Infection perturbs Bach2- and Bach1-dependent erythroid lineage ‘choice’ to cause anemia

Kato, Hiroki; Itoh-Nakadai, Ari; Matsumoto, Mitsuyo; Ishii, Yusho; Watanabe-Matsui, Miki; Ikeda, Masatoshi; Ebina-Shibuya, Risa; Sato, Yuki; Kobayashi, Masahiro; Nishizawa, Hironari; Suzuki, Katsushi; Muto, Akihiko; Fujiwara, Tohru; Nannya, Yasuhito; Malcovati, Luca; Cazzola, Mario; Ogawa, Seishi; Harigae, Hideo; Igarashi, Kazuhiko

doi:10.1038/s41590-018-0202-3

Cited by 31 publications

(33 citation statements)

References 64 publications

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“…This suggest that hosts exposed to heme, such as would occur in malaria or other form of hemolysis, prime hematopoeitc stem cells towards adapted myelopoiesis. The heme-dependent transcriptional repressor BACH-1 plays an essential role in the heme induced increase of myeloid cells, since it was shown that heme binding to BACH-1 causes a shift from erythropoiesis towards myelopoiesis in the bone marrow 52 , similar to observed in this study. Whether the effects observed in our study rely on heme-driven modulation of BACH-1 remains to be established.…”

Section: /37supporting

confidence: 89%

Heme induces innate immune memory

Jentho

Novakovic

Ruiz-Moreno

et al. 2019

Preprint

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Trained immunity defines long-lasting adaptive responses of innate immunity, mediated by transcriptional and epigenetic modifications of myeloid cells. Here, we report that labile heme, an alarmin released extracellularily upon tissue damage and hemolysis, induces trained immunity in human and murine primary cells and in mice. Heme-trainning in monocytes is associated with epigenetic and transcriptional profiles that overlap to some extent with those seen in β-glucan-training, the prototype agonist of trained immunity. In sharp contrast to β -glucan training however, heme-training relied on activation of the Syk/JNK-pathway. Heme training in mice was associated with long-lasting expansion of myeloid-biased progenitor cells as well as with altered chromatin accessibility in hematopoietic stem and progenitor cells. Finally, heme-induced training was protective against bacterial sepsis in mice.In conclusion, we reveal that heme, a bona fide alarmin, induces innate immune memory regulating host response to infection.Jentho et al. 3/37

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Section: /37supporting

confidence: 89%

Heme induces innate immune memory

Jentho

Novakovic

Ruiz-Moreno

et al. 2019

Preprint

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“…This is attributed to their ability to target and activate the mTOR pathway, inducing glycolysis and triggering enhanced myelopoiesis. Additionally, in a setting of LPS-induced systemic inflammation, myelopoiesis is controlled via the expression of the CEBPb targeting transcription factors BACH 1 and 2 fostering myelopoiesis over erythropoiesis (Kato et al, 2018). During bacteria-induced sepsis and Schistosoma japonicum infection regulation of 5-Methylcytosine mRNA oxidation by ten-eleven translocation protein 2 (tet2) occurs.…”

Section: Myelopoiesis In the Face Of Major Infectionsmentioning

confidence: 99%

Emerging Principles in Myelopoiesis at Homeostasis and during Infection and Inflammation

2019

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Myelopoiesis ensures the steady state of the myeloid cell compartment. Technological advances in fate mapping and genetic engineering, as well as the advent of single cell RNA-sequencing, have highlighted the heterogeneity of the hematopoietic system and revealed new concepts in myeloid cell ontogeny. These technologies are also shedding light on mechanisms of myelopoiesis at homeostasis and at different phases of infection and inflammation, illustrating important feedback loops between affected tissues and the bone marrow. We review these findings here and revisit principles in myelopoiesis in light of the evolving understanding of myeloid cell ontogeny and heterogeneity. We argue for the importance of system-wide evaluation of changes in myelopoiesis and discuss how even after the resolution of inflammation, long-lasting alterations in myelopoiesis may play a role in innate immune memory or trained immunity.

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“…During erythropoiesis, elevated levels of free heme bind to and inhibit Bach1, thereby activating the expression of Beta-globin and other genes involved in erythroid differentiation 48 . Although Bach2 functions as a transcriptional repressor during B-cell maturation and has been implicated in B-cell neoplasms, other studies have shown the Bach2 is also regulated by heme binding and that overexpression of Bach2 in hematopoietic stem cells promotes erythroid commitment, suggesting it may also play an early role in directing erythroid lineage fate decisions 49 .…”

Section: Discussionmentioning

confidence: 99%

Insertional mutagenesis using the Sleeping Beauty transposon system identifies drivers of erythroleukemia in mice

Loeb

Hughes

Fissel

et al. 2019

Sci Rep

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Insertional mutagenesis is a powerful means of identifying cancer drivers in animal models. We used the Sleeping Beauty (SB) transposon/transposase system to identify activated oncogenes in hematologic cancers in wild-type mice and mice that express a stabilized cyclin E protein (termed cyclin ET74AT393A). Cyclin E governs cell division and is misregulated in human cancers. Cyclin ET74AT393A mice develop ineffective erythropoiesis that resembles early-stage human myelodysplastic syndrome, and we sought to identify oncogenes that might cooperate with cyclin E hyperactivity in leukemogenesis. SB activation in hematopoietic precursors caused T-cell leukemia/lymphomas (T-ALL) and pure red blood cell erythroleukemias (EL). Analysis of >12,000 SB integration sites revealed markedly different oncogene activations in EL and T-ALL: Notch1 and Ikaros were most common in T-ALL, whereas ETS transcription factors ( Erg and Ets1 ) were targeted in most ELs. Cyclin E status did not impact leukemogenesis or oncogene activations. Whereas most SB insertions were lost during culture of EL cell lines, Erg insertions were retained, indicating Erg’s key role in these neoplasms. Surprisingly, cyclin ET74AT393A conferred growth factor independence and altered Erg-dependent differentiation in EL cell lines. These studies provide new molecular insights into erythroid leukemia and suggest potential therapeutic targets for human leukemia.

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Infection perturbs Bach2- and Bach1-dependent erythroid lineage ‘choice’ to cause anemia

Cited by 31 publications

References 64 publications

Heme induces innate immune memory

Heme induces innate immune memory

Emerging Principles in Myelopoiesis at Homeostasis and during Infection and Inflammation

Insertional mutagenesis using the Sleeping Beauty transposon system identifies drivers of erythroleukemia in mice

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