AN INTACT GUT MICROBIOME PROTECTS GENETICALLY PREDISPOSED MICE AGAINST LEUKEMIA
Author(s): ,
Carolina Vicente-Dueñas
Affiliations:
CANC-15,Institute of Biomedical Research of Salmanca (IBSAL),Salamanca,Spain
,
Stefan Janssen
Affiliations:
Algorithmic Bioinformatics,Justus Liebig University,Giessen,Germany
,
Marina Oldenburg
Affiliations:
Pediatric Oncology, Hematology and Clinical Immunology,Medical Faculty, Heinrich Heine University,Düsseldorf,Germany
,
Ana Casado-García
Affiliations:
Experimental Therapeutics and Translational Oncology Program,Instituto de Biología Molecular y Celular del Cáncer, CSIC/Universidad de Salamanca,Salamanca,Spain
,
Javier Raboso-Gallego
Affiliations:
Experimental Therapeutics and Translational Oncology Program,Instituto de Biología Molecular y Celular del Cáncer, CSIC/Universidad de Salamanca,Salamanca,Spain
,
Marta Isidro-Hernández
Affiliations:
CANC-15,Institute of Biomedical Research of Salmanca (IBSAL),Salamanca,Spain
,
Julia Hauer
Affiliations:
Department of Pediatrics, Pediatric Hematology and Oncology,University Hospital Carl Gustav Carus, Technische Universität Dresden,Dresden,Germany
,
Ute Fischer
Affiliations:
Pediatric Oncology, Hematology and Clinical Immunology,Medical Faculty, Heinrich Heine University,Düsseldorf,Germany
,
Isidro Sánchez-García
Affiliations:
Experimental Therapeutics and Translational Oncology Program,Instituto de Biología Molecular y Celular del Cáncer, CSIC/Universidad de Salamanca,Salamanca,Spain
Arndt Borkhardt
Affiliations:
Pediatric Oncology, Hematology and Clinical Immunology,Medical Faculty, Heinrich Heine University,Düsseldorf,Germany
(Abstract release date: 05/14/20) EHA Library. Vicente-Dueñas C. 06/12/20; 294920; S100
Carolina Vicente-Dueñas
Carolina Vicente-Dueñas
Contributions
Abstract
This abstract is embargoed until Friday, June 12, 08:30 CEST.

Abstract: S100

Type: Presidential Symposium

Session title: Presidential Symposium

Background

The majority of childhood leukemias (precursor B cell acute lymphoblastic leukemia, pB-ALL) are caused by the cooperation of prenatal genetic predisposition and oncogenic events taking place after birth. Genetic predisposition is frequent in children (>1-5%), but less than 1% of genetic carriers will develop the disease. Infectious stimuli are believed to play a major role, but the critical determinants leading to oncogenesis in children are unknown. The link between infections and childhood B-precursor Acute Lymphoblastic Leukemia (pB-ALL) was proposed more than 100 years ago. The first biological evidence supporting this hypothesis came up just a few years ago in genetically predisposed pB-ALL mice. pB-ALL only appeared in predisposed mice when exposed to natural infections. The leukemia arising in these mice are phenotypically and genetically similar to the human counterpart. Hence, these models are key tools to understand the aetiology of the disease. Now we are trying to understand the mechanism by which natural exposure to common infections triggers the disease with the ultimate goal of trying to identify potential preventive strategies.


Aims

 As there is a clear crosstalk between commensal bacteria and the immune system, the gut microbiome may serve as an integration hub for environmental signals that modulate the risk of developing B-cell ALL. This may be achieved through e.g. shaping of the immune system in general or by a direct impact on an expanded pool of pre-B cells in genetically predisposed carriers. For all this, we aim to study the role of the gut microbiome in infection-driven leukemias.


Methods

 We have analysed the host-gut microbiome of Pax5+/- mice housed in a specific-pathogen-free (SPF) facility and mice housed in a conventional (pathogen-containing) facility (CF). We used wild type (WT) mice in both housing conditions as a control. Furthermore, to determine the contribution of intestinal microbiota to pB-ALL development, we depleted it at the time of infection exposure in Pax5+/- and WT mice by treating them with an antibiotic cocktail added to their drinking water ad libitum for a period of eight weeks. Afterward, we analysed during 2 years the gut microbiome by targeted 16S V4 region sequencing and leukemia development by FACs analysis.

Results

 Here, employing a murine model of human pB-ALL (Pax5+/- mice), we show that microbiome disturbance by antibiotic treatment early in life was sufficient to induce leukemia in predisposed mice (48%) even in the absence of an infective environment. In the presence of infectious stimuli, antibiotic treatment increased pB-ALL incidence in predisposed mice from 22% to 63%. In longitudinal time series (≈2 years) of fecal sample 16S rRNA amplicon sequencing, we found that genetic predisposition to pB-ALL shapes a distinct gut microbiome. Artificial intelligence accurately (96.8%) predicted genetic predisposition using 40 of 20,127 amplicon sequence variants (ASVs) as proxies for bacterial species. Prior to leukemia onset, discrete FDR identified 75 ASVs whose abundance differentiated predisposed mice that developed pB-ALL from those that remained healthy.

Conclusion
 Our results demonstrate that the microbiome profile provides a biomarker that might be used to identify predisposed carriers at risk to develop leukemia. Furthermore, we identify microbiome deprivation via antibiotic treatment as a risk factor for leukemia development. We anticipate that by modulating the microbiome early in life the risk to develop leukemia may be reduced.

Session topic: 01. Acute lymphoblastic leukemia - Biology & Translational Research

Keyword(s): Acute lymphoblastic leukemia, Mouse model

This abstract is embargoed until Friday, June 12, 08:30 CEST.

Abstract: S100

Type: Presidential Symposium

Session title: Presidential Symposium

Background

The majority of childhood leukemias (precursor B cell acute lymphoblastic leukemia, pB-ALL) are caused by the cooperation of prenatal genetic predisposition and oncogenic events taking place after birth. Genetic predisposition is frequent in children (>1-5%), but less than 1% of genetic carriers will develop the disease. Infectious stimuli are believed to play a major role, but the critical determinants leading to oncogenesis in children are unknown. The link between infections and childhood B-precursor Acute Lymphoblastic Leukemia (pB-ALL) was proposed more than 100 years ago. The first biological evidence supporting this hypothesis came up just a few years ago in genetically predisposed pB-ALL mice. pB-ALL only appeared in predisposed mice when exposed to natural infections. The leukemia arising in these mice are phenotypically and genetically similar to the human counterpart. Hence, these models are key tools to understand the aetiology of the disease. Now we are trying to understand the mechanism by which natural exposure to common infections triggers the disease with the ultimate goal of trying to identify potential preventive strategies.


Aims

 As there is a clear crosstalk between commensal bacteria and the immune system, the gut microbiome may serve as an integration hub for environmental signals that modulate the risk of developing B-cell ALL. This may be achieved through e.g. shaping of the immune system in general or by a direct impact on an expanded pool of pre-B cells in genetically predisposed carriers. For all this, we aim to study the role of the gut microbiome in infection-driven leukemias.


Methods

 We have analysed the host-gut microbiome of Pax5+/- mice housed in a specific-pathogen-free (SPF) facility and mice housed in a conventional (pathogen-containing) facility (CF). We used wild type (WT) mice in both housing conditions as a control. Furthermore, to determine the contribution of intestinal microbiota to pB-ALL development, we depleted it at the time of infection exposure in Pax5+/- and WT mice by treating them with an antibiotic cocktail added to their drinking water ad libitum for a period of eight weeks. Afterward, we analysed during 2 years the gut microbiome by targeted 16S V4 region sequencing and leukemia development by FACs analysis.

Results

 Here, employing a murine model of human pB-ALL (Pax5+/- mice), we show that microbiome disturbance by antibiotic treatment early in life was sufficient to induce leukemia in predisposed mice (48%) even in the absence of an infective environment. In the presence of infectious stimuli, antibiotic treatment increased pB-ALL incidence in predisposed mice from 22% to 63%. In longitudinal time series (≈2 years) of fecal sample 16S rRNA amplicon sequencing, we found that genetic predisposition to pB-ALL shapes a distinct gut microbiome. Artificial intelligence accurately (96.8%) predicted genetic predisposition using 40 of 20,127 amplicon sequence variants (ASVs) as proxies for bacterial species. Prior to leukemia onset, discrete FDR identified 75 ASVs whose abundance differentiated predisposed mice that developed pB-ALL from those that remained healthy.

Conclusion
 Our results demonstrate that the microbiome profile provides a biomarker that might be used to identify predisposed carriers at risk to develop leukemia. Furthermore, we identify microbiome deprivation via antibiotic treatment as a risk factor for leukemia development. We anticipate that by modulating the microbiome early in life the risk to develop leukemia may be reduced.

Session topic: 01. Acute lymphoblastic leukemia - Biology & Translational Research

Keyword(s): Acute lymphoblastic leukemia, Mouse model

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