Frequency of SAMD9L mutation in hematopoietic stem, progenitor, and differentiated cell populations and interferon-stimulated expression of SAMDL. (A) Quantification of the frequency of the SAMD9L c.2956C>T in distinct bone marrow–derived HSPC populations from F1:II-2, as indicated. (B-C) Quantification of the frequency of the SAMD9L (B) c.2956C>T and (C) c.2672T>C mutations in specific peripheral blood–derived immune cell populations from F1:III-2 and F2:II-1, respectively, as indicated. For each sample, values represent the mean of at least 2 chips. Error bars denote 95% confidence levels. (D-F) Evaluation of SAMD9L and SAMD9 expression in (D) bone marrow-derived CD34⁺ HSPCs, (E) peripheral blood–derived NK cells, and (F) fibroblasts stimulated with interferon (IFN)-α or IFN-γ, as indicated. (G) Hypothetical model of the pathophysiology of germ line SAMD9L gain-of-function (GoF) mutations in relation to HSPC proliferation and differentiation. Healthy individuals, with 2 wild-type SAMD9L copies (top panel), have (1) normal, steady-state hematopoiesis, and (2) increased cellular output upon infection-induced, demand-adapted hematopoiesis. In contrast, carriers of heterozygous SAMD9L GoF mutations (middle panel) may (1) display grossly normal (and perhaps subclinical) hematopoiesis for some time, but (2) experience cytopenias and immunodeficiency upon infection early in life. In this setting, interferons can promote SAMD9L expression, with SAMD9L GoF mutants acting as potent suppressors of cell proliferation, dramatically impairing hematopoiesis and immunity. The ensuing hematopoietic crisis can facilitate (3) selection and expansion of revertant mutants, by UPD(7q), SAMD9L loss-of-function (LoF) mutations in cis, or monosomy 7. Whereas UPD(7q) and in cisSAMD9L LoF mutations can support clonal hematopoiesis and recovery from cytopenia, monosomy 7 is associated with development of MDS. Finally, carriers of combined SAMD9L GoF mutation and rare LoF variants in trans (bottom panel) are asymptomatic, suggesting they have normal (1) steady-state and (2) demand-adapted hematopoiesis. As such, pathogenic effects of SAMD9L GoF mutations may be balanced by SAMD9L LoF mutations. Mono, monocyte; Neu, neutrophil.