Laboratory of Human Genetics of Infectious Diseases, Necker Hospital for Sick Children, Paris, France.
Paris Cité University, Imagine Institute, INSERM U1163, Paris, France.
J Clin Invest. 2024 Oct 15;134(20):e181604. doi: 10.1172/JCI181604.
Patients heterozygous for germline CBL loss-of-function (LOF) variants can develop myeloid malignancy, autoinflammation, or both, if some or all of their leukocytes become homozygous for these variants through somatic loss of heterozygosity (LOH) via uniparental isodisomy. We observed an upregulation of the inflammatory gene expression signature in whole blood from these patients, mimicking monogenic inborn errors underlying autoinflammation. Remarkably, these patients had constitutively activated monocytes that secreted 10 to 100 times more inflammatory cytokines than those of healthy individuals and CBL LOF heterozygotes without LOH. CBL-LOH hematopoietic stem and progenitor cells (HSPCs) outgrew the other cells, accounting for the persistence of peripheral monocytes homozygous for the CBL LOF variant. ERK pathway activation was required for the excessive production of cytokines by both resting and stimulated CBL-LOF monocytes, as shown in monocytic cell lines. Finally, we found that about 1 in 10,000 individuals in the UK Biobank were heterozygous for CBL LOF variants and that these carriers were at high risk of hematological and inflammatory conditions.
携带 CBL 胚系功能丧失（LOF）变异的杂合子患者，如果其部分或全部白细胞通过单亲二体同源丢失（LOH）而成为这些变异的纯合子，就可能发展为髓系恶性肿瘤、自身炎症或两者兼有。我们观察到这些患者的全血中炎症基因表达谱上调，类似于自身炎症的单基因先天性错误。值得注意的是，这些患者的单核细胞持续激活，分泌的炎症细胞因子比健康个体和无 LOH 的 CBL LOF 杂合子多 10 到 100 倍。CBL-LOH 造血干细胞和祖细胞（HSPCs）比其他细胞生长更快，导致外周单核细胞纯合 CBL LOF 变异体的持续存在。ERK 通路的激活对于静止和刺激后的 CBL-LOF 单核细胞产生过多的细胞因子都是必需的，这在单核细胞系中得到了证实。最后，我们发现英国生物库中约有 1/10000 的个体为 CBL LOF 变异的杂合子，这些携带者存在血液系统和炎症疾病的高风险。
