Does immune destruction drive all forms of bone marrow failure?
Brian M. Dulmovits, Timothy S. Olson
Brian M. Dulmovits, Timothy S. Olson
Published August 1, 2022
Citation Information: J Clin Invest. 2022;132(15):e161288. https://doi.org/10.1172/JCI161288.
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Commentary

Does immune destruction drive all forms of bone marrow failure?

Abstract

Current paradigms of bone marrow failure (BMF) pathophysiology suggest that immune-mediated destruction of hematopoietic stem and progenitor cells (HSPCs) drives acquired aplastic anemia. In contrast, loss of HSPCs due to senescence and/or apoptosis causes BMF in inherited BMF syndromes. In this issue of the JCI, Casado and colleagues challenge this dichotomous conception by demonstrating that NK cell–dependent, immune-mediated hematopoietic suppression and HSPC clearance drive BMF in Fanconi anemia (FA). They show that genotoxic stress upregulates natural killer group 2 member D ligands (NKG2D-L) on FA HSPCs leading to NK cell cytotoxicity through NKG2D receptor activation. Inhibition of NKG2D–NKG2D-L interactions enhanced FA HSPC clonogenic potential and improved cytopenias in vivo. These results provide alternative targets for the development of immunosuppressive therapies to reduce HSPC loss and mitigate the risk of hematologic malignancies in FA.

Authors

Brian M. Dulmovits, Timothy S. Olson

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Figure 1

NKG2D/NKG2D-L interactions lead to NK cell–mediated loss of HSPCs in FA.

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NKG2D/NKG2D-L interactions lead to NK cell–mediated loss of HSPCs in FA....
Genotoxic stress promotes ICL formation, which results in the recruitment of FA/BRCA pathway members. In the setting of FANC mutations, DNA lesions remain unrepaired, causing activation of the DNA damage response (DDR) in HSPCs. Phosphorylation of ATR and CHEK1 stimulates the expression of NKG2D-Ls. NKG2D-Ls engage at the surface of HSPCs with NKG2D on NK cells, inducing HSPC apoptosis and subsequent bone marrow failure. Mutations in the FA core complex, including FANCA and FANCG protein mutations, were predominantly studied by Casado and colleagues (7).