Inhibition of precursor B-cell malignancy progression by toll-like receptor ligand-induced immune responses

Fidanza, Mario; Seif, Alix E.; DeMicco, Amy; Rolf, Nina; Jo, Sumin; Yin, Bu; Li, Yimei; Barrett, David M.; Duque‐Afonso, Jesús; Cleary, Michael L.; Bassing, Craig H.; Grupp, Stephan A.; Reid, Gregor S. D.

doi:10.1038/leu.2016.152

Cited by 18 publications

(19 citation statements)

References 16 publications

(19 reference statements)

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“…These murine models support the 'two hit' hypothesis for BCP-ALL and have also provided evidence for the role of common infections in the development of BCP-ALL (table below) [134][135][136] . Delay and reduced penetrance of BCP-ALL…”

Section: Boxsupporting

confidence: 53%

“…Another mouse model has provided evidence that early stimulation of the immune system can be protective. Exposure of mice transgenic for Eμ-Ret or E2A-PBX1 to oligodeoxynucleotides (which bind to TLR7, TLR8 and TLR9) at four weeks depleted both normal and pre-leukaemic precursors and both delayed and diminished risk of progression to ALL 136 . This effect was dependent upon IFNγ.…”

Section: Modelling the 'Missing Link' In Allmentioning

confidence: 99%

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A causal mechanism for childhood acute lymphoblastic leukaemia

2018

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In this Review, I present evidence supporting a multifactorial causation of childhood acute lymphoblastic leukaemia (ALL), a major subtype of paediatric cancer. ALL evolves in two discrete steps. First, in utero initiation by fusion gene formation or hyperdiploidy generates a covert, pre-leukaemic clone. Second, in a small fraction of these cases, the postnatal acquisition of secondary genetic changes (primarily V(D)J recombination-activating protein (RAG) and activation-induced cytidine deaminase (AID)-driven copy number alterations in the case of ETS translocation variant 6 (ETV6)-runt-related transcription factor 1 (RUNX1) ALL) drives conversion to overt leukaemia. Epidemiological and modelling studies endorse a dual role for common infections. Microbial exposures earlier in life are protective but, in their absence, later infections trigger the critical secondary mutations. Risk is further modified by inherited genetics, chance and, probably, diet. Childhood ALL can be viewed as a paradoxical consequence of progress in modern societies, where behavioural changes have restrained early microbial exposure. This engenders an evolutionary mismatch between historical adaptations of the immune system and contemporary lifestyles. Childhood ALL may be a preventable cancer.

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Section: Boxsupporting

confidence: 53%

Section: Modelling the 'Missing Link' In Allmentioning

confidence: 99%

A causal mechanism for childhood acute lymphoblastic leukaemia

2018

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“…An influence of the immune environment on ALL risk during the neonatal period does also not rule out a subsequent, potentially infection‐induced impact later in life. We have recently reported that IFN‐γ is a significant contributor to TLR‐induced depletion of Eμ‐ret and E2A‐PBX1 LICs . Along with the reports of increased AID‐induced transformation of ETV6‐RUNX1 expressing BCP cells following TLR4 stimulation and increased penetrance of leukemia in Pax5 heterozygotic mice after delayed exposure to pathogens , these studies are revealing mechanisms that may underlie the association of infection with ALL onset.…”

Section: Discussionmentioning

confidence: 66%

“…In vitro support for direct leukemia‐promoting effects is provided by the detection of a TGF‐β‐mediated growth advantage and a TLR4‐driven upregulation of intrinsic mutagenic activity in BCP cells expressing the ALL‐associated ETV6‐RUNX1 fusion gene . With regard to potential protective effects, we have reported that TLR stimulation in the presence of immune effector cells results in an IFN‐mediated depletion of LICs in both the Eμ‐ret‐ and E2A‐PBX1‐driven BCP ALL mouse models, resulting in delayed disease onset .…”

Section: Introductionmentioning

confidence: 99%

IFN‐γ directly inhibits murine B‐cell precursor leukemia‐initiating cell proliferation early in life

Fidanza

Seif

et al. 2017

Eur J Immunol

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The early-life immune environment has been implicated as a modulator of acute lymphoblastic leukemia (ALL) development in children, with infection being associated with significant changes in ALL risk. Furthermore, polymorphisms in several cytokine genes, including IL-10 and IFN-γ, are associated with leukemia development. However, the mechanisms and timing of these influences remain unknown. Here, we use the Eμ-ret transgenic mouse model of B-cell precursor ALL to assess the influence of IFN-γ on the early-life burden of leukemia-initiating cells. The absence of IFN-γ activity resulted in greater numbers of leukemia-initiating cells early in life and was associated with accelerated leukemia onset. The leukemia-initiating cells from IFN-γ-knockout mice had reduced suppressor of cytokine signaling (SOCS-1) expression, were significantly more sensitive to IFN-γ, and exhibited more rapid expansion in vivo than their wild-type counterparts. However, sensitivity to this inhibitory pathway was lost in fully transformed IFN-γ-knockout leukemia cells. These results demonstrate that the influence of IFN-γ on ALL progression may not be mediated by selection of nascent transformed cells but rather through a general SOCS-mediated reduction in B-cell precursor proliferation. Thus, while cytokine levels may influence leukemia at multiple points during disease progression, our study indicates a significant early influence of basal, infection-independent cytokine production on leukemogenesis.

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“… 24 Another report found that genomic alterations caused by RAG1/RAG2 off-target activity, characterized by recombination signal sequence-like motifs near the breakpoints, dominated in patient- and clone-specific ETV6-RUNX1 fusions. 25 Further reports showed that infection-induced RAG1/2- and AID -dependent genomic alterations 24 and the composition of the hematopoietic niche, including the cytokine milieu 26-28 and presence of innate immune cells, 29 were critical to progression of preleukemia to BCP-ALL. ETV6-RUNX1 + cells demonstrated a competitive advantage in the presence of transforming growth factor-β compared with their wild-type counterparts.…”

Section: Infection Exposure Triggers Bcp-all: Evidence From Epidemiology and Preclinical Mouse Modelsmentioning

confidence: 99%

Toward prevention of childhood ALL by early-life immune training

Hauer

Fischer

2021

Blood

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B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is the most common form of childhood cancer. Chemotherapy is associated with life-long health sequelae and fails in approximately 20% of cases. Thus, prevention of leukemia would be preferable to treatment. Childhood leukemia frequently starts before birth, during fetal hematopoiesis. A first genetic hit (e.g. the ETV6-RUNX1 gene fusion) leads to the expansion of pre-leukemic B-cell clones, which are detectable in healthy newborn cord blood (up to 5%). These pre-leukemic clones give rise to clinically overt leukemia in only about 0.2% of carriers. Experimental evidence suggests that a major driver of conversion from the pre-leukemic to the leukemic state is exposure to immune challenges. Novel insights have shed light on immune host responses and how they shape the complex interplay between (A) inherited or acquired genetic predispositions, (B) exposure to infection, and (C) abnormal cytokine release from immunologically untrained cells. Here, we integrate the recently emerging concept of "trained immunity" into existing models of childhood BCP-ALL and suggest future avenues towards leukemia prevention.

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Inhibition of precursor B-cell malignancy progression by toll-like receptor ligand-induced immune responses

Cited by 18 publications

References 16 publications

A causal mechanism for childhood acute lymphoblastic leukaemia

A causal mechanism for childhood acute lymphoblastic leukaemia

IFN‐γ directly inhibits murine B‐cell precursor leukemia‐initiating cell proliferation early in life

Toward prevention of childhood ALL by early-life immune training

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