Macrophage colony-stimulating factor receptor marks and regulates a fetal myeloid-primed B-cell progenitor in mice

Zriwil, Alya; Böiers, Charlotta; Wittmann, Lilian; Green, Joanna C.A.; Woll, Petter S.; Jacobsen, Sten Eirik W.; Sitnicka, Ewa

doi:10.1182/blood-2016-01-693887

Cited by 28 publications

(13 citation statements)

References 41 publications

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“…Differentiation of B cell subsets into macrophages is a generally accepted process 30 , 31 , 54 , 55 . More recently, an early Pro-B cell subpopulation in the bone marrow was reported to possess the functional plasticity to differentiate into tissue-resident or inflammatory macrophages 32 , and early B cell precursors that express CD115 in fetal liver were identified 56 . Our study agrees with these findings, demonstrating that the early B cell precursors can transdifferentiate to osteoclasts and that it can be mediated via the differentiation of the B cells to macrophages, which then differentiate into osteoclasts.…”

Section: Discussionmentioning

confidence: 99%

Erythropoietin receptor in B cells plays a role in bone remodeling in mice

Deshet-Unger¹,

Kim²,

Ben‐Califa³

et al. 2020

Theranostics

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Erythropoietin (EPO) is a key regulator of erythropoiesis. However, EPO receptors (EPO-Rs) are also expressed on non-erythroid cell types, including myeloid and bone cells. Immune cells also participate in bone homeostasis. B cells produce receptor activator of nuclear factor kappa-Β ligand (RANKL) and osteoprotegerin (OPG), two pivotal regulators of bone metabolism. Here we explored the ability of B cells to transdifferentiate into functional osteoclasts and examined the role of EPO in this process in a murine model. Methods: We have combined specifically-designed experimental mouse models and in vitro based osteoclastogenesis assays, as well as PCR analysis of gene expression. Results: (i) EPO treatment in vivo increased RANKL expression in bone marrow (BM) B cells, suggesting a paracrine effect on osteoclastogenesis; (ii) B cell-derived osteoclastogenesis occured in vivo and in vitro, as demonstrated by B cell lineage tracing in murine models; (iii) B-cell-derived osteoclastogenesis in vitro was restricted to Pro-B cells expressing CD115/CSF1-R and is enhanced by EPO; (iv) EPO treatment increased the number of B-cell-derived preosteoclasts (β3 + CD115 + ), suggesting a physiological rationale for B cell derived osteoclastogenesis; (v) finally, mice with conditional EPO-R knockdown in the B cell lineage (cKD) displayed a higher cortical and trabecular bone mass. Moreover, cKD displayed attenuated EPO-driven trabecular bone loss, an effect that was observed despite the fact that cKD mice attained higher hemoglobin levels following EPO treatment. Conclusions: Our work highlights B cells as an important extra-erythropoietic target of EPO-EPO-R signaling and suggests their involvement in the regulation of bone homeostasis and possibly in EPO-stimulated erythropoietic response. Importantly, we present here for the first time, histological evidence for B cell-derived osteoclastogenesis in vivo .

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Section: Discussionmentioning

confidence: 99%

Erythropoietin receptor in B cells plays a role in bone remodeling in mice

Deshet-Unger¹,

Kim²,

Ben‐Califa³

et al. 2020

Theranostics

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“… 9 , 10 In an ALL CAR T retreatment clinical trial, 64% of murine CD19 CAR T cell-resistant patients had disease remission induced by humanized CD19 CAR T cells. 45 …”

Section: Discussionmentioning

confidence: 99%

Checkpoint Blockade Reverses Anergy in IL-13Rα2 Humanized scFv-Based CAR T Cells to Treat Murine and Canine Gliomas

Yin

Boesteanu

Binder

et al. 2018

Molecular Therapy - Oncolytics

125

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We generated two humanized interleukin-13 receptor α2 (IL-13Rα2) chimeric antigen receptors (CARs), Hu07BBz and Hu08BBz, that recognized human IL-13Rα2, but not IL-13Rα1. Hu08BBz also recognized canine IL-13Rα2. Both of these CAR T cell constructs demonstrated superior tumor inhibitory effects in a subcutaneous xenograft model of human glioma compared with a humanized EGFRvIII CAR T construct used in a recent phase 1 clinical trial (ClinicalTrials.gov: NCT02209376). The Hu08BBz demonstrated a 75% reduction in orthotopic tumor growth using low-dose CAR T cell infusion. Using combination therapy with immune checkpoint blockade, humanized IL-13Rα2 CAR T cells performed significantly better when combined with CTLA-4 blockade, and humanized EGFRvIII CAR T cells’ efficacy was improved by PD-1 and TIM-3 blockade in the same mouse model, which was correlated with the levels of checkpoint molecule expression in co-cultures with the same tumor in vitro. Humanized IL-13Rα2 CAR T cells also demonstrated benefit from a self-secreted anti-CTLA-4 minibody in the same mouse model. In addition to a canine glioma cell line (J3T), canine osteosarcoma lung cancer and leukemia cell lines also express IL-13Rα2 and were recognized by Hu08BBz. Canine IL-13Rα2 CAR T cell was also generated and tested in vitro by co-culture with canine tumor cells and in vivo in an orthotopic model of canine glioma. Based on these results, we are designing a pre-clinical trial to evaluate the safety of canine IL-13Rα2 CAR T cells in dog with spontaneous IL-13Rα2-positive glioma, which will help to inform a human clinical trial design for glioblastoma using humanized scFv-based IL-13Rα2 targeting CAR T cells.

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“…Previous studies have suggested that the cytokine requirement might be distinct for fetal and adult lymphoid progenitors (Carvalho et al , ; Vosshenrich et al , ; Hesslein et al , ; Beaudin et al , ; Zriwil et al , ). Moreover, LMPPs in the FL express higher levels of lymphoid genes, including Rag1, when compared to their adult counterparts (Boiers et al , ).…”

Section: Resultsmentioning

confidence: 98%

Direct role of FLT3 in regulation of early lymphoid progenitors

et al. 2018

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Summary Given that FLT 3 expression is highly restricted on lymphoid progenitors, it is possible that the established role of FLT 3 in the regulation of B and T lymphopoiesis reflects its high expression and role in regulation of lymphoid‐primed multipotent progenitors ( LMPP s) or common lymphoid progenitors ( CLP s). We generated a Flt3 conditional knock‐out ( Flt3 fl/fl ) mouse model to address the direct role of FLT 3 in regulation of lymphoid‐restricted progenitors, subsequent to turning on Rag1 expression, as well as potentially ontogeny‐specific roles in B and T lymphopoiesis. Our studies establish a prominent and direct role of FLT 3, independently of the established role of FLT 3 in regulation of LMPP s and CLP s, in regulation of fetal as well as adult early B cell progenitors, and the early thymic progenitors ( ETP s) in adult mice but not in the fetus. Our findings highlight the potential benefit of targeting poor prognosis acute B‐cell progenitor leukaemia and ETP leukaemia with recurrent FLT 3 mutations using clinical FLT 3 inhibitors.

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Macrophage colony-stimulating factor receptor marks and regulates a fetal myeloid-primed B-cell progenitor in mice

Abstract: Key Points CSF1R is expressed on the earliest fetal B-cell progenitors, and CSF1R deficiency impairs fetal B-cell development. CSF1R+ fetal ProB cells have a B-myeloid gene signature and possess B and myeloid potential.

Cited by 28 publications

References 41 publications

Erythropoietin receptor in B cells plays a role in bone remodeling in mice

Erythropoietin receptor in B cells plays a role in bone remodeling in mice

Checkpoint Blockade Reverses Anergy in IL-13Rα2 Humanized scFv-Based CAR T Cells to Treat Murine and Canine Gliomas

Direct role of FLT3 in regulation of early lymphoid progenitors

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