IKZF1突变通过FAK通路调控Ph+急性淋巴细胞白血病生物学行为的机制研究

In both Ph positive and Ph negative acute lymphoblastic leukemia (ALL), IKZF1 alterations are associated with inferior treatment outcome. Although loss of normal Ikaros function clearly cooperates with BCR-ABL1 or other kinase-activating lesions during Ph+ and Ph-like B-ALL pathogenesis, the specific mechanistic basis for this genetic interaction remains unknown. FAK plays a central role in integrin-mediated signaling, and regulates cellular processes, such as adhesion, proliferation, survival, and cell migration. Our previous study showed that FAK pathway was upregulated in Ph+ ALL. The expression of FAK in bone marrow of IKZF mutated ALL were higher than that in IKZF wild type counterparts. Thus, we hypothized that the continuous activation of FAK signaling had a role in the pathogenesis of IKZF mutated ALL, which promoted the proliferation, decreased apoptosis, and most importantly, helped the leukemic cell migration. In the present project,we will further identify the association between FAK signaling, IKZF mutation and prognosis in a expanded case-control study. The specific function of FAK signaling in the IKZF mutated ALL will be investigated through gene, protein, cell and on the whole. And the aberrant up-stream signal pathway regulated FAK will be investigated through the animal model. The results obtained from cell lines will be verified in humanized leukemia model and clinical samples. The project will specify the function and mechanism of aberrant upregulated FAK in ALL, especially in IKZF mutated ALL, and provide evidences for potential target in leukemia therapy.

IKZF1突变（IKZF1mu）是急性B 淋巴细胞白血病（B-ALL）的预后不良因素。但IKZF1影响白血病细胞生物学行为的分子机制尚不清楚。FAK (focal adhesion kinase) 整合素介导信号通路起中心作用，调控细胞细胞粘附、增殖、凋亡和生存。我们的前期研究显示伴有IKZF1mu的白血病细胞FAK通路高度活化，抑制FAK表达后白血病细胞凋亡增加，和基质细胞的粘附减少。我们提出假设，FAK 通路的持续活化在IKZF1mu的B-ALL中起重要作用，从而影响白血病细胞的增殖和细胞迁移等特征。本项目拟从分子、细胞以及动物水平多方面探讨FAK在IKZF1mu 的B-ALL的确切功能，揭示FAK在伴有IKZF1mu的B-ALL发病机制中的作用。本研究将从FAK通路这个新角度初步揭示伴有IKZF1mu B-ALL 疗效差、易发生髓外侵犯的机制，为临床靶向治疗奠定基础。