Inflammation fuels bone marrow exhaustion caused by Samd9l mutation
Moonjung Jung
Moonjung Jung
Published November 1, 2022
Citation Information: J Clin Invest. 2022;132(21):e164136. https://doi.org/10.1172/JCI164136.
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Commentary

Inflammation fuels bone marrow exhaustion caused by Samd9l mutation

Abstract

Sterile α motif domain–containing 9 (SAMD9) and SAMD9-like (SAMD9L) syndromes are inherited bone marrow failure syndromes known for their frequent development of myelodysplastic syndrome with monosomy 7. In this issue of the JCI, Abdelhamed, Thomas, et al. report a mouse model with a hematopoietic cell–specific heterozygous Samd9l mutation knockin. This mouse model resembles human disease in many ways, including bone marrow failure and the nonrandom loss of the mutant allele. Samd9l-mutant hematopoietic stem progenitor cells showed reduced fitness at baseline, which was further exacerbated by inflammation. TGF-β hyperactivation was found to underlie reduced fitness, which was partially rescued by a TGF-β inhibitor. These findings illustrate the potential role of TGF-β inhibitors in the treatment of SAMD9/SAMD9L syndromes.

Authors

Moonjung Jung

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Figure 1

Model for bone marrow exhaustion and monosomy 7 exacerbated by inflammation in SAMD9/SAMD9L syndromes.

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Model for bone marrow exhaustion and monosomy 7 exacerbated by inflammat...
In a mouse model of SAMD9/SAMD9L syndrome, exposure to type I IFNs increases the expression of both WT and mutant Samd9l expression in HSPCs. However, only mutant Samd9l leads to upregulation of TGF-β and subsequent p-SMAD2/3 signaling upon inflammatory insults, which further exacerbate already severely decreased HSPC fitness, BM exhaustion, and promote nonrandom loss of mutant allele (equivalent to human monosomy 7) in mutant mice.