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Extended myeloid-based model of lineage commitment
Figure 5. The fortifying role of BACH for the next emergency. BACH factors sup- port erythropoiesis and repress myelopoiesis in steady-state conditions. BACH2 in particular supports the development of memory B cells, non-IgM plasma cells, regulatory T cells and memory T cells in the steady state while repressing the development of IgM plasma cells and effector T cells. Since BACH factors sup- port the development of the cells needed for the suppression of a previous emergency reaction and the preparation for the next emergency, BACH factors can be considered “fortifying factors”.
pany changes in other lineages in the opposite direction. Infection and inflammation cause anemia of inflamma- tion, which is frequently observed in chronic infections and autoimmune diseases.8 Inflammatory cytokines, such as interleukin-6, induce the expression of hepcidin, resulting in the inhibition of ferroportin.92 This regulato- ry axis is the mechanism by which the iron supply for erythroblast maturation is limited, resulting in anemia.8 However, this mechanism may not explain how the dif- ferentiation trajectory is modulated at the erythroid- myeloid bifurcation point during an infection and in inflammatory conditions.6 In those circumstances, the expression of BACH factors is repressed in HSPC,19,93 leading to increased myelopoiesis at the expense of ery- thropoiesis. Therefore, the reduced activity of BACH factors might be a novel mechanism underlying anemia of inflammation.
MDS is a major hematopoietic malignancy and is caused by a clonal disorder in HSC.94 The phenotypic features of MDS, such as anemia, autoimmune reactions and transformation into acute myeloid leukemia, may also be attributed to alterations in the state of gene regu- latory networks. The expression of BACH2 is repressed in MDS.19 Since the loss of BACH2 is expected to induce anemia, an inflammatory reaction and myeloid skewing of progenitors, the repression of BACH2 that has been observed in MDS patients might be one of the causes of the characteristic symptoms of MDS. A recent genome- wide analysis showed that MDS clones frequently have mutations in epigenetic modifiers and splicing factors,95 suggesting that such genetic alterations may lead to a reduction in BACH2 expression. BACH2 repression is also observed in lymphocytes on aging, with PRDM1
induction in humans.96 Since the loss of BACH2 causes
autoimmune-like disorders,28 BACH2 repression (and the
induction of the “inner myeloid”) during aging may be
one of the causes of aging-related inflammation.
Interestingly, HSC in mice become restricted to a
myeloid fate upon aging.97 This may be due to a reduc-
tion in BACH2 expression. Moreover, mutations of epi-
genetic modifiers, such as those observed in clonal
hematopoiesis with aging,98 may cause dysregulation of
the repression of the “inner myeloid”, resulting in
myeloid skewing and inflammation. If this is the case,
aging-related dysregulation of the “inner myeloid” is part
of a vicious circle since inflammation per se can cause
99
in aged HSC can rescue the phenotype related to aging.
Conclusions
In this review, we have highlighted recent findings concerning the differentiation of HSPC and their limita- tions. Novel findings from single-cell analyses suggest the need to reconsider the canonical hierarchical differ- entiation model of the hematopoietic system. However, we should also consider the limitations associated with these single-cell analyses, as discussed above. The myeloid-based model involving the gene regulatory net- works of BACH factors may provide a further molecular basis for understanding lineage commitment, evolution- ary perspectives and pathological processes of the hematopoietic system. Understanding the roles of BACH factors as repressors of the “inner myeloid”’ and “fortify- ing factors” in preparation for future emergency situa- tions will help us to develop a more comprehensive model of the hematopoietic system.
Acknowledgments
We thank Prof. Hideo Harigae, Dr. Akihiko Muto, Dr. Kyoko Ochiai and Dr. Yusho Ishii for discussion and comments on the manuscript. Studies at Tohoku University are supported by Grants-in-Aid from the Japan Society for the Promotion of Science (18H04021, 18H05374, and 15H02506 to KI and 17H06527 to HK).
BACH2 haploinsufficiency in humans has been reported to cause BACH2-related immunodefi- ciency and autoimmunity (BRIDA),100 a finding that may further support these possibilities. In contrast, BACH2 overexpression in progenitor cells induces erythropoiesis by repressing myelopoiesis.19 Therefore, BACH factors might be new therapeutic targets of refractory anemia induced by inflammation and MDS. Further investiga- tions will be needed in order to determine whether or not BACH2 re-activation (or “inner myeloid” repression)
DNA mutations.
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