Jak2/STAT6/c-Myc pathway is vital to the pathogenicity of Philadelphia-positive acute lymphoblastic leukemia caused by P190(BCR-ABL)
作者全名："Qin, Run; Wang, Teng; He, Wei; Wei, Wei; Liu, Suotian; Gao, Miao; Huang, Zhenglan"
作者地址："[Qin, Run; He, Wei; Wei, Wei; Liu, Suotian; Huang, Zhenglan] Chongqing Med Univ, Sch Lab Med, Dept Clin Hematol, Key Lab Lab Med Diagnost Designated,Minist Educ, Chongqing, Peoples R China; [Wang, Teng] Chongqing Med Univ, Affiliated Hosp 2, Dept Hematol, Chongqing, Peoples R China; [Gao, Miao] Chongqing Med Univ, Affiliated Hosp 1, Dept Lab Med, 1,Youyi Rd, Chongqing 400016, Peoples R China"
通信作者："Huang, ZL (通讯作者)，Chongqing Med Univ, Sch Lab Med, Dept Clin Hematol, Key Lab Lab Med Diagnost Designated,Minist Educ, Chongqing, Peoples R China.; Gao, M (通讯作者)，Chongqing Med Univ, Affiliated Hosp 1, Dept Lab Med, 1,Youyi Rd, Chongqing 400016, Peoples R China."
来源：CELL COMMUNICATION AND SIGNALING
ESI学科分类：MOLECULAR BIOLOGY & GENETICS
关键词：Philadelphia-positive chronic myeloid leukemia; Philadelphia-positive acute lymphoblastic leukemia; STAT6; c-Myc; Jak2
摘要："Background The Philadelphia chromosome encodes the BCR-ABL fusion protein, which has two primary subtypes, P210 and P190. P210 and P190 cause Philadelphia-positive chronic myeloid leukemia (Ph+ CML) and Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL), respectively. The Ph+ ALL is more malignant than Ph+ CML in disease phenotype and progression. This implies the key pathogenic molecules and regulatory mechanisms caused by BCR-ABL in two types of leukemia are different. It is reported that STAT6 was significantly activated only in P190 transformed cells. However, the potential role and the mechanism of STAT6 activation in Ph+ ALL and its activation mechanism by P190 are still unknown.Methods The protein and mRNA levels of STAT6, c-Myc, and other molecules were measured by western blot and quantitative real-time PCR. The STAT6 inhibitor AS1517499 was used to specifically inhibit p-STAT6. The effect of p-STAT6 inhibition on Ph+ CML and Ph+ ALL cells was identified by CCK-8 and FCM assay. Dual luciferase reporter and ChIP assay were performed to confirm the direct binding between STAT6 and c-Myc. The impact of STAT6 inhibition on tumor progression was detected in Ph+ CML and Ph+ ALL mouse models.Results Our results demonstrated that P210 induced CML-like disease, and P190 caused the more malignant ALL-like disease in mouse models. STAT6 was activated in P190 cell lines but not in P210 cell lines. Inhibition of STAT6 suppressed the malignancy of Ph+ ALL in vitro and in vivo, whereas it had little effect on Ph+ CML. We confirmed that p-STAT6 regulated the transcription of c-Myc, and STAT6 was phosphorylated by p-Jak2 in P190 cell lines, which accounted for the discrepant expression of p-STAT6 in P190 and P210 cell lines. STAT6 inhibition synergized with imatinib in Ph+ ALL cells.Conclusions Our study suggests that STAT6 activation plays an essential role in the development of Ph+ ALL and may be a potential therapeutic target in Ph+ ALL."
基金机构："Scientific and Technological Research Program of Chongqing Municipal Education Commission, China [KJQN202200450]; Natural Science Foundation of Chongqing, China [cstc2019jcyj-msxmX0422]; Scientific research and Cultivation Project of College of Laboratory Medicine, Chongqing Medical University, China [JYPY202206]"
基金资助正文："This work was funded by Scientific and Technological Research Program of Chongqing Municipal Education Commission, China (No. KJQN202200450), the Natural Science Foundation of Chongqing, China (No. cstc2019jcyj-msxmX0422), and sponsored by Scientific research and Cultivation Project of College of Laboratory Medicine, Chongqing Medical University, China (No. JYPY202206)"