PARP-1 expression in CD34+ leukemic cells in childhood acute lymphoblastic leukemia: relation to response to initial therapy and other prognostic factors

Abstract

Poly(ADP-ribose) polymerase-1 (PARP-1) is a nuclear protein that impacts DNA repair and apoptosis. Both experimental and ongoing clinical studies indicate that PARP-1 inhibitors are potent and promising anticancer agents. However, the outcome of treatment with PARP-1 inhibitors depends on the expression of PARP-1 protein in the tumor cells. This study aimed to assess PARP-1 expression in peripheral blood CD34+ leukemic cells before and after 12 hours of prednisone administration as well as the relation between PARP-1 expression and early treatment response to initial therapy and other prognostic factors (immunophenotype, age, initial peripheral blood white blood count [WBC], and risk factor group). The study comprised 43 children with de novo ALL. Cytospins of peripheral blood were stained with mouse anti-CD34-FITC and anti-PARP-1 antibody followed by goat anti-mouse APC-conjugated antibody. DNA was counterstained with PI (propidium iodide). Cellular fluorescence was measured by a laser scanning cytometer. Statistically significant differences in baseline PARP-1 expression with respect to early treatment response (good vs. poor), ALL immunophenotype (ALL B vs. ALL T), age (children < 1 years and > 6 years vs. children 1-6 years), initial WBC (< 20 000/µl vs. ≥ 20 000/µl), and risk factor group (SR vs. IR vs. HR) were not found. PARP-1 expression was increased 12 hours after treatment in poor early treatment responders, whereas it remained statistically unchanged with respect to ALL immunophenotype, age, initial WBC, risk factor group and early treatment response. The overexpression of PARP-1 in poor early treatment responders suggests that it may contribute to treatment failure in this group of children with ALL. Our observation -if confirmed by other studies -may form the rationale for administration of PARP inhibitors in selected subsets of ALL children.

Therapeutic and prognostic significance of PARP‐1 in advanced mycosis fungoides and Sezary syndrome

“…Although MF, in general, demonstrated increased expression of PARP‐1 compared to normal skin throughout this study, there was a large difference in expression seen on IHC when comparing non‐aggressive and aggressive MF. This is not uncommon to PARP‐1, as there is evidence in other studies that increased expression in malignant cells of other cancers is related to a worse prognosis . We found that patients with tumor stage MF (stage IIB) had a higher level of cleaved PARP than patients with early stage of MF (stage IA) or healthy controls (113.1 ± 88.9 MFI in tumor MF vs 3.9 ± 3.2 MFI in early MF vs 14.1 ± 21.4 MFI in control, P < .05) (Figure A).…”

“…The following proteins including PARP‐1, heat‐shock protein family A (Hsp70) member 1 like (HSAP1L), Hsp70 member 1A (HSPA1A), ATP‐depending RNA helicase (DDX17) and the α‐isoform of lamina‐associated polypeptide 2 (TMPO) were increased in aggressive disease samples vs non‐aggressive (Figure B). PARP‐1 is a nuclear protein involved in regulating DNA damage and has been observed to have multiple roles in several cancers . PARP‐1 has also been found to be an important protein in the BRCA mutations of ovarian cancers .…”

“…Several PARP inhibitors (PARPi) have been developed and are currently in use as treatment options for ovarian cancers . Their effectiveness for these cancers is primarily due to their ability to affect the repair of DNA strand breaks . There is also evidence of PARPi having effectiveness in other haematologic malignancies such as leukaemia .…”

“…Their effectiveness for these cancers is primarily due to their ability to affect the repair of DNA strand breaks . There is also evidence of PARPi having effectiveness in other haematologic malignancies such as leukaemia . PARPi have not been specifically tested for benefit in MF.…”

Strictly Approximating Attributes of DNA Lesion Repair in Terms of Inherent DNA Responses to Mutability and Malignant Transformation

“…The further spectral exposure of mammalian cells to mutagenesis is substantial contribution to the initiation and further progression of multiple types of neoplasia as an important series of hotspots in carcinogenesis. PARP1 impacts DNA repair and apoptosis and PARP-1 inhibitors are potent anticancer agents, including children with acute lymphoblastic leukemia [12]. Such stereotypical acquisition of DNA lesions is further confirmatory to the attributes of the central malignant transformational event itself.…”