Regulatory Network and Prognostic Effect Investigation of PIP4K2A in Leukemia and Solid Cancers

Abstract

Germline variants of PIP4K2A impact susceptibility of acute lymphoblastic leukemia (ALL) through inducing its overexpression. Although limited reports suggested the oncogenic role of PIP4K2A in cancers, regulatory network and prognostic effect of this gene remains poorly understood in tumorigenesis and leukemogenesis. In this study, we conducted genome-wide gene expression association analyses in pediatric B-ALL cohorts to discover expression associated genes and pathways, which is followed by the bioinformatics analyses to investigate the prognostic role of PIP4K2A and its related genes in multiple cancer types. 214 candidates were identified to be significantly associated with PIP4K2A expression in ALL patients, with known cancer-related genes rankings the top (e.g., RAC2, RBL2, and TFDP1). These candidates do not only tend to be clustered in the same types of leukemia, but can also separate the patients into novel molecular subtypes. PIP4K2A is noticed to be frequently overexpressed in multiple other types of leukemia and solid cancers from cancer cohorts including TCGA, and associated with its candidates in subtype-specific and cancer-specific manners. Interestingly, the association status varied in tumors compared to their matched normal tissues. Moreover, PIP4K2A and its related candidates exhibit stage-independent prognostic effects in multiple cancers, mostly with its lower expression significantly associated with longer overall survival (p < 0.05). Our findings reveal the transcriptional regulatory network of PIP4K2A in leukemia, and suggest its potentially important role on molecular subtypes of multiple cancers and subsequent treatment outcomes.

Crucial Players for Inter-Organelle Communication: PI5P4Ks and Their Lipid Product PI-4,5-P2 Come to the Surface

“…Further, we have shown elevated expression of the PI5P4Ks in breast tumors compared to normal breast tissue (Emerling et al, 2013) and other studies have shown the impact of the kinases in breast cancer (Luoh et al, 2004;Keune et al, 2013). Similarly, PI5P4Ks have been demonstrated to be upregulated in several cancer subtypes, including glioblastomas, AML, and sarcomas (Fiume et al, 2015;Jude et al, 2015;Zhang et al, 2018;Lima et al, 2019;Shin et al, 2019;Ravi et al, 2021). Moreover, we recently illustrated the requirement of the PI5P4Ks for not only the establishment of sarcoma tumors but also in maintaining them, possibly through their role in regulating peroxisomemitochondrial interplay (Ravi et al, 2021).…”

Expanding role of PI5P4Ks in cancer: A promising druggable target

“…High expression of not only PI5P4Ka but also of PI5P4Kc was found to be associated with unfavorable clinical outcomes for AML patients [43]. Genome-wide association studies have also identified several single nucleotide polymorphisms (SNPs) in the PIP4K2Α locus that have been associated with a genetic predisposition in ALL [48][49][50]; however, the contribution of the SNPs to PIP4K2A expression or the functional involvement of PI5P4Ka to the leukemogenesis of ALL is still unexplored. Nevertheless, targeting PI5P4Ks in acute leukemias could be a promising treatment either by itself or as a combination therapy [45].…”

The PIP4K2 inhibitor THZ-P1-2 exhibits antileukemia activity by disruption of mitochondrial homeostasis and autophagy

“…High transcript levels of PIP4K2A and PIP4K2C were predictive of poor prognosis in AML patients [22,23]. Furthermore, SNPs in the regulatory region of the PIP4K2A gene were associated with increased mRNA levels and susceptibility to ALL development [19,20].…”

“…; https://doi.org/10.1101/2022.08. 20.504641 doi: bioRxiv preprint 4 PIP4K2C transcript levels were associated with adverse cytogenetic risk and poor clinical outcome [22,23]. THZ-P1-2 is the prototype of a new class of drugs that acts as a selective pan-inhibitor of PIP4K2s.…”