Defects in the Transition from Neonatal to Adult HSCs as the Etiology and a Therapeutic Target in Fanconi Anemia
Abstract
Bone marrow failure (BMF) typically results from a defect in hematopoietic stem cells (HSCs), which give rise to the various lineages of blood cells. BMF can either be inherited or acquired, and can necessitate transplantations for treatment and increase the death rate. The most frequently observed inherited bone marrow disease is Fanconi anemia (FA). Elucidation of the mechanism underling BMF in FA is highly important for understanding what causes it, and possibly for development of improved diagnostic, preventative, and/or treatment approaches for BMF that may be extensible to other BMF syndromes. Thus, while the primary Focus Area is understanding causes of BMF, this proposal is also relevant to finding effective treatments. While FA proteins have a role in repairing damage to the genetic material present in cells, the basis for BMF in FA is unclear. Notably, recent work has demonstrated that different populations of HSCs with distinct properties predominate at different stages of the life of an individual (or mouse). These include fetal HSCs present during development prior to birth, neonatal HSCs that predominate from just after birth through childhood, and then adult HSCs, which are subsequently the main type. Interestingly, there is a transition from neonatal to adult HSCs, and we propose the paradigm-shifting concept that BMF in FA is due to a defect in this transition. The proper function of adult HSCs depends on their remaining largely dormant. Thus, we posit that a defect in the transition from neonatal HSCs causes a premature shift to adult HSCs, which makes them exit from dormancy and that this is the primary basis for HSC dysfunction in FA. We also propose that a factor within the HSC itself (intrinsic) and one outside the HSC (extrinsic) drive this premature shift to adult HSCs in FA, and that counteracting these intrinsic and extrinsic factors may provide a basis for early detection of BMF in FA and for preventing and/or treating it. The intrinsic factor is a structure formed by nucleic acids (RNA hybrids with DNA) termed R-loops; the extrinsic factor is normally a response to infections and other conditions, termed stress granulopoiesis, mediated by signals from cells in the blood called neutrophils/granulocytes. Our objective in this proposal is to understand how inactivation of FA proteins, due to mutations in FA genes, leads to BMF through a defect in the transition from neonatal to adult HSCs, and to determine the role of both R-loops and stress granulopoiesis in this process. This will be accomplished in two parts. In the first part, using a mouse model for the most commonly mutated FA gene, we will determine whether HSC dysfunction that underlies BMF in FA is due to intrinsic loss of suppression of R-loops, both in HSCs and in neutrophils. This will be done by introducing genes for ribonucleases and other enzymes that can resolve such structures. In the second part of the proposal, we will mate mice with genetic deficiencies for factors involved in stress granulopoiesis signaling with FA mice. This will determine the role of extrinsic stress granulopoiesis in mediating the premature shift to adult HSCs in FA. In both parts, we will explore novel preventative and/or treatment strategies for BMF in FA. Additionally, this work may explain why BMF in FA typically occurs during childhood. Our findings could also help explain why other BMF diseases, including Diamond-Blackfan anemia, Shwachman-Diamond syndrome, and dyskeratosis congenita, also typically confer BMF during childhood. The proposed work is highly innovative because: (1) Our novel finding that stress granulopoiesis is associated with FA; (2) Our conceptually novel mechanism for BMF in FA based on a shift from neonatal to adult HSCs and our novel mechanistic explanation that BMF occurs during childhood in FA because of this shift from neonatal to adult HSCs. (3) Another innovative aspect of this proposal is our initial exploration of
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210410
Entities
People
- Paul Andreassen
Organizations
- United States Army