Ph-like ALL是近年来新发现的ALL亚型，其特点为具有与BCR-ABL ALL相似的基因表达谱。研究表明激酶异常激活是Ph-like ALL发生的原因之一，酪氨酸激酶抑制剂（Tyrosine kinase inhibitor，TKI）可用于治疗Ph-like ALL。通过对Ph-like ALL患儿初诊、常规化疗不缓解、TKI耐药等不同时间点的白血病细胞进行转录组测序和全基因组测序，发现在所有时间点均存在融合基因AGGF1-PDGFRB和IKZF1缺失突变，且在TKI处理后出现了IKZF1和PDGFRB的点突变。因此，本项目拟在细胞系及小鼠模型中探索融合基因AGGF1-PDGFRB协同IKZF缺失突变诱发Ph-like ALL的机制，阐明PDGFRB与IKZF1点突变与TKI耐药的关系，揭示B-ALL发生以及TKI耐药的机制，为临床治疗Ph-like ALL患儿提供靶向治疗新方案。

Ph-like (BCR-ABL1-like) ALL is one of the newly discovered subtypes of acute lymphoblastic leukemia (ALL), with the characteristics of BCR-ABL1 negative, but exhibiting a gene expression profile similar to that of BCR-ABL1-positive ALL. Recent researches found that tyrosine kinase inhibitor (TKI) can also have effect on Ph-like ALL with specific kinase-activating alterations, including the rearrangements involving PDGFRB. To explore the pathogenesis and mechanism of TKI resistance in a 5-year-old Ph-like patient who experienced chemo-resistance and twice TKI resistance, we presented whole genome sequencing and mRNA sequencing of the samples at 4 time points: the diagnosis, the chemoUnCR (chemo-resistance), the first relapse after Imatinib (the first-generation TKI) and the second relapse after dasatinib (the second-generation TKI). We found a novel partner of PDGFRB fusion (AGGF1-PDGFRB) and IKZF1 deletions during the whole course of diseases; moreover, two somatic point mutations in IKZF1 and PDGFRB was found respectively only in the two samples at relapse (TKI resistance). This study was aimed to elucidate synergistic effects of PDGFRB translocation and IKZF1 mutation in the detailed pathogenesis and mechanisms of drug resistance in Ph-like ALL by constructing AGGF1-PDGFRB transducted Ba/F3 cell lines and mouse models wt/wo IKZF1 mutations, with a view to find potential targeting therapeutic ways in preclinical practice.