Human monopoiesis is characterized by distinct and stage‐specific gene expression profiles

Monocytes are mononuclear cells of the myelomonocytic lineage, originating from the bone marrow and representing approximately 10% of human leucocytes. Together with their further differentiated descendants – macrophages and myeloid dendritic cells (DC) – monocytes constitute the mononuclear phagocyte system and support the activation of the adaptive immune system by antigen presentation, thus acting as a link between innate and adaptive immunity (Auffray et al, 2009; Huber et al, 2014). Monopoiesis is characterized by a succession of increasingly developed progenitors comprising hematopoietic stem cells and multipotent progenitors, a variety of myeloid and premonocytic cells, as well as monoblasts, promonocytes, and monocytes (Auffray et al, 2009; Huber et al, 2014). Mature monocytes enter the blood stream, where they patrol with a half-life of a few days and, in response to signs of infection or injury, they transmigrate into the affected tissue (Ziegler-Heitbrock et al, 2010; Swirski, 2011). Various severe diseases are based on the dysregulation of proliferation and differentiation of myelomonocytic cells, including myelodysplastic syndromes (Kulasekararaj et al, 2013) and leukaemias, such as acute myeloid leukaemia (Falini et al, 2015) or chronic myeloid leukaemia (Kavalerchik et al, 2008), indicating the necessity of precisely assessing the molecular events driving normal as well as dysregulated monopoiesis. Therefore, substantial efforts have been made over the decades to elucidate the molecular processes regulating monocytic development, which have led to a refined knowledge on maturation especially during the late phases of monocyte differentiation (Friedman, 2007) and during the differentiation of monocytes towards macrophages or DC (Geissmann et al, 2010). The precise analysis of the early phases, however, remained a complex problem due to the limited amount of progenitor cells and the lack of stagespecific biological markers. Commonly, a number of surface markers is used to identify multiple forms of leukaemias and lymphomas (van Dongen et al, 2012) or to distinguish between different developmental stages of a certain lineage, e.g., CD14, CD16 and CD34 (amongst others) in the myelomonocytic lineage (Auffray et al, 2009), but often these panels were not consistently validated and the existence of partially overlapping markers complicated a distinct identification of cellular entities (van Dongen et al, 2012; Matarraz et al, 2015). This situation was markedly improved by the recent efforts of the EuroFlow consortium to establish validated panels of flow cytometry antibodies for the immunophenotyping of haematological malignancies and the characterization of bone marrow-derived (pre)monocytic cells. Based on a combination of several surface markers with specific expression profiles, different stages could be identified during normal monocytic maturation in the bone marrow, ranging from early progenitor cells (e.g., CD14 , CD34, CD36 , CD117, CD300e ), via monoblasts and promonocytes to mature monocytes (CD14, CD34 , CD36, CD117 , CD300e) (van Dongen et al, 2012; Matarraz et al, 2015). This advanced classification represented an important improvement in the assessment of individual pre-monocytic developmental steps. The underlying changes in gene expression, however, remained quite unclear. In the current issue of the British Journal of Haematology, de Mello et al (2016) address this gap by presenting a ground-breaking study focusing on the analysis of gene expression profiles (GEP) in these bone marrow-derived precursors. Based on the results of the EuroFlow consortium, de Mello et al (2016) were able to characterize a variety of specifically regulated genes and their respective expression pattern changes in five distinct maturation stages and between these stages, respectively. Thus, in addition to cell surface markers, selected pre-monocytic cell populations can be further assessed by specific GEP. Moreover, the regulated genes could be assigned to defined cellular functions, e.g., showing a decrease in proliferationand an increase in differentiationassociated genes. These events illustrate that monopoiesis is characterized by a controlled transition from (a limited number of) considerably proliferating progenitor cells to (a large number of) further differentiated (pre)monocytic phenotypes Correspondence: Dr. Ren e Huber, Institute of Clinical Chemistry, OE8110, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany. E-mail: huber.rene@mh-hannover.de editorial comment