• Monocytosis associates with a higher frequency of CH with spliceosome and multiple gene mutations, but not isolated DNMT3A/TET2/ASXL1

  • Few community-based individuals with monocytosis and CH develop a myeloid malignancy (among 167 individuals: n=4 cases including n=1 CMML)

Monocytosis may occur in numerous inflammatory conditions but is also the defining feature of chronic myelomonocytic leukemia (CMML). Clonal somatic mutations detectable in CMML may occur with ageing in otherwise healthy individuals, so-called "clonal hematopoiesis" (CH). We investigated whether the combination of CH and monocytosis would represent an early developmental stage of CMML. We studied community-dwelling individuals with monocytosis (≥ 1 x 109/L and ≥10% of leukocytes) in the population-based Lifelines cohort (n=144676 adults). The prevalence and spectrum of CH were evaluated for individuals ≥60 years with monocytosis (n=167, 0.8%) and controls 1:3 matched for age and sex (n=501). Diagnoses of hematological malignancies were retrieved by linkage to the Netherlands Cancer Registry. Monocyte counts and the prevalence of monocytosis increased with advancing age. Older individuals with monocytosis more frequently carried CH (50.9% versus 35.5%, P<0.001). Monocytosis associated with enrichment of multiple gene mutations (P=0.006) and spliceosome mutations (P=0.007) but not isolated mutated DNMT3A, TET2 or ASXL1. Persistent monocytosis over four years was observed in 30/102 evaluable individuals and associated with higher prevalence of CH (63%). Myeloid malignancies, including one case of CMML, developed in four individuals with monocytosis that all carried CH. In conclusion, monocytosis and CH both occur at older age and do not necessarily reflect clonal monocytic proliferation. In a fraction of older subjects with monocytosis, CH might constitute early clonal dominance in developing malignant myelomonocytic disease. Mutational spectra deviating from age-related CH require attention.

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