A novel gain‐of‐function PIP4K2A mutation elevates the expression of β‐globin and aggravates the severity of α‐thalassemia

Abstract

SummaryHaemoglobin H (Hb H) disease (intermediate status of α‐thalassemia) shows marked phenotypic variability from asymptomatic to severe anaemia. Apart from the combined β‐thalassemia allele ameliorating clinical severity, reports of genetic modifier genes affecting the phenotype of Hb H disease are scarce which bring inconvenience to precise diagnosis and genetic counselling of the patients. Here, we present a novel mutation (c.948C>A, p.S316R) in the PIP4K2A gene in a female Hb H disease patient who displayed moderate anaemia and a relatively high Hb H level. Haematological analysis in her family members revealed that individuals carrying this mutation have upregulated β‐globin expression, leading to a more imbalanced β/α‐globin ratio and more Hb H inclusion bodies in peripheral red blood cells. According to functional experiments, the mutant PIP4K2A protein exhibits enhanced protein stability, increased kinase activity and a stronger regulatory effect on downstream proteins, suggesting a gain‐of‐function mutation. Moreover, introduction of the S316R mutation into HUDEP‐2 cells increased expression of β‐globin, further inhibiting erythroid differentiation and terminal enucleation. Thus, the S316R mutation is a novel genetic factor associated with β‐globin expression, and the PIP4K2A gene is a new potential modifier gene affecting the α‐thalassemia phenotype.

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).…”