Oncostatin M silence and neopeptide: the value of exploring patients with rare inherited bone marrow failure
Selket Delafontaine, Isabelle Meyts
Selket Delafontaine, Isabelle Meyts
Published March 17, 2025
Citation Information: J Clin Invest. 2025;135(6):e190955. https://doi.org/10.1172/JCI190955.
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Oncostatin M silence and neopeptide: the value of exploring patients with rare inherited bone marrow failure

Abstract

Inherited bone marrow failure syndromes (IBMFSs) encompass a diverse group of hematological disorders characterized by a progressive single-lineage cytopenia or pancytopenia. Despite their heterogeneity, these syndromes often result from genetic errors affecting key biological mechanisms, including telomere maintenance, DNA repair and chromosomal stability, and ribosome assembly, generally leading to accelerated apoptosis of hematopoietic cells. Nevertheless, a genetic diagnosis remains elusive in more than half of the cases. The increased risk of myelodysplastic syndrome (MDS), acute leukemia, and solid tumors associated with IBMFS frequently prompts early hematopoietic stem cell transplantation (HSCT). In this issue of the JCI, Garrigue, Kermasson, and colleagues identified a homozygous variant in Oncostatin M (OSM) in 3 children from a consanguineous family presenting with IBMFS characterized by profound anemia, thrombocytopenia, and neutropenia. The findings suggest that the loss-of-function OSM variant affected hematopoietic stem cell function through changes to the bone marrow microenvironment (BMM).

Authors

Selket Delafontaine, Isabelle Meyts

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Figure 1

Autosomal recessive OSM deficiency causes an isolated phenotype of IBMFS through an alteration of the BMM.

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Autosomal recessive OSM deficiency causes an isolated phenotype of IBMFS...
OSM is a pleiotropic cytokine, secreted by activated immune cells such as T cells, monocytes, macrophages, and neutrophils. Upon binding to its receptors, composed of gp130 and LIFR and/or gp130 and OSMRb, which are widely expressed in hematopoietic and nonhematopoietic tissue, OSM activates the JAK/STAT, the RAS/MAPK, and the PI3K/AKT signaling pathways. Garrigue, Kermasson, and colleagues (1) demonstrated how a homozygous LoF mutation, found in three children from a consanguineous family, leads to the production of a neopeptide, impeding the interaction with both OSM receptors on HSPCs, which ultimately underlies an IBMFS characterized by profound anemia, neutropenia, and thrombocytopenia. This discovery demonstrates that genetic causes of IBMFS extend beyond HSPC intrinsic defects, as alterations of the BMM and inflammatory cytokines can play a pathogenic role in the development of IBMFS.