Intracellular IL-23R is necessary for mitotic spindle formation and viability in AML

Area of Science:

• Molecular Biology
• Cell Biology
• Hematology
• Cancer Research

Background:

• Interleukin-23 receptor (IL-23R) is a known cell surface receptor primarily expressed on T cells, regulating T cell activation.
• The role and localization of IL-23R in hematological malignancies, particularly Acute Myeloid Leukemia (AML), remain largely unexplored.

Purpose of the Study:

• To investigate the novel intracellular localization and function of IL-23R in Acute Myeloid Leukemia (AML).
• To determine the impact of IL-23R's intracellular role on AML cell proliferation and stem cell function.

Main Methods:

• Comparative analysis of IL-23R expression in primary AML samples versus normal hematopoietic cells.
• BioID proximity labeling mass spectrometry to identify IL-23R interacting proteins within AML cells.
• Confirmation of endogenous IL-23R interactions with mitotic spindle proteins using cellular and molecular techniques.
• Genetic depletion of IL-23R to assess its functional impact on AML cell proliferation and progenitor function.

Main Results:

• IL-23R expression is significantly increased in primary AML samples compared to normal hematopoietic cells.
• IL-23R is predominantly localized intracellularly within AML cells, interacting with mitotic spindle proteins via its (S/T)x(I/L)P motif.
• Genetic depletion of IL-23R disrupts mitotic spindle formation, reduces AML cell proliferation, and impairs stem cell/progenitor function.
• Depletion of IL-23R does not adversely affect normal hematopoietic cells and progenitors.

Conclusions:

• IL-23R exhibits a novel intracellular function in regulating mitotic spindle formation within AML cells.
• Targeting intracellular IL-23R represents a potential therapeutic strategy for Acute Myeloid Leukemia, selectively impacting malignant cells.
• The findings reveal IL-23R as a key regulator of AML cell growth and stemness.