TFDP3 confers chemoresistance in minimal residual disease within childhood T-cell acute lymphoblastic leukemia.

Ming Chu,Yuedan Wang,Kailin Yin,Yuqi Wang,Yujun Dong,Pingzhang Wang,Peng Zhou,Yun Xue

doi:10.18632/oncotarget.13630

Ming Chu, Yuedan Wang + Show 6 more

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https://doi.org/10.18632/oncotarget.13630

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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.

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Acute lymphoblastic leukemia (ALL) is the most common childhood malignancy, and the most frequent cause of death from cancer before 20 years of age [1, 2]
To assess the expression status of TFDP3 in childhood T-cell acute lymphoblastic leukemia (T-ALL), we determined the mRNA levels of TFDP3 in the mononuclear cells (MNCs) from 60 T-ALL childhood patients at diagnosis (Table 1)
The first group consisted of patients with undetectable minimal residual disease (MRD) loads (MRDnegative), the second group had detectable MRD loads (

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Introduction

Acute lymphoblastic leukemia (ALL) is the most common childhood malignancy, and the most frequent cause of death from cancer before 20 years of age [1, 2]. T-cell ALL (T-ALL) accounts for 10% to 15% of childhood ALL, and constitutes up to 48% of highrisk patients [3, 4]. Recent advances in the treatment of childhood T-ALL have improved the 5-year survival rate above 75%, which is due to the intensive combination chemotherapies [5, 6]. Despite the induction therapy resulting in complete remission rates of >95%, up to 25% of patients relapse and experience a 30% to 50% likelihood of survival [7]. Relapse of childhood T-ALL remains the major cause of treatment failure, and suggests rapidly acquired resistance to multiple drugs [8]

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