Targeting Marrow Niche Dysregulation During Stem Cell Transplant for Bone Marrow Failure Associated with Monosomy 7 Myelodysplastic Syndromes
Abstract
Background: Individuals born with gene mutations that cause bone marrow failBurMe 2sy2n0d0r3o7m:eTsim(BoMthFySO) alsreon at high risk for acquiring a pre-leukemia state in bone marrow (BM) known as myelodysplastic syndrome (MDS). The most severe bone marrow failure syndromes (BMFS) are associated with BM cells acquiring MDS defined by loss of chromosome 7 monosomy 7) which initially improves impaired blood cell production. Unfortunately, monosomy 7 ultimately makes BM more likely to acquire more genetic changes that lead to leukemia. Patients with these BMFS require stem cell (bone marrow) transplant to cure bone marrow failure or prevent/treat MDS or leukemia. At best, if Monosomy 7 is caught early, cure after transplant is seen in up to 60% of patients. Patients with advanced Monosomy 7 MDS/AML and additional high-risk features have cure rates as low as 10%. During transplant, interactions between donor stem cells (the seeds) and the patient’s own specialized bone marrow support cells known as niches (the soil) are required for blood and immune recovery (engraftment). In prior studies, our research team has found that in BMFS associated with monosomy 7, the same genetic mutation that causes BM failure in the patient’s blood stem cells that we replace by stem cell transplant, also causes niche (soil) dysfunction in cell types that are not replaced by conventional transplant. This poor niche function impairs donor engraftment, explaining why patients with BMFS associated with monosomy 7 are at high risk for transplant failure and even death caused by poor graft function and relapse. The critical problem/question our proposal addresses is how genetic mutations that predispose to BMFS associated with monosomy 7 prevent normal niche (soil) function during stem cell transplant. This knowledge will allow us to develop new therapies targeting restoration of niche function to improve outcomes of stem cell transplant for patients with severe BMFS. Our primary hypothesis is that our novel mouse and patient-derived cell models of two severe BMFS associated with monosomy 7, Shwachman-Diamond Syndrome and SAMD9/SAMD9L syndromes, will prove that decreased production and survival of bone-forming cells (osteoprogenitors) within bone marrow niches is the primary cause of impaired host ability to engraft donor cells efficiently and durably during transplant. Our two primary objectives address both of the fiscal year 2022 Bone Marrow Failure Research Program Idea Development Award Focus Areas: • Understand the causes and progression of BMF diseases: Our proposal seeks to define the cellular and molecular mechanisms that explain why, in severe BMFS associated with monosomy 7, the patient’s own bone marrow environment is dysfunctional and fails to support baseline blood cell production and reliable donor engraftment after stem cell transplantation. • Find effective BMF treatments and cures: Understanding how stem cell transplant outcomes for severe BMFS can be compromised by poor bone marrow niche (soil) function is a critical first step to defining strategies to improve treatment outcomes. In our proposal, we will test several strategies to improve niche function during transplant in our models of Shwachman-Diamond and SAMD9/SAMD9L syndromes. Innovation: Our proposal is innovative in that while most research devoted to improving stem cell transplant outcomes for BMFS focuses on preventing infections, immune rejection, and graft versus host disease, we are focused on targeting the patient’s own bone marrow niches (soil) to improve the quality of donor blood and immune production after transplant regardless of the type of donor available. Additional innovations include developing novel animal and patient-derived cell models of BMFS, use of cutting-edge gene expression techniques to precisely define the bone marrow environment during transplant, and development of a screening platform to iden
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310569
Entities
People
- Timothy M. Olson
Organizations
- United States Army