The journey of human neutrophils: from immature CD34+ progenitors to mature cells

A precise immunophenotypic and molecular characterization of neutrophil differentiation from CD34+ cells has not yet been fully explored. Recently, however, novel progenitors such as proNeus and eNePs have been identified, but these cells express the lineage markers CD66b and CD15, thus resembling promyelocytes (PMs) or more advanced maturation stages. In this context, our group more recently has identified four neutrophil-committed progenitors (NCPs) within the SSCloLin−CD45dim flow cytometry region of human bone marrow (BM), close to that of CD34+ hematopoietic stem cells (HSCs). These precursors have been characterized based on their differential expression of CD34 and CD45RA and subdivided into CD34+CD45RA− NCP1s, CD34+CD45RA+ NCP2s, CD34dim/−CD45RA+ NCP3s, and CD34dim/−CD45RA− NCP4s. Additionally, we uncovered that NCP1s directly mature into NCP4s, while NCP2s mature into NCP4s through NCP3s. These results are in concordance with the transition of neutrophil precursors associated with CD45RA upregulation but also revealed the existence of a second maturation route that is exclusively CD45RA-. In this context, my work has identified two novel NCPs within the SSChiCD66b- flow cytometry region of human bone marrow. These progenitors are located between NCP4s and PMs along the neutropoiesis cascade, and similarly to SSCloCD45RA+NCP2s/NCP3s and SSCloCD45RA-NCP1s/NCP4s, exhibit phenotypic differences in CD45RA expression levels and, therefore, were named as SSChiCD45RA+NCP5s and SSChiCD45RA-NCP6s. Furthermore, NCP5s were found to be more immature than NCP6s, as assessed by cell differentiation and proliferative potential, as well as by transcriptomic and phenotypical features. Moreover, my studies have also uncovered that in chronic-phase chronic myeloid leukemia (CP-CML), but not in systemic mastocytosis (SM), there is an increased frequency of specific BM NCPs, in particular of NCP4s, NCP6s, and all downstream CD45RA-negative neutrophil progenitors. My additional work also provided a more in-depth analytical evaluation, at the phenotypic and molecular levels, of the cells generated by NCPs which, depending on the type of NCPs investigated, result neutrophilic cells at different stages of maturation but not neutrophil-like CXCR1+CD14+CD16- monocytes, as erroneously proposed by other researchers. Altogether, the data emerging from my studies not only enhance the understanding of human neutropoiesis occurring within the human bone marrow but also offer novel information important for the pathogenesis of chronic myeloid leukemia.