Prevention of childhood Acute Lymphoblastic Leukemia immunology links oncology

Projektinformationen

PreventALL

ID Finanzhilfevereinbarung: 852222

DOI

10.3030/852222

EK-Unterschriftsdatum 20 Februar 2020

Startdatum 1 Juli 2020

Enddatum 30 Juni 2026

Finanziert unter

• EXCELLENT SCIENCE - European Research Council (ERC)

Gesamtkosten

€ 1 498 925,00

EU-Beitrag

€ 1 498 925,00

Koordiniert durch

KLINIKUM DER TECHNISCHEN UNIVERSITÄT MÜNCHEN (TUM KLINIKUM)
Germany

Periodic Reporting for period 3 - PreventALL (Prevention of childhood Acute Lymphoblastic Leukemia immunology links oncology)

Berichtszeitraum: 2023-05-01 bis 2024-10-31

Zusammenfassung vom Kontext und den Gesamtzielen des Projekts

PreventALL analyzes genetic risk in infection induced ALL and will pioneer leukemia prevention. Acute lymphoblastic leukemia (ALL) is the most common type of childhood cancer and it remains a major cause of death in children aged 2-6 years in high-income countries. Exposure to infection, as a potential trigger for the development of childhood ALL was theorized a century ago with several possibilities of exposure to infection in infancy. Consequently, the overall objectives of PreventALL is to systematically analyze postnatally the genetic risk to develop B-cell-precursor (BCP)-ALL and to decipher the infectious mechanism by which exposure to infection causes BCP-ALL. This opens a new horizon for the understanding of leukemia etiology and foster innovation in the development of novel preventive strategies such as diet supplementation or vaccination. To this end, appropriate methods of postnatal risk calculation and in vivo models are needed. We have recently developed the first in vivo murine models with infection-dependent BCP-ALL, based on a genetic predisposition. PreventALL aims to extend this knowledge and to set off for cutting edge research to explore the synergy of genetic predisposition and exposure to infection in BCP-ALL as a proof-of-concept for the role of infection in precancerous disease. In PreventALL Aim 1 will compile novel strategies to identify patients at risk for BCP-ALL, in Aim 2 I will develop preclinical infection-dependent BCP-ALL in vivo models and identify the mechanism how infection triggers BCP-ALL with respect to the genetic predisposition and finally Aim 3 will set up to develop preclinical prevention programs.
In summary, PreventALL will establish a significant milestone in the understanding of childhood leukemia and set the starting point for the development of novel and innovative leukemia precision prevention.

Arbeit, die ab Beginn des Projekts bis zum Ende des durch den Bericht erfassten Berichtszeitraums geleistet wurde, und die wichtigsten bis dahin erzielten Ergebnisse

Period: Beginning of project until October 2022: PreventALL has established TRIO Exome sequencing at pediatric university oncology centers at two partner site of TU dresden and TU Munich. In total more than 150 TRIO exomes have been sequenced. We identified there novel predisposition syndrome and have published together with our collaborators at HHU Düsseldorf an additional cohort of ore than 15 TRIO exams. In a european EU COST Action "LEGEND" we have described to a novel predisposition syndrome with STAG1/2 mutations and have described clinical characteristics of patients with Pax5 germline variants.
Furtherer our infection driven murine models ETV6/RUNX1 and Pax5+/- have been deeply characterized and we identified preleucemic populations and characteristic Toll-like receptor expression patterns. Further work will elucidate how these preleukemic cells expand or regress under infection exposure.
A first preventive aspect was detected in a collaborative study analyzing the micro biome in Pax5+/- mice, concluding that antibiotic treatment has a negative impact on ALL development in children.
The summary of our first results was published as a review in BLOOD proposing an extended model of ALL integrating immune-modulation in the common model of ALL development.
PreventALL propelled my personal career as within the cod year I was offered a full professor ship and head of department of child and adolescent health at TU 6

Fortschritte, die über den aktuellen Stand der Technik hinausgehen und voraussichtliche potenzielle Auswirkungen (einschließlich der bis dato erzielten sozioökonomischen Auswirkungen und weiter gefassten gesellschaftlichen Auswirkungen des Projekts)

We have contributed to the characterization of childhood ALL and the role of genetic predisposition. We have furthermore deeply analyzed our murine infection driven ALL models and set the basis to systematically analyze environmental challenges.
This and the implementation of preventive aspects will be the focus of the upcoming grant periods.

PreventALL_concept of ALL development in children and preventive aspects