBP1 downmodulation and PAD (e.g. OSU2S, FTY720) treatment on Ph+ B-ALL LIC survival/self-renewal by colony- forming cell/replating and serial BM transplantation assays. We are confident that the successful completion of this work will not only advance our knowledge on the role of SETBP1 in leukemias but based on the discoveries we made in the past few years, will also facilitate new observations in the field of Ph+ B-ALL and that some of them will reveal new PAD-based strategies for therapeutic intervention. Hence, the strong importance and high relevance of this work for basic and translational cancer research.