Estudo translacional de um inibidor da enzima poli-ADP-ribose polimerase-1 (PARP1) em modelos de leucemia Linfoblástica aguda p190+

Abstract

Acute Lymphoid Leukemia (ALL) is a clonal disturbance of hematopoietic cells that may present a diverse set of molecular characteristics. Although pediatric patients have high curative rates, survival probability is low for adult patients afflicted with the disease. One of the worst prognosis of ALL revolves around the presence of a translocation of the chromosome 9 and 22 (t(9;22)) which originates the oncogene BCR-ABL p190+. Adult ALL patients from the subtype BCR-ABL p190+ have a low 5- year overall survival due to non-responsiveness to the conventional tyrosine-kinase inhibitors available in the oncological practice. However, recent studies utilizing poli- ADP-ribose polimerase-1 (PARP1) inhibitors demonstrate the effectiveness of this drug class when treating tumors with high rates of genomic instability, which is a hallmark associated with the presence of the chimeric gene BCR-ABL p190+. Even then, PARP inhibitors (PARPi) still have no approval for use as treatment in any cases of hematological malignancies. In this context, this study aims to evaluate the potential of PARP inhibition as a treatment option for models of ALL BCR-ABL p190+. PARP1 expression profile was characterized through real-time PCR in a cohort of cell models representative of hematological malignancies. A cell line representative of ALL BCR- ABL p190+ and other cell lines representative of B-cell malignancies were then used for cytotoxic assays utilizing a PARPi, AZD2461, and the BCR-ABL inhibitor, Imatinib. Phenotypical parameters associated with the proposed treatments were analyzed, as well as PARP1 and BCR-ABL p190 expression. Finally, PARP1 expression levels were measured in LLA BCR-ABL p190+ patients, being compared to healthy donors. The usage of AZD2461 present cytotoxic levels similar to that of Imatinib when treating BCR-ABL positive malignancies, also inducing presentation of premature death markers and modulating BCR-ABL expression in a similar manner. Patient analysis with a larger n are still warranted, however the experimental findings point towards PARP1 significant overexpression in BCR-ABL p190+ patient cohorts. Thereby, the pharmacological study of PARP1 inhibition has potential as a therapeutic option in the treatment of ALL BCR-ABL p190+, being able to limit cell viability in cell lines representative of this malignancy.