Product Citations: 5

Certain subtypes of acute myeloid leukemia (AML) in children have inferior outcome, such as AML with translocation t(7;12)(q36;p13) leading to an MNX1::ETV6 fusion along with high expression of MNX1. We have identified the transforming event in this AML and possible ways of treatment. Retroviral expression of MNX1 was able to induce AML in mice, with similar gene expression and pathway enrichment to t(7;12) AML patient data. Importantly, this leukemia was only induced in immune incompetent mice using fetal but not adult hematopoietic stem and progenitor cells. The restriction in transforming capacity to cells from fetal liver is in alignment with t(7;12)(q36;p13) AML being mostly seen in infants. Expression of MNX1 led to increased histone 3 lysine 4 mono-, di- and trimethylation, reduction in H3K27me3, accompanied with changes in genome-wide chromatin accessibility and genome expression, likely mediated through MNX1 interaction with the methionine cycle and methyltransferases. MNX1 expression increased DNA damage, depletion of the Lin-/Sca1+/c-Kit+ population and skewing toward the myeloid lineage. These effects, together with leukemia development, were prevented by pre-treatment with the S-adenosylmethionine analog Sinefungin. In conclusion, we have shown the importance of MNX1 in development of AML with t(7;12), supporting a rationale for targeting MNX1 and downstream pathways.

  • Mus musculus (House mouse)
  • Cancer Research
  • Cardiovascular biology
  • Genetics

Mnx1 Induces Leukemia Transformation Through Altering Histone Methylation in a Model of Pediatric t(7;12) Acute Myeloid Leukemia

Preprint on BioRxiv : the Preprint Server for Biology on 12 June 2022 by Waraky, A., Ostlund, A., et al.

h4>SUMMARY/h4> Acute myeloid leukemia (AML) in children with certain genetic aberrations is still associated with inferior outcome. One of these AML subtypes has a translocation t(7;12)(q36;p13) and in this study we have investigated the transforming event behind this AML and possible ways to target its effects. This translocation leads to a gene fusion MNX1::ETV6 but also to high ectopic expression of MNX1. However, only MNX1 was able to induce AML in a mouse model and this was only observed using hematopoietic stem and progenitor cells (HSPC) derived from fetal origin and not from adult bone marrow. This AML was highly penetrant in immunocompromised mice but only partly so in immunocompetent mice. The restriction in transforming capacity to cells from fetal liver origin is in concordance with the clinical finding that t(7;12)(q36;p13) AML is mostly restricted to infants. Molecularly, ectopic expression of MNX1 led to increased H3K4mono, di- and trimethylation and reduction in H3K27me3, both globally and on specific gene promoters. These alternations in histone methylation appeared to be mediated through MNX1 interaction with the methionine cycle and different methyl transferases. The alternations in histone methylation were accompanied with changes in genome wide chromatin accessibility as evident by ATAC-sequencing. We also found that high MNX1 expression resulted in increased DNA damage, which was accompanied by a depletion in the Lin-/Sca1+/c-Kit+ population and skewing toward myeloid lineage. These effects could be prevented by Sinefungin treatment of HSPC, which also halted leukemia development in mice. Comparison of gene expression profile of leukemia cells from our mouse AML model with human induced pluripotent stem cells with t(7;12) differentiated into HSPC showed similar pathway enrichment. In conclusion, we have shown the importance of MNX1 in leukemia development in the t(7;12) AML subtype and the rationale for targeting MNX1 and its downstream pathways.

  • Mus musculus (House mouse)
  • Cancer Research
  • Genetics

Development and function of conventional dendritic cell (cDC) subsets, cDC1 and cDC2, depend on transcription factors (TFs) IRF8 and IRF4, respectively. Since IRF8 and IRF4 can each interact with TF BATF3 at AP1-IRF composite elements (AICEs) and with TF PU.1 at Ets-IRF composite elements (EICEs), it is unclear how these factors exert divergent actions. Here, we determined the basis for distinct effects of IRF8 and IRF4 in cDC development. Genes expressed commonly by cDC1 and cDC2 used EICE-dependent enhancers that were redundantly activated by low amounts of either IRF4 or IRF8. By contrast, cDC1-specific genes relied on AICE-dependent enhancers, which required high IRF concentrations, but were activated by either IRF4 or IRF8. IRF8 was specifically required only by a minority of cDC1-specific genes, such as Xcr1, which could distinguish between IRF8 and IRF4 DNA-binding domains. Thus, these results explain how BATF3-dependent Irf8 autoactivation underlies emergence of the cDC1-specific transcriptional program.
Copyright © 2020 Elsevier Inc. All rights reserved.

  • Mus musculus (House mouse)
  • Biochemistry and Molecular biology
  • Immunology and Microbiology

Immunoprophylactic and immunotherapeutic control of hormone receptor-positive breast cancer.

In Nature Communications on 30 July 2020 by Buqué, A., Bloy, N., et al.

Hormone receptor (HR)+ breast cancer (BC) causes most BC-related deaths, calling for improved therapeutic approaches. Despite expectations, immune checkpoint blockers (ICBs) are poorly active in patients with HR+ BC, in part reflecting the lack of preclinical models that recapitulate disease progression in immunocompetent hosts. We demonstrate that mammary tumors driven by medroxyprogesterone acetate (M) and 7,12-dimethylbenz[a]anthracene (D) recapitulate several key features of human luminal B HR+HER2- BC, including limited immune infiltration and poor sensitivity to ICBs. M/D-driven oncogenesis is accelerated by immune defects, demonstrating that M/D-driven tumors are under immunosurveillance. Safe nutritional measures including nicotinamide (NAM) supplementation efficiently delay M/D-driven oncogenesis by reactivating immunosurveillance. NAM also mediates immunotherapeutic effects against established M/D-driven and transplantable BC, largely reflecting increased type I interferon secretion by malignant cells and direct stimulation of immune effector cells. Our findings identify NAM as a potential strategy for the prevention and treatment of HR+ BC.

  • FC/FACS
  • Mus musculus (House mouse)
  • Cancer Research
  • Endocrinology and Physiology

Innate immune memory is an emerging area of research. However, innate immune memory at major mucosal sites remains poorly understood. Here, we show that respiratory viral infection induces long-lasting memory alveolar macrophages (AMs). Memory AMs are programed to express high MHC II, a defense-ready gene signature, and increased glycolytic metabolism, and produce, upon re-stimulation, neutrophil chemokines. Using a multitude of approaches, we reveal that the priming, but not maintenance, of memory AMs requires the help from effector CD8 T cells. T cells jump-start this process via IFN-γ production. We further find that formation and maintenance of memory AMs are independent of monocytes or bone marrow progenitors. Finally, we demonstrate that memory AMs are poised for robust trained immunity against bacterial infection in the lung via rapid induction of chemokines and neutrophilia. Our study thus establishes a new paradigm of immunological memory formation whereby adaptive T-lymphocytes render innate memory of mucosal-associated macrophages.
Copyright © 2018 Elsevier Inc. All rights reserved.

  • Mus musculus (House mouse)
  • Immunology and Microbiology
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