Deuterium labelling uncovers deregulated myeloid cell kinetics in chronic myelomonocytic leukemia

The hallmark of chronic myelomonocytic leukemia (CMML) is an abnormal increase in circulating monocytes and neutrophils. Several non-exclusive scenarios could explain this accumulation, including extended lifespan in blood and/or increased production in bone marrow (BM). To test these, we generated quantitative, in vivo measurements of how myeloid cells are produced, mature, and survive by using deuterium-glucose incorporation, mathematical modelling, and Bayesian inference, in 25 CMML patients and 10 aged healthy donors. Results showed no evidence for increased lifespans of monocytes and neutrophils in peripheral blood. Conversely, CMML boosts the production of monocytes by ∼7-fold and neutrophils by ∼1.8-fold. The lack of correlation between this increased production and cell subset kinetic parameters supports the hypothesis that an increased number of progenitors is the main source of enhanced myeloid cell production. Beyond this generic observation, kinetic parameters were more divergent in CMML patients than in controls. The most divergent outlier subjects tended to higher IPSS-M scores (Molecular International Prognostic Scoring System for Myelodysplastic Syndromes). Delayed maturation of neutrophils was observed in patients with a SRSF2 mutation, while BM retention of mature monocytes and neutrophils was diversely associated with inflammatory markers. Occasionally, CMML patients release immature granulocytes (iGRANs) into the circulation. We found that these iGRANs had distinct kinetics, including delayed maturation, rapid release, and longer survival in the bloodstream. Overall, these data support a model in which increased myeloid cell production stems from greater progenitor numbers, generating cells with increasingly diverse kinetics as the disease progresses, including a specifically-dysregulated iGRAN population.