title: TFDP3 confers chemoresistance in minimal residual disease within childhood T-cell acute lymphoblastic leukemia.
abstract: Acquired drug resistance in childhood T-cell acute lymphoblastic leukemia (T-ALL) remains a significant clinical problem. In this study, a novel gene therapy target for childhood T-ALL to overcome chemoresistance was discovered: TFDP3 increased in the minimal residual disease (MRD) positive childhood T-ALL patients. Then, we established a preclinical model of resistance to induction therapy to examine the functional relevance of TFDP3 to chemoresistance in MRD derived from Jurkat/E6-1. Jurkat xenografts in NOD/SCID mice were exposed to a four drug combination (VXLD) of vincristine (VCR), dexamethasone (DEX), L-asparaginase (L-asp) and daunorubicin (DNR). During the 4-week VXLD treatment, the level of TFDP3 increased 4-fold. High expression of TFDP3 was identified in the re-emerging lines (Jurkat/MRD) with increased chemoresistance, which is correlated with partially promoter demethylation of TFDP3. Downregulation of TFDP3 by RNA interference reversed chemoresistance in Jurkat/MRD accompanied by reinstated E2F1 activity that coincided with increased levels of p53, p73, and associated proapoptotic target genes. Importantly, TFDP3 silencing in vivo induced apparent benefit to overcome chemoresistance in combination with VXLD treatment. Collectively, TFDP3 confers chemoresistance in MRD within childhood T-ALL, indicating that TFDP3 is a potential gene therapy target for residual cancer.
authors.affiliation: Department of Immunology, School of Basic Medical Sciences, Peking University, Beijing, China.|Key Laboratory of Medical Immunology, Ministry of Health, Beijing, China.
authors.forename: Ming
authors.initials: M
authors.lastname: Chu
authors.affiliation: Department of Immunology, School of Basic Medical Sciences, Peking University, Beijing, China.|Key Laboratory of Medical Immunology, Ministry of Health, Beijing, China.
authors.forename: Kailin
authors.initials: K
authors.lastname: Yin
authors.affiliation: Department of Hematology, Peking University First Hospital, Beijing, China.
authors.forename: Yujun
authors.initials: Y
authors.lastname: Dong
authors.affiliation: Department of Immunology, School of Basic Medical Sciences, Peking University, Beijing, China.|Key Laboratory of Medical Immunology, Ministry of Health, Beijing, China.
authors.forename: Pingzhang
authors.initials: P
authors.lastname: Wang
authors.affiliation: Department of Anesthesiology, Fuling Center Hospital of Chongqing City, Chongqing, China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Xue
authors.affiliation: Department of Immunology, School of Basic Medical Sciences, Peking University, Beijing, China.|Key Laboratory of Medical Immunology, Ministry of Health, Beijing, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Zhou
authors.affiliation: Department of Immunology, School of Basic Medical Sciences, Peking University, Beijing, China.|Key Laboratory of Medical Immunology, Ministry of Health, Beijing, China.
authors.forename: Yuqi
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Immunology, School of Basic Medical Sciences, Peking University, Beijing, China.|Key Laboratory of Medical Immunology, Ministry of Health, Beijing, China.
authors.forename: Yuedan
authors.initials: Y
authors.lastname: Wang
mesh_terms: D000293:Adolescent; D045744:Cell Line, Tumor; D002648:Child; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D019169:Jurkat Cells; D008297:Male; D018365:Neoplasm, Residual; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D050680:Transcription Factor DP1 / Q000096:biosynthesis* / Q000235:genetics
chemical_list: C516920:TFDP3 protein, human; D050680:Transcription Factor DP1
keywords: E2F1; TFDP3; chemoresistance; childhood T-ALL; minimal residual disease