Exploring the nexus of nuclear receptors in hematological malignancies

Abstract

Hematological malignancies (HM) represent a subset of neoplasms affecting the blood, bone marrow, and lymphatic systems, categorized primarily into leukemia, lymphoma, and multiple myeloma. Their prognosis varies considerably, with a frequent risk of relapse despite ongoing treatments. While contemporary therapeutic strategies have extended overall patient survival, they do not offer cures for advanced stages and often lead to challenges such as acquisition of drug resistance, recurrence, and severe side effects. The need for innovative therapeutic targets is vital to elevate both survival rates and patients' quality of life. Recent research has pivoted towards nuclear receptors (NRs) due to their role in modulating tumor cell characteristics including uncontrolled proliferation, differentiation, apoptosis evasion, invasion and migration. Existing evidence emphasizes NRs' critical role in HM. The regulation of NR expression through agonists, antagonists, or selective modulators, contingent upon their levels, offers promising clinical implications in HM management. Moreover, several anticancer agents targeting NRs have been approved by the Food and Drug Administration (FDA). This review highlights the integral function of NRs in HM's pathophysiology and the potential benefits of therapeutically targeting these receptors, suggesting a prospective avenue for more efficient therapeutic interventions against HM.

Keywords: Apoptosis; Differentiation; Hematological malignancies; Homeostasis; Leukemia; Lymphoma; Multiple myeloma; Nuclear receptors.

Fig. 1

Nuclear receptor general signaling mechanism: a In the presence of agonists; b In the presence of antagonists. The ligands affiliated with nuclear receptors can exhibit either agonistic or antagonistic properties. Agonists, upon binding, induce structural alterations in nuclear receptors, facilitating the association with coactivators. This interaction subsequently triggers the transcriptional activation of downstream target genes. In contrast, the binding of antagonists hinders the transcription of target genes by engaging corepressors, leading to transcriptional suppression

Fig. 2

Nuclear receptors and their ligands that are involved in the modulation of cellular functions in leukemia. Numerous investigations have elucidated the pivotal role of nuclear receptors in the modulation of cellular signaling processes. The exploration of nuclear receptor functions in the context of leukemic cell characteristics has been conducted employing diverse inducers or agonists. Through these mechanistic inquiries, the engagement of key molecular entities such as TNF, TGF-β, EGFR, integrins, STAT3, and TLR has been unveiled, shedding light on their intricate involvement in the initiation and advancement of leukemia

Fig. 3

Nuclear receptors and their ligands that are involved in the modulation of cellular functions in lymphoma. Scientific investigations have provided compelling evidence demonstrating the participation of nuclear receptors, specifically AR, ER, PPARα, PPARβ, and PPARγ, in the regulation of key characteristics of lymphoma cells. Through functional studies based on ligand interactions, it has been established that these nuclear receptors play a pivotal role in modulating the proliferation and apoptosis of lymphoma cells

Fig. 4

Nuclear receptors and their ligands that are involved in the modulation of cellular functions in multiple myeloma. Nuclear receptors, including ER, GR, RAR, RXR, PPAR, and VDR, have been demonstrated to exert significant influence over myeloma cell growth, proliferation, and apoptosis. Notably, the administration of a VDR agonist, specifically dexamethasone, has been proven to augment both the overall response rate and progression-free survival in affected patients. Consequently, these receptors emerge as promising therapeutic targets for the treatment of multiple myeloma