Project Details
Projekt
Humanized NSG mouse model to study combinatorial leukemogenic effects of inherited ELANE and acquired CSF3R/RUNX1 mutations in congenital neutropenia
Subject Area
Hematology, Oncology
Term
from 2016 to 2021
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 290677262
Severe congenital neutropenia (CN) is a pre-leukemic bone marrow failure syndrome with a high risk of evolving into leukemia or myelodysplastic syndrome (MDS). Recently we demonstrated a very high frequency of cooperating RUNX1 and CSF3R mutations in CN patients who developed leukemia or MDS. CSF3R mutations alone are unable to induce leukemia in CN patients or in mice expressing a transgenic mutated G-CSFR (d715) and we hypothesized, that co-acquisition of RUNX1 on the background of inherited ELANE mutations is an essential step in the leukemogenic transformation in CN. Moreover, we recently found that 27 % of ELANE-mutated CN patients who developed leukemia harbor same ELANE mutation at the position p.C151Y. Interestingly, sequential analysis of the gene expression signature of hematopoietic cells of CN patients who harbors C151Y ELANE mutation and developed leukemia revealed rapid transformation of CSF3R-mutated hematopoietic progenitors into more primitive hematopoietic progenitors after co-acquisition of RUNX1 mutation. Based on these observations, we hypothesized, that co-acquisition of RUNX1 and CSF3R mutations on the pathological background due to inheritance of ELANE mutations, especially C151Y mutation, shifts the hematopoietic differentiation program towards more primitive hematopoietic progenitors with elevated proliferative capacity and reduced myeloid differentiation, which ultimately lead to leukemia. In the present study we aimed to further investigate the role of cooperative inherited ELANE and acquired CSF3R and RUNX1 mutations on the leukemogenic transformation of HSCs in humanized mouse model in vivo. We plan to study the importance of the time sequence of acquisition of RUNX1 and CSF3R mutations in leukemogenic transformation and the role of inherited CN-specific ELANE mutation (C151Y) in this process. We also plan to delineate leukemogenic intracellular signal transduction pathway/s activated in HSCs in the presence of ELANE, CSF3R and RUNX1 mutations. Our long-term aim is to establish methods of correction of the leukemogeinc factors/signaling pathways using small molecules in order to prevent or to treat leukemia in CN patients harboring ELANE mutations.
DFG Programme
Research Grants
Cooperation Partner
Professorin Dr. Jadwiga Jablonska-Koch
