p53 Protein Isoform Profiles in AML: Correlation with Distinct Differentiation Stages and Response to Epigenetic Differentiation Therapy

Abstract

p53 protein isoform expression has been found to correlate with prognosis and chemotherapy response in acute myeloid leukemia (AML). We aimed to investigate how p53 protein isoforms are modulated during epigenetic differentiation therapy in AML, and if p53 isoform expression could be a potential biomarker for predicting a response to this treatment. p53 full-length (FL), p53β and p53γ protein isoforms were analyzed by 1D and 2D gel immunoblots in AML cell lines, primary AML cells from untreated patients and AML cells from patients before and after treatment with valproic acid (VPA), all-trans retinoic acid (ATRA) and theophylline. Furthermore, global gene expression profiling analysis was performed on samples from the clinical protocol. Correlation analyses were performed between p53 protein isoform expression and in vitro VPA sensitivity and FAB (French–American–British) class in primary AML cells. The results show downregulation of p53β/γ and upregulation of p53FL in AML cell lines treated with VPA, and in some of the patients treated with differentiation therapy. p53FL positively correlated with in vitro VPA sensitivity and the FAB class of AML, while p53β/γ isoforms negatively correlated with the same. Our results indicate that p53 protein isoforms are modulated by and may predict sensitivity to differentiation therapy in AML.

Expression of p53 protein isoforms predicts survival in patients with multiple myeloma

“…We also noted a negative impact of the high level of expression of TAp53β/γ proteins on the survival of MM patients. These data are consistent with another study of acute myeloid leukemia patients in which high levels of TAp53α and low levels of TAp53β/γ were associated with a greater sensitivity to valproic acid treatment 35 . Elevated TAp53γ mRNA levels have also been associated with reduced progression‐free survival in uterine serous carcinoma 36 .…”

“…These data are consistent with another study of acute myeloid leukemia patients in which high levels of TAp53α and low levels of TAp53β/γ were associated with a greater sensitivity to valproic acid treatment. 35 Elevated TAp53γ mRNA levels have also been associated with reduced progression-free survival in uterine serous carcinoma. 36 However, opposite results showing an association between low levels of TAp53β and TAp53γ mRNAs and worse prognosis have also been reported.…”

p53 Isoforms as Cancer Biomarkers and Therapeutic Targets

“…The core domain of p53 also demonstrates aggregation propensity, particularly with the influence of various RNAs (mRNA and rRNA), which may have implications in cancer [39,40]. Treatment with the histone deacetylase inhibitor valproic acid resulted in downregulation of p53β/γ and upregulation of p53α in acute myeloid leukemia, suggesting that p53 isoforms have the potential to predict therapy response [41]. p53 isoforms, especially the N-terminally truncated ones ∆40p53, ∆133p53, and ∆160p53, play an important role in the development of cancers [13].…”