Expression profiles of phosphatidylinositol phosphate kinase genes during normal human in vitro erythropoiesis

Abstract

ABSTRACT. Phosphatidylinositol phosphate kinases (PIPKs) are enzymes that participate in diverse intracellular signaling pathways. They are classified into 3 functionally distinct subfamilies -PIPKI (a, b, g), PIPKII (a, b, g), and PIPKIII -located in various subcellular compartments. Recently, the PIPKIIa and b-globin genes were found to be overexpressed in reticulocytes from 2 siblings with hemoglobin H disease, suggesting a possible relationship between PIPKIIa and the production of globins. The main aim of this study was to determine the expression profiles of PIPK genes in healthy individuals during in vitro erythropoiesis using quantitative real-time polymerase chain reaction and to compare these profiles with profiles of globin genes. Our results showed that expression of all PIPKs increases as the cells differentiate, coinciding with the expression profiles of globins. Analysis of the effects of globins on PIPK genes revealed that they varied significantly between the globins, the most noticeable being the effect of a-globin on PIPKIIa (P < 0.0001) and g-globin on PIPKIIg (P < 0.0001). The relationship between the expression of PIPKs and globin genes was statistically significant, particularly between PIPKIIa and a-globin (P = 0.0002) and PIPKIIg and b-globin (P < 0.0001). Linear correlation analysis revealed a strong relationship between PIPKIIa and a-globin genes. This study is the first to establish the expression profiles of PIPK genes during in vitro erythropoiesis in healthy individuals and suggests a parallel between the expression of PIPK and globin genes, reinforcing the hypothesis that they may be related.

Pharmacological Inhibition of PIP4K2 Potentiates Venetoclax-Induced Apoptosis in Acute Myeloid Leukemia

“…Here, we characterized PIP4K2 expression in normal and malignant myeloid cells. The high expression of PIP4K2A found in erythroid cells agrees with the initial description of this protein in the literature, reporting its abundance in erythrocytes [15], and with more recent findings showing that it participates in the process of erythroid differentiation and hemoglobin production [16][17][18]. Along the same line, we described high levels of PIP4K2A in myeloid cell lines committed to the erythro-megakaryocytic compartment (K-562, KU812, SET2, and HEL).…”

Differential profile of PIP4K2A expression in hematological malignancies

“…Furthermore, our results in Namalwa cells highlighted the importance of the study of PIP4K2A inhibition in different cell models and cell signaling background, including the constitutive PI3K/AKT activation, to attempt to better define the potential cell types responsive to inhibition PIP4K2A. It is important to point out that HEL [21] and Namalwa [22,23] cells have mutated p53, which has been reported to modulate the response to PIPK inhibition [11].…”

“…However, due to our limited number of healthy donors and ALL patients, these findings should be validated in larger cohorts. Our research group previously reported that PIP4K2A is upregulated during hematopoietic cell differentiation [18,22]; thus, the association between low PIP4K2A expression and high bone marrow blast percentage could reflect the impaired cell differentiation found in RAEB-1/RAEB-2 MDS patients. In contrast, both HEL and Namalwa leukemia cell lines used in our functional studies, presented constitutive activation of PI3K/AKT and p38 MAPK cell signaling.…”

PIP4K2A (phosphatidylinositol-5-phosphate 4-kinase, type II, alpha)

“…For instance, PIP4K2A silencing reduces cell survival in THP1 cells (an acute myeloid leukemia cells) , but not in K562 cells (a chronic myeloid leukemia cell line) (Peretti de Albuquerque Wobeto, et al, 2014), whereas its overexpression reduces clonogenicity and sensibility to oxidative stress in O2OS cells . PIP4K2A was initially identified in erythrocytes (Ling, et al, 1989) and its expression was found to be upregulated during erythroid differentiation (Peretti de Albuquerque Wobeto, et al, 2014, Zaccariotto, et al, 2012, suggesting a potential participation in cell differentiation. Of note, among the PIP4K proteins, which include PIP4K2A, PIP4K2B and PIP4KC, PIP4K2A has been reported as having the highest kinase activity (Bultsma, et al, 2010).…”