Small PARP inhibitor PJ-34 induces cell cycle arrest and apoptosis of adult T-cell leukemia cells

Xue Tao Bai,Ramona Moles,Hassiba Chaib-Mezrag,Christophe Nicot

doi:10.1186/s13045-015-0217-2

Abstract

BackgroundHTLV-I is associated with the development of an aggressive form of lymphocytic leukemia known as adult T-cell leukemia/lymphoma (ATLL). A major obstacle for effective treatment of ATLL resides in the genetic diversity of tumor cells and their ability to acquire resistance to chemotherapy regimens. As a result, most patients relapse and current therapeutic approaches still have limited long-term survival benefits. Hence, the development of novel approaches is greatly needed.MethodsIn this study, we found that a small molecule inhibitor of poly (ADP-ribose) polymerase (PARP), PJ-34, is very effective in activating S/G2M cell cycle checkpoints, resulting in permanent cell cycle arrest and reactivation of p53 transcription functions and caspase-3-dependent apoptosis of HTLV-I-transformed and patient-derived ATLL tumor cells. We also found that HTLV-I-transformed MT-2 cells are resistant to PJ-34 therapy associated with reduced cleaved caspase-3 activation and increased expression of RelA/p65.ConclusionSince PJ-34 has been tested in clinical trials for the treatment of solid tumors, our results suggest that some ATLL patients may be good candidates to benefit from PJ-34 therapy.

Highlights

Human T-cell leukemia virus type I (HTLV-I) is etiologically linked to the development of an aggressive type of peripheral T-cell leukemia known as adult T-cell leukemia/lymphoma (ATLL) [1]
PJ-34 induces cell cycle arrest in HTLV-I-transformed and ATLL-derived cell lines HTLV-I-transformed and ATLL cells are characterized by excessive chromosomal instability associated with defects in homologous recombination repair (HR) DNA repair pathways
HTLV-I-transformed T-cell lines MT-2, MT-4, C8166, and patient-derived ATLL cell lines ED and ATL-25 were treated with PJ-34 for 3 days and cell cycle was analyzed by propidium iodide staining and DNA content analyses on live gated cells by FACS

Summary

Introduction

Human T-cell leukemia virus type I (HTLV-I) is etiologically linked to the development of an aggressive type of peripheral T-cell leukemia known as ATLL [1]. The mechanism by which HTLV-I causes ATLL is still not fully understood, but a latency period of several decades before the onset of the disease suggests that long-term survival and expansion of virus-infected cells are required. Along these lines, we have previously shown that reactivation of telomerase activity is one of the essential steps in the transformation process of HTLV-I-infected cells [6]. The molecular basis for IL-2 independence is still unknown a majority of HTLV-I-transformed cells simultaneously acquire constitutive JAK/STAT activation.

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