Project Details
Projekt
A bad seed in bad soil: understanding the effect of altered NFE2 levels on HSC cell fate, MPN-progression and its modification by the bone marrow niche
Applicant
Professorin Dr. Heike L. Pahl
Subject Area
Hematology, Oncology
Term
since 2024
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 517204983
We have shown that activity of the transcription factor NFE2 is altered in the vast majority of MPN patients, either by overexpression of the wild-type protein or by mutations. In mouse models, altering NFE2 activity causes an MPN phenotype with spontaneous transformation to acute leukemia, accompanied by the acquisition of AML-specific chromosomal alterations and mutations. Our data demonstrate that changing the level of NFE2 activity in hematopoietic stem cells (HSCs) is sufficient both to induce an MPN phenotype and to promote the acquisition of additional mutations, causing leukemic transformation. To date, the role of NFE2 in HSC homeostasis has not been investigated in detail. NFE2 is regarded as an erythroid and megakaryocytic transcription factor, however, our unpublished data suggest that NFE2 plays an important and yet unrecognized role in HSC cell fate. While transplantation of wild-type fetal liver cells fully reconstitutes the bone marrow of mice lethally irradiated with 12 Gy, mice transplanted with NFE2 deficient, knock-out (ko) fetal liver cells, despite engrafting fully, die within 40 days, displaying anemia, thrombocytopenia and a hypocellular, monomorphic erythroblastic bone marrow. We therefore propose that loss of NFE2 perturbs HSC homeostasis, causing lineage restriction and stem cell exhaust. However, our model introduces another layer of complexity. Mice irradiated with a lower, nonetheless lethal dose of 9 Gy survive long-term when reconstituted with NFE2-ko fetal liver cells and show only mild perturbations in CBC. We therefore postulate that the effect of NFE2 deletion on HSC cell fate is modulated by exogenous factors, stemming from the bone marrow niche. Vice versa, we have also observed that transplantation of NFE2-ko cells significantly alters the bone marrow niche - the malignant cells shape their microenvironment. Based on our preliminary data, we will therefore investigate three hypotheses in this project: Hypothesis 1: Loss of NFE2 alters HSC cell fate. Hypothesis 2: Composition and integrity of the stem cell niche influences NFE2-ko HSC potential. Hypothesis 3: NFE2-ko HSCs alter the bone marrow niche - the bad seed causes bad soil. Having completed this project, we will have demonstrated a novel role for NFE2 in HSC homeostasis, delineating its role in HSC self-renewal and lineage commitment. We will have identified the molecular mechanisms by which altered NFE2 levels affect HSC pathophysiology. Moreover, we will have delineated the role of the BM microenvironment in modifying the effect of altered NFE2 activity in HSCs, contributing mechanistic insight into the interaction between BM and HSC and how this contributes to the persistence of neoplastic MPN cells. Our ultimate aim is the suppression or eradication of the malignant MPN clone. Our project will provide a mechanistic rationale for targeting both the HSC and the BM niche, which may greatly increase our chances of achieving this goal.
DFG Programme
Research Units
