Genetic instability in BCR-ABL1-transformed B cell lineage leukemia

B细胞系急性淋巴细胞白血病（ALL）具有所谓的费城染色体（Ph）编码致癌性BCR-ABL1激酶，预后特别差。Ph+ ALL通常用BCR-ABL1激酶抑制剂如伊马替尼治疗。然而，对伊马替尼的治疗反应并不持久，在仅仅几个月的潜伏期后，Ph+ ALL细胞就会产生耐药性，ALL复发。与Ph+ ALL相比，伊马替尼长期治疗Ph+慢性髓性白血病（CML）是有效的，除非疾病进展为B淋巴细胞危象（CML- lbc），否则很少出现耐药性。在大多数情况下，Ph+ ALL和CML-LBC对伊马替尼的获得性耐药可归因于BCR-ABL1激酶结构域内的体细胞突变，这损害了伊马替尼的疗效。在本提案的初步实验中，我们发现AID在bcr - abl1驱动的白血病（Ph+ ALL和CML-LBC）的B细胞谱系克隆中特异性表达。在这些细胞中，AID作为一个突变体发挥作用，从而有助于在Ph+ ALL和CML-LBC中观察到的典型耐药性。基于这些发现，我们的建议解决了以下问题：(1)AID如何导致Ph+ ALL的遗传不稳定性（例如aids特异性缺失；Aim 1）； (2) AID在多大程度上促进了慢性粒细胞白血病向CML- lbc的进展(携带有利突变的B淋巴亚克隆的产物；Aim 2),(3)哪些因素导致AID在Ph+ ALL和CML-LBC中异常表达（Aim 3），(4)以及在Ph+ ALL和CML-LBC中表达AID的克隆是否可以通过基于前药的方法特异性靶向，利用AID的酶活性（Aim 4）。总之，这四个目标将有助于阐明Ph+ ALL和CML-LBC的耐药机制，并提出一种新的靶向治疗Ph+ ALL和CML-LBC的概念，用于临床前评估。

B cell lineage acute lymphoblastic leukemia (ALL) with the so-called Philadelphia chromosome (Ph) encoding the oncogenic BCR-ABL1 kinase has a particularly poor prognosis. Ph+ ALL is typically treated with BCR-ABL1 kinase inhibitors such as Imatinib. The treatment response to Imatinib, however, is not durable and after a latency of only a few months, Ph+ ALL cells become drug-resistant and ALL relapses. In contrast to Ph+ ALL, long-term treatment of Ph+ chronic myeloid leukemia (CML) with Imatinib is effective and resistance develops only rarely, unless the disease progresses into B lymphoid blast crisis (CML-LBC). In most cases, acquired resistance to Imatinib in Ph+ ALL and CML-LBC can be attributed to somatic mutations within the BCR-ABL1 kinase domain, which compromise the efficacy of Imatinib. In preliminary experiments for this proposal, we show that AID is specifically expressed in B cell lineage clones of BCR-ABL1-driven leukemia (Ph+ ALL and CML-LBC). In these cells, AID functions as a mutator and thereby contributes to the drug-resistance typically observed in Ph+ ALL and CML-LBC. Based on these findings, our proposal addresses the question of(1) how AID contributes to genetic instability in Ph+ ALL (e.g. AID-specific deletions; Aim 1),(2) to which extent AID contributes to the progression of chronic phase CML to CML-LBC (outgrowth of B lymphoid subclones that carry advantageous mutations; Aim 2),(3) which factors cause aberrant expression of AID in Ph+ ALL and CML-LBC (Aim 3),(4) and whether AID-expressing clones in Ph+ ALL and CML-LBC can be specifically targeted in a prodrug based approach that takes advantage of the enzymatic activity of AID (Aim 4).Together, these four Aims will help to elucidate mechanisms of drug-resistance in Ph+ ALL and CML-LBC and propose a novel concept of targeted treatment Ph+ ALL and CML-LBC for pre-clinical evaluation.