Targeting Muscarinic Acetylcholine Receptor Pathway in Myelodysplastic Syndrome
Abstract
Myelodysplastic syndromes (MDS) are a heterogeneous group of disorders characterized by inefficient blood production. MDS represents the most common cause of acquired bone marrow failure in adults. There are few effective therapies for the majority of MDS patients, and one major cause for death and difficult symptoms experienced by MDS patients is due to anemia, or an inadequate ability to generate red blood cells. We recently discovered that inhibiting a specific cell surface protein called CHRM4 boosts the bone marrow’s ability to produce red blood cells. CHRM4 is a protein called a muscarinic acetylcholine receptor and has a very well established role in regulating the functions of nerve cells in the body. Moreover, drugs targeting CHRM4 have existed for several decades, are safe to be used in patients, and have been used for a variety of medical purposes unrelated to MDS or cancer (including regulating pupil size, urinary incontinence, and peptic ulcer disease). These drugs have been utilized in patients in a variety of formulations, but the potential effects of systematically administering these drugs on bone marrow function had never been evaluated in detail. Our preliminary data indicate that inhibiting CHRM4, using either established drugs or genetic tools to knockout or knockdown the gene encoding CHRM4 protein, boosts the ability to produce red blood cells. This is clear in cells from normal mice and normal human subjects but also in animal models of MDS and MDS patient samples. Moreover, the effect of CHRM4 inhibition appears to be occurring at the level of the earliest red blood cell precursor, a cell type called the BFU-E (for burst forming unit-erythroid). At the same time, we have also identified that inhibiting CHRM4 in an established mouse model of MDS extends the survival of MDS mice to those of wildtype control mice. To further dissect the mechanisms of CHRM4 pathway in regulating red blood cell production and translate our basic discovery into novel therapeutics for MDS treatment, the overall goals of our proposal are therefore aimed at (1) further understanding the role of CHRM4 in red blood cell precursor function in MDS and normal blood production in greater detail and (2) evaluating the therapeutic implications of CHRM4 inhibition as a novel therapeutic for MDS patients. The innovative aspects of this proposal include the use of drug and genetic screening technologies that we applied to look for ways to improve blood production in MDS. This led us to identify a novel therapeutic target for MDS patients in a pathway that has been virtually unstudied in MDS. Given that drugs targeting CHRM4 already exist and are felt to be safe based on earlier clinical trials, we expect that there may be immediate therapeutic implications for MDS patients from this work. Finally, we will combine the expertise of two scientists with different but complimentary expertise. This includes a basic scientist with a very strong background in red blood cell development (Dr. Zhang) and a physician-scientist with a long-standing interest in treating and understanding MDS (Dr. Abdel-Wahab). We are combining our collective knowledge, expertise, and intellectual resources of our two institutions (Cold Spring Harbor Laboratory and Memorial Sloan Kettering Cancer Center) in hopes of developing new approaches to understand and treat MDS. We expect our research to further our understanding of how MDS develops, and ultimately to lead to the identification of new drugs and therapeutic approaches for treating MDS. If successful, this proposal could have tremendous therapeutic impact for patients with bone marrow failure due to MDS.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210380
Entities
People
- Lingbo Zhang
Organizations
- Cold Spring Harbor Laboratory
- United States Army