Unexpected Findings Reveal a Complex Role for the NF-κB pathway in Hematopoiesis

Review of “Constitutive Activation of NIK Impairs the Self-Renewal of Hematopoietic Stem/Progenitor Cells and Induces Bone Marrow Failure” from Stem Cells by Stuart P. Atkinson

A previous Stem Cells study from the laboratory of Chen Zhao (University of Iowa, USA) described the importance of non-canonical NF-κB signaling in the regulation of hematopoietic stem/progenitor cells (HSPCs) and the stromal/osteoblastic niche they call home [1]. The team now return to Stem Cells with another excellent study in which they investigate the role of the NF-κB Inducing Kinase (NIK), a key signaling molecule in the non-canonical NF-κB pathway. Their unexpected findings reveal a complex role for the NF-κB pathway in hematopoiesis and in the development of bone marrow failure [2].

The model system employed an engineered HSPC-specific mutation of the tumor necrosis factor receptor-associated factor 3 (TRAF3)-binding domain of NIK which impairs degradation and allows constitutive NIK activity. Unexpectedly, mice overexpressing NIK displayed growth retardation, post-natal mortality, smaller spleen size, and displayed signs of bone marrow failure, all suggesting a detrimental effect of constitutive activation of NIK to normal hematopoiesis. Indeed, the authors soon discovered that NIK activation actually impaired HSPC self-renewal, reduced cell proliferation, increased apoptosis and inflammatory cytokine responses, and disrupted the bone marrow environment via enhanced levels of osteoclast formation. 

Importantly, non-canonical signaling through NIK activation displayed distinct phenotypes compared to the activation of canonical NF-κB signaling. Reinforcing this point, RNA-Seq experiments in NIK-overexpressing HSPCs demonstrated changes to non-canonical NF-κB signaling genes and not canonical pathway-associated genes. These experiments also highlighted decreases in genes associated with stemness, HSPC self-renewal, and HSPC differentiation and increases in genes associated with inflammatory responses and cell cycle inhibition.

Overall, these unexpected but vital findings reveals a complex role for the NF-κB pathway in hematopoietic homeostasis and the development of bone marrow failure. Stay tuned to the Stem Cells Portal to find out more!

References

1. Zhao C, Xiu Y, Ashton J, et al. Noncanonical NF-kappaB signaling regulates hematopoietic stem cell self-renewal and microenvironment interactions. Stem Cells 2012;30:709-718.
2. Xiu Y, Xue WY, Lambertz A, et al. Constitutive Activation of NIK Impairs the Self-Renewal of Hematopoietic Stem/Progenitor Cells and Induces Bone Marrow Failure. Stem Cells 2017;35:777-786.