Characterization of purine‐rich element binding protein B as a novel biomarker in acute myelogenous leukemia prognostication

Abstract

Acute myelogenous leukemia (AML) is an aggressive hematologic cancer characterized by infiltration of proliferative, clonal, abnormally differentiated cells of myeloid lineage in the bone marrow and blood. Malignant cells in AML often exhibit chromosomal and other genetic or epigenetic abnormalities that are useful in prognostic risk assessment. In this study, the relative expression and novel single-stranded DNA (ssDNA) binding function of purine-rich element binding proteins A and B (Purα and Purβ) were systematically evaluated in established leukemia cell lines and in lineage committed myeloid cells isolated from patients diagnosed with a hematologic malignancy. Western blotting revealed that Purα and Purβ are markedly elevated in CD33 /CD66b cells from AML patients compared to healthy subjects and to patients with other types of myeloid cell disorders. Results of in silico database analysis of PURA and PURB mRNA expression during hematopoiesis in conjunction with the quantitative immunoassay of the ssDNA-binding activities of Purα and Purβ in transformed leukocyte cell lines pointed to Purβ as the more distinguishing biomarker of myeloid cell differentiation status. Purβ ssDNA-binding activity was significantly increased in myeloid cells from AML patients but not from individuals with other myeloid-related diseases. The highest levels of Purβ activity were detected in myeloid cells from primary AML patients and from AML patients displaying other risk factors forecasting a poor prognosis. Collectively, these findings suggest that the enhanced ssDNA-binding activity of Purβ in transformed myeloid cells may serve as a unique and measurable phenotypic trait for improving prognostic risk stratification in AML.

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“…PURB has been reported to be a transcriptional co-activator and binds to the single strand of the repeated purine-rich element PUR which is present in promoter regions and as such has been implicated in transcriptional control. PURB plays different roles in many physiological and pathological processes [51][52][53] . For example, PURB has been shown to be overexpressed in several different cancer types 54 .…”

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“…Two other proteins of interest that bind to single-stranded DNA in the nucleus are encoded by Purb and Fubp1. In the first case, purine-rich element-binding proteins A and B are implicated in the regulation of gene expression at both transcription and translation levels, the highest levels of PURB being observed in myeloid cells from patients with primary acute myelogenous leukemia displaying risk factors forecasting a poor prognosis [63]. At the end of the 2010s, FUBP1 represented one of the fifty types of specific factors already reported to regulate c-myc transcription [64], whose overexpression was associated with the regulation of proliferation and migration in liver cancer cells [65].…”

Structural and functional analysis of single‐nucleotide polymorphic variants of purine‐rich element‐binding protein B

“…42 Fluid-phase Purβ WT and variant proteins were evaluated at a limiting protein concentration of 1.0 nM in the primary binding step in the ELISA. Solutions of 300 μg/mL protein in aqueous buffer containing SYPRO Orange were heated in 1°C increments/min and changes in fluorescence were monitored over time.…”

“…Additionally, a purine-rich element from the 5′-flanking region of the human MYC gene (PUR24-bF) was utilized as an independent positive control for Purβ-ssDNA interaction. 42 Fluid-phase Purβ WT and variant proteins were evaluated at a limiting protein concentration of 1.0 nM in the primary binding step in the ELISA. Subsequent antibody-based detection of solid-phase nucleoprotein complexes revealed that the interaction of Purβ P223L and R297Q with purine-rich ssDNA sequences was indistinguishable from wild-type Purβ ( Figure 5B).…”