CRLF2 cytokine receptor signaling in acute leukemia

CRLF2;cytokine;signaling;leukemia;proteomis;Human Genetics and Molecular Biology

Huang, Tai-Chung JohnPandey, Akhilesh ;

Johns Hopkins University

关键词: CRLF2;    cytokine;    signaling;    leukemia;    proteomis;    Human Genetics and Molecular Biology;   

Others  :  https://jscholarship.library.jhu.edu/bitstream/handle/1774.2/40670/HUANG-DISSERTATION-2015.pdf?sequence=1&isAllowed=y

瑞士|英语

来源: JOHNS HOPKINS DSpace Repository

【 摘 要 】

Cytokine Receptor Like Factor 2 (CRLF2) is the receptor of the cytokine Thymic Stromal Lymphopoietin (TSLP).CRLF2 plays a role in lymphocyte development, differentiation and homeostasis.Recently, CRLF2 is implicated in a subset of precursor B cell acute lymphoblastic leukemia (pre-B ALL), which is the most common pediatric malignancy.Long-term survival of this disease is stratified into different risk groups dictating treatment plans for patients. Among pre-B ALL risk groups, a much worse prognosis is observed in patients with the gene rearrangement of CRLF2 as well as with the fusion gene BCR-ABL1.Previous transcriptomic analyses indicated a similar gene expression profile for CRLF2 and BCR/ABL1 signaling in pre-B ALL.While both CRLF2 and BCR/ABL1 have potent effects on cell signaling pathways, their total protein and global phosphorylation profiles might be different.In order to interrogate this hypothesis, we leveraged the Ba/F3 cell culture system to carry out a series of quantitative proteomics analysis to compare BCR/ABL1 and multiple forms of aberrant CRLF2 signaling.Our study identified major differences between CRLF2 and BCR/ABL1 signaling including EIF2/EIF4 signaling related to translation initiation regulation, DNA methylation/transcription repression pathways, IKZF2-INPP5D signaling axis, JAK2-mediated H3Y42 phosphorylation, among others.In addition, we took advantage of a kinase and small molecule inhibitor screen to identify PLK1 as a potential therapeutic target downstream of the leukemic CRLF2 signaling.PLK1 dysregulation resulting from the aberrant CRLF2 JAK2 signaling might provide an opportunity to develop CRLF2-targeted therapy in the future.In conclusion, CRLF2 and BCR/ABL1 signaling differs in many aspects that might affect therapy development for the different types of pre-B ALL.