Nuclear Receptors as Potential Therapeutic Targets for Myeloid Leukemia

Abstract

The nuclear receptor (NR) superfamily has been studied extensively in many solid tumors and some receptors have been targeted to develop therapies. However, their roles in leukemia are less clear and vary considerably among different types of leukemia. Some NRs participate in mediating the differentiation of myeloid cells, making them attractive therapeutic targets for myeloid leukemia. To date, the success of all-trans retinoic acid (ATRA) in treating acute promyelocytic leukemia (APL) remains a classical and unsurpassable example of cancer differentiation therapy. ATRA targets retinoic acid receptor (RAR) and forces differentiation and/or apoptosis of leukemic cells. In addition, ligands/agonists of vitamin D receptor (VDR) and peroxisome proliferator-activated receptor (PPAR) have also been shown to inhibit proliferation, induce differentiation, and promote apoptosis of leukemic cells. Encouragingly, combining different NR agonists or the addition of NR agonists to chemotherapies have shown some synergistic anti-leukemic effects. This review will summarize recent research findings and discuss the therapeutic potential of selected NRs in acute and chronic myeloid leukemia, focusing on RAR, VDR, PPAR, and retinoid X receptor (RXR). We believe that more mechanistic studies in this field will not only shed new lights on the roles of NRs in leukemia, but also further expand the clinical applications of existing therapeutic agents targeting NRs.

Synergistic effects of PI3K inhibition and pioglitazone against acute promyelocytic leukemia cells

“…From the day that the tumor suppressor activity of PPARγ has been established, a wave of interest has been awoken to examine the therapeutic value of PPARγ stimulators in different human cancers (Pan & Chen, 2020). The unprecedented success of pioglitazone (glitazones) in the pre‐clinical trials encouraged us to evaluate the effect of this drug in a panel of leukemic cells consists of acute myeloid leukemia (AML) cells (U937 and KG‐1), acute promyelocytic leukemia (APL) cells (NB4), acute lymphoblastic leukemia (ALL) cells (Nalm‐6), and chronic myeloid leukemia cells (K562).…”

Exploring the nexus of nuclear receptors in hematological malignancies

“…Given that the majority of these receptors can be selectively modulated by small molecular entities, they stand as significant targets for therapeutic interventions [ 56 ]. According to the literature, several PPAR agonists, vitamin D derivatives, and all-trans retinoic acid (ATRA) have been identified to modulate apoptosis, differentiation, and cell proliferation in distinct leukemic cells [ 37 ]. When these compounds are introduced either alone or in combination, showed improved outcomes, thereby suggesting the participation of multiple NRs in the pathophysiology of leukemia.…”

“…Historically, nuclear receptors (NRs) have been playing a crucial role in oncogenesis, acting as important regulators in the disease process [ 36 ] . The NR superfamily encompasses a broad group of transcription factors (TF) with 48 members and is categorized into six distinct subfamilies, based on their evolutionarily conserved sequences and structures [ 37 , 38 ]. The first subfamily encompasses thyroid hormone receptor-like members, including vitamin D receptor (VDR), thyroid hormone receptor (THR), retinoic acid receptors (RARs), all peroxisome proliferator-activated receptors (PPARs), and orphan receptors like RORs, Rev-Erb receptor, pregnane X receptor (PXR), liver X receptor (LXR), constitutive androstane receptor (CAR), and others.…”

“…Finally, the sixth category consists solely of receptors not aligned with the preceding subfamilies, designated as the germ cell nuclear factor 1 (GCNF1) [ 39 ]. The NRs basic structure comprises an N-terminal regulatory domain (NTD) featuring the activation function (AF1), a ligand-binding domain (LBD), a DNA-binding domain (DBD), and an intervening hinge region [ 37 , 40 ]. Certain NRs recognize and bind to conserved DNA sequences named hormone response elements (HRE) either as monomers, homodimers, or heterodimers.…”

Prognostic Relevance of Nuclear Receptors in Relation to Peritumoral Inflammation and Tumor Infiltration by Lymphocytes in Breast Cancer

“…Although the links between TILs and steroid hormone receptors (type I nuclear receptors) are intensely studied in BC [ 20 ], the association between type II nuclear receptors and TILs has not been investigated. Type II nuclear receptors form heterodimers with RXR and consist of a variety of subtypes, including thyroid hormone and vitamin D receptors, PPARs, AhR, LXR, and others [ 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 ]. Their role in BC biology and their impact on patient survival have been reported by our group and others [ 24 , 29 , 30 , 31 , 32 , 33 ].…”