Chronic myelomonocytic leukemia (CMML) is a severe myeloid malignancy that straddles the boundary between myeloproliferative and myelodysplastic neoplasms. It primarily affects elderly individuals, and the mutational signatures of leukemic cells suggest that aging is its main driver. Diagnosis relies on persistent peripheral blood monocytosis, an abnormal distribution of monocyte subsets, and the presence of clonal cytogenetic or molecular abnormalities. Therapeutic options remain limited: allogeneic stem cell transplantation, the only potentially curative treatment, is often precluded by advanced age and comorbidities, while hypomethylating agents neither reduce the variant allele frequency nor prevent progression to acute myeloid leukemia. Single-cell analysis of clonal architecture reveals early clonal dominance, leaving only few wild-type hematopoietic stem cells. Based on the hypothesis that the inflammatory component generated by the myeloid cells of the leukemic clone contributes to disease progression, the authors investigated the role of immature granulocytes (iGRAN).
These cells were detected and quantified in the peripheral blood of patients using spectral and conventional flow cytometry. Their accumulation proved to be a strong and independent adverse prognostic factor. Exome sequencing of sorted populations established that these immature granulocytes belong to the leukemic clone, and their behavior resembles that of myeloid-derived suppressor cells. Bulk and single-cell RNA sequencing highlighted their pro-inflammatory status: they secrete multiple cytokines, among which CXCL8 reached the highest level.
Functional analyses showed that CXCL8 inhibits the proliferation of wild-type hematopoietic stem and progenitor cells (HSPCs), but not that of CMML-derived HSPCs, in which CXCL8 receptors are underexpressed. This difference confers a selective advantage to the leukemic clone. Using liquid cultures of CD34+ cells from healthy and CMML bone marrow, complemented by mathematical modeling of clonal dynamics, the authors quantified the effect of this cytokine on cell growth.
Inhibition of CXCL8 receptors and blockade of CXCL8 restored the proliferation of wild-type HSPCs. These findings suggest that relieving the selective pressure exerted by CXCL8 on healthy HSPCs represents a potential strategy to slow CMML progression and restore a degree of healthy hematopoiesis.