Absence of terminal deoxynucleotidyl transferase expression in T‐ALL/LBL accumulates chromosomal abnormalities to induce drug resistance

Abstract

T-acute lymphoblastic leukemia/lymphoma (T-ALL/LBL) is a malignant neoplasm of immature lymphoblasts. Terminal deoxynucleotidyl transferase (TDT) is a templateindependent DNA polymerase that plays an essential role in generating diversity for immunoglobulin genes. T-ALL/LBL patients with TDT À have a worse prognosis. However, how TDT À promotes the disease progression of T-ALL/LBL remains unknown. Here we analyzed the prognosis of T-ALL/LBL patients in Shanghai Children's Medical Center (SCMC) and confirmed that TDT À patients had a higher rate of recurrence and remission failure and worse outcomes. Cellular experiments demonstrated that TDT was involved in DNA damage repair. TDT knockout delayed DNA repair, arrested the cell cycle and decreased apoptosis to induce the accumulation of chromosomal abnormalities and tolerance to abnormal karyotypes. Our study demonstrated that the poor outcomes in TDT À T-ALL/LBL might be due to the drug resistance (VP16 and MTX) induced by chromosomal abnormalities. Our findings revealed novel functions and mechanisms of TDT in T-ALL/LBL and supported that hematopoietic stem cell transplantation (HSCT) might be a better choice for these patients.

Genomic determinants of response and resistance to inotuzumab ozogamicin in B-cell ALL

“…26 Another study reported that TdT-negative T cell acute lymphoblastic leukemia/lymphoma (T-ALL/LBL) patients had poor therapeutic responses; TdT loss decreased apoptosis, induced the accumulation of chromosomal abnormalities and tolerance to abnormal karyotypes. 27 DNTT loss might modulate the DSBs repair response to InO and result in increased tolerance to InO-induced DNA damage, leading to InO resistance. We observed decreased DNTT RNA expression in patient samples at post-InO ( P =0.03, mean of different -1.19 log2[counts per million], 95% CI [-2.23, -0.11], Supplemental Figure 3D); no post-InO acquired DNTT mutations were identified in this dataset.…”

“…26 Another study reported that TdT-negative T cell acute lymphoblastic leukemia/lymphoma (T-ALL/LBL) patients had poor therapeutic responses; TdT loss decreased apoptosis, induced the accumulation of chromosomal abnormalities and tolerance to abnormal karyotypes. 27 Moreover, loss of CHEK2, the crucial G1/S checkpoint gene, led to InO resistance (Supplemental Figure 3A and 3C). This supported the observation and hypothesis from patient data (Figure 4D) that tumor cells resisted InO by compromise of the G1/S DNA damage checkpoint.…”

Chidamide combined with a modified Bu-Cy conditioning regimen improves survival in patients with T-cell acute lymphoblastic leukemia/lymphoma undergoing allogeneic hematopoietic stem cell transplantation.

“…The poor prognosis of DT-negative T-ALL patients was associated with abnormal DNA aggregation leading to drug resistance (e.g. VP16, MTX) [32,33], and chidamide may be able to overcome conventional chemotherapy resistance based on its chromatin-releasing activity. 4) Chidamide combined with chemotherapy regimens can effectively decrease MRD in T-ALL patients with NOTCH1 mutation [21].…”

Pharmacodynamic and Toxicity Studies of 6-Isopropyldithio-2′-guanosine Analogs in Acute T-Lymphoblastic Leukemia

“…The clinical treatment of T-ALL currently relies on traditional chemotherapy modalities. However, T-ALL is not very responsive to current chemotherapeutic agents and is prone to developing drug resistance [3,4]. Additionally, T-ALL has a high relapse rate in the central nervous system [5], and traditional chemotherapeutic drugs are not effective in inducing remission.…”