Page 28 - 2019_10 resto del Mondo_web

H. Kato et al.
HSPC, originally described as the “myeloid-based model”,74 and repression of the myeloid differentiation program appears important for lineage commitment in HSPC. In line with this, recent reports suggest the impor- tance of myeloid-biased HSC in emergency myelopoiesis.75-77 Further analysis is still needed to clarify how the gene regulatory networks are altered in myeloid-biased HSC.
In addition to the repression of the myeloid program during progenitor cell differentiation, re-activation of the myeloid program is observed in some mature hematopoietic cells. During maturation of erythroid and lymphoid cells, the function and expression of BACH factors are repressed, which can induce part of the myeloid program. For instance, Prdm1 (encoding TF BLIMP-1) is a repressed target of BACH2, and its repres- sion is necessary for the proper development of B cells.26 BLIMP-1 per se is necessary for the proper development of plasma cells and T cells.78 Since BLIMP-1 is important for myeloid cell development as well,79 BLIMP-1 can be considered as a part of the myeloid program deployed during plasma-cell and T-cell development. To support this notion, some of the myeloid genes are expressed in plasma cells.17 From the perspective of erythropoiesis, the expression of Hmox1 (encoding heme oxygenase-1) is induced to avoid the toxic activity of free heme during erythroblast maturation,80 On the other hand, heme oxy- genase-1 is also important for the proper function of myeloid cells.81 Therefore, heme oxygenase-1 can be considered as a part of the myeloid program deployed during the development of erythroid cells. Both mature myeloid cells and non-myeloid cells (erythroid and lym- phoid cells) must cope with conditions of stress (such as oxidative stress during oxygen transportation or at the site of inflammation). We therefore assume that mature hematopoietic cells may reactivate a part of the myeloid program, such as heme oxygenase-1, to protect them- selves from stresses, irrespective of their lineages. The myeloid program, which is temporarily repressed upon lineage commitment, is thus referred to as the “inner myeloid”,82 because part of it can be re-activated in mature cells. Given these findings, we propose “an extended myeloid-based model” of hematopoiesis, which posits that the myeloid program possesses impor- tant roles not only in hematopoietic cell differentiation but also in mature cell function.
The extended myeloid-based model with the “inner myeloid” is well understandable when the history of bio- logical evolution is considered. Lower organisms, such as insects, possess phagocytic cells but lack erythroid and lymphoid cells.83 A human-like HSC system was recently found in the chordate Botryllus schlosseri, with stem cells generating solely cells of myeloid lineage, such as phago- cytic cells and granulocytes.84 It should be noted that a BACH-like TF is present in chordates and vertebrates85 but not in lower organisms. The prototype BACH TF may restrict myeloid differentiation of HSC. Since ery- throid cells and lymphoid cells arose in the hematopoiet- ic system during the evolution of higher organisms, repressing the myeloid program in progenitor cells (“inner myeloid”) might be necessary to make non- myeloid cells (erythroid and lymphoid cells). The find- ings regarding the function of BACH factors as repressors of the “inner myeloid” may constitute the molecular foundation of the myeloid-based model of
hematopoiesis and lineage commitment. The hematopoietic system in higher eukaryotes is therefore evidence of our ancient history, just like our other body systems.86
Fortifying roles of BACH factors in blood homeostasis
BACH factors play not only repressive roles in the myeloid program in progenitor cells but also several indispensable roles in the operation of the hematopoietic system. For instance, BACH1 works as a balancer of glo- bins and heme during erythroid cell maturation.22 BACH2 is required for the development of non-IgM type plasma cells, memory B cells, regulatory T cells and memory T cells.23-30,87,88 and therefore works as a regulator of lymphocyte effector versus non-effector differentia- tion. Remarkably, these functions of BACH2 in lym- phoid cells might be explained by its binding to the AP- 1 site as a transcription repressor, which is in contrast to the other TF (Fos, Jun, etc.) targeting the AP-1 site, many of which work as transcription activators.89
These functions of BACH factors in erythroid and lym- phoid cells can be interpreted as indicative of their role as ‘fortifying factors’, since they shape steady-state hematopoiesis to prepare for infection at multiple points, as described below. With regard to erythropoiesis, the hemoglobin concentration in human blood is kept around 14 g/dL in the steady state whereas, in general, a hemoglobin concentration <7 g/dl is life-threatening. There is therefore sufficient capacity for erythropoiesis to endure emergency conditions. For instance, progenitor cell differentiation can be shifted toward myelopoiesis, thus promoting the innate immune defense at the expense of erythropoiesis during a state of infection. This means that BACH factors support erythropoiesis by suppressing myelopoiesis in the steady state, fortifying the system for infection. With regard to the B-cell response, IgM-secreting plasma cells work as the first line of defense against pathogens, whereas non-IgM- type plasma cells and memory B cells are produced at a later phase or after the infection as a more effective sec- ond-line defense.90 With regard to the T-cell response, effector T cells provide the first line of defense against pathogens whereas regulatory T cells and memory T cells work to repress an excess immune response and/or to return the state to the steady condition in preparation for the next infection.91 These responses may be coordi- nated by the expression of BACH factors. When their expression is reduced in response to infection, IgM- secreting plasma cells and effector T cells are preferen- tially generated. Conversely, resumption of the expres- sion of BACH factors leads to the generation of non-IgM plasma cells, memory B cells, regulatory T cells and memory T cells. Therefore, BACH factors are required to fortify the hematopoietic system as a whole, in prepara- tion for future infections (Figure 5).
Hematologic disorders as failures of BACH gene regulatory networks
The gene regulatory networks of HSPC may explain why pathological alterations in one lineage often accom-
1924
haematologica | 2019; 104(10)