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.

中文翻译：

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白细胞 CBL 杂合性缺失患者的自身炎症是由组成型 ERK 介导的单核细胞活化引起的


种系 CBL 功能丧失 （LOF） 变异杂合子患者可发展为髓系恶性肿瘤、自身炎症或两者兼而有之，如果他们的部分或全部白细胞通过单亲同源杂合性 （LOH） 体细胞缺失 （LOH） 成为这些变异的纯合子。我们观察到这些患者全血中炎症基因表达特征的上调，模拟了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组成性激活，其分泌的炎性细胞因子是健康个体和无 LOH 的 CBL LOF 杂合子的 10 至 100 倍。CBL-LOH 造血干细胞和祖细胞 （HSPC） 的生长速度超过其他细胞，这是 CBL LOF 变体纯合子外周单核细胞的持久性的原因。静息和刺激的 CBL-LOF 单核细胞过量产生细胞因子都需要 ERK 通路激活，如单核细胞系所示。最后，我们发现英国生物样本库中约有 10,000 人是 CBL LOF 变体的杂合子，并且这些携带者患血液学和炎症疾病的风险很高。