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成年人的预后- 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耐药性的产生或化疗引起的不良反应仍然是主要的治疗方法 挑战。此外，并不是所有的TKI都对Ph+白血病启动细胞(LIC)有效。肿瘤 抑制蛋白磷酸酶2A(PP2A)在几乎所有实体和造血肿瘤中都是不活跃的。PP2A 抑制与不良预后和疾病进展相关，并在很大程度上依赖于异常表达。 CIP2A、SET和/或SETBP1。SETBP1被发现是一种SET相互作用蛋白，最近被描述 在几种髓系恶性肿瘤中突变或过度表达，在这些肿瘤中它作为独立的阴性 作为PP2A的抑制因子和预后因子。因此，SETBP1可能调节生存和自我 抑制PP2A对Ph+B-ALL LIC的更新作用已发表的工作和初步数据表明：SET- Ph+(CML和B-ALL)祖细胞和静止期TKI抗性CML中依赖的PP2A抑制增加 分别为LICs；SET下调或药理学(即SET相互作用的PP2A激活药物；PADS) PP2A活性的恢复严重损害了恶性但不正常的造血；SETBP1被诱导在 伊马替尼(IM)对PP2A抑制和Ph+B-ALL克隆潜能的不敏感方式及其必要性 在Ph+细胞中可能存在SETBP1-SET/CIP2A复合体，提示SETBP1可能起到 招募SET和CIP2A抑制PP2A活性。基于这些考虑，并基于SETBP1 稳定SET并增强PP2A抑制，异位表达SETBP1促进小鼠自我更新 并与bcr-abl1合作在小鼠中诱导CML原始细胞危象样疾病， 支持这一提议的假说是SETBP1的异常表达显著地促进了 抗TKI Ph+B-所有LIC。因此，这项建议的总体目标有两个：a)理解 SETBP1-PP2A相互作用对Ph+B-ALL LIC自我更新/生存的要求，以及b)评估 SETBP1下调和PP2A活性恢复对TKI-1的治疗意义 抗性LIC。具体地说，我们将：1)确定Ph+B-ALL LIC中的PP2A是否被抑制，如果是， 评估SETBP1是否是PP2A抑制复合体的一部分；以及2)研究SETBP1的作用 下调和PAD(如OSU2S、FTY720)对Ph+B-ALL LIC存活/集落自我更新的影响 形成细胞/复制和系列骨髓移植试验。我们相信，成功完成 这项工作不仅将促进我们对SETBP1在白血病中的作用的了解，而且基于 我们在过去几年中的发现，也将有助于在Ph+B-ALL和 其中一些将揭示基于PAD的治疗干预新策略。因此，强者 这项工作对于基础和转化性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.