In this issue of the JCI, Garrigue, Kermasson, and colleagues demonstrate that human oncostatin M (OSM) deficiency underlies profound anemia, thrombocytopenia, and neutropenia, unraveling another inherited bone marrow failure syndrome (IBMFS) (1). Using a combination of whole-genome homozygosity mapping (WGHM) and whole-exome sequencing (WES), the group identified a homozygous loss-of-function (LoF) variant in three children from a consanguineous family presenting with a particular phenotype of isolated pancytopenia (1) (Figure 1). IBMFSs represent a heterogenous group of rare monogenic disorders characterized by a progressive mono-, bi-, or trilineage cytopenia, often associated with nonhematological manifestations (2, 3). Known genetic causes of IBMFS comprise deleterious germline variants affecting DNA repair, telomere maintenance, and ribosome biogenesis and function, processes which are essential for the self-renewal of hematopoietic stem and progenitor cells (HSPCs) (4). Finally, defects in erythromyeloid differentiation, metabolism, and HSPC homeostasis can also underlie IBFMS. In IBMFSs such as Fanconi anemia, Diamond-Blackfan syndrome, dyskeratosis congenita, constitutional thrombocytopenia, and congenital neutropenia, different stresses elicit a p53-dependent growth arrest, resulting in an accelerated apoptosis of HSPCs (5).

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

Garrigue, Kermasson, and colleagues expand the etiology of IBMFS, demonstrating that next to intrinsic genetic defects affecting HSPCs, genetically defined alterations of the bone marrow microenvironment (BMM) may cause an IBMFS (1). Indeed, patients’ HSPCs differentiated normally into erythroblasts and thrombocytes in vitro, suggesting that OSM deficiency hampers maturation after erythroblast and megakaryocyte differentiation in an HSPC-intrinsic way, or that it alters the BMM. This hypothesis was supported by the normal colony-forming assay results and mega-cult assays using patient cells and previously by decreases in erythroid and megakaryocytic cells following transfer of bone marrow cells from WT mice to OSM receptor-deficient (OSMR-deficient) mice (1, 6). Furthermore, the Garrigue et al. findings support the emerging concept that sustained or aberrant exposure to inflammatory signals, force repeated HSC cycling, which can result in HSC exhaustion and hematopoietic failure (4).