Targeting PRL phosphatases in hematological malignancies

ABSTRACT

Introduction

Phosphatase of regenerating liver (PRL) family proteins, also known as protein tyrosine phosphatase 4A (PTP4A), have been implicated in many types of cancers. The PRL family of phosphatases consists of three members, PRL1, PRL2, and PRL3. PRLs have been shown to harbor oncogenic potentials and are highly expressed in a variety of cancers. Given their roles in cancer progression and metastasis, PRLs are potential targets for anticancer therapies. However, additional studies are needed to be performed to fully understand the roles of PRLs in blood cancers.

Areas covered

In this review, we will summarize recent studies of PRLs in normal and malignant hematopoiesis, the role of PRLs in regulating various signaling pathways, and the therapeutic potentials of targeting PRLs in hematological malignancies. We will also discuss how to improve current PRL inhibitors for cancer treatment.

Expert opinion

Although PRL inhibitors show promising therapeutic effects in preclinical studies of different types of cancers, moving PRL inhibitors from bench to bedside is still challenging. More potent and selective PRL inhibitors are needed to target PRLs in hematological malignancies and improve treatment outcomes.

KEYWORDS:

• Phosphatase of regenerating liver
• protein tyrosine phosphatase
• hematological malignancies
• leukemia
• AML
• therapeutic target
• oncogenic signaling
• hematopoietic stem cells

Article highlights

• Phosphatase of regenerating livers (PRL) family proteins plays diverse and indispensable roles in normal hematopoiesis, including the regulation of hematopoietic stem cells (HSCs) proliferation and self-renewal, T cell development, erythroid differentiation, and more.

• Expression patterns of PRL family proteins vary across different hematopoietic cell types, reflecting distinct functions and regulatory mechanisms involved in the self-renewal, differentiation, proliferation, and maturation of hematopoietic cells.

• PRLs, particularly PRL2 and PRL3, regulate diverse oncogenic signaling pathways in hematological malignancies and play crucial roles in disease progression.

• PRLs are overexpressed in a range of hematological malignancies, and associated with poor prognosis, highlighting their potential as therapeutic targets.

• Targeting PRLs with small-molecule inhibitors, trimerization disruptors, antibodies, or PROTACs represent novel approaches for treating hematological malignancies.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

Y Liu was supported by NIH R01 HL150624, R56 DK119524, R56 AG052501, DoD W81XWH-18-1-0265, DoD W81XWH-19-1-0575, the Leukemia & Lymphoma Society Translational Research Program award 6581-20 and the St Baldrick’s Foundation Scholar Award. Y Bai and ZY Zhang were supported by NIH R01 CA069202 and the Robert C. and Charlotte Anderson Chair Endowment. The authors also acknowledge the support from NIH to the Purdue Institute for Cancer Research [P30CA023168].