Selective Clonal Growth in Myelodysplastic Syndrome
Abstract
Ataxia-pancytopenia syndrome (ATXPC) is an inherited disease characterized by bone marrow failure (BMF) and cerebellar ataxia. The hematologic manifestations range from a small decrease in a single type of blood cell (platelets, red cells, white cells) to profound decrease in all three lineages. In addition to bleeding problems, anemia, and susceptibility to infection, people with ATXPC have an increased risk to develop myelodysplasia (MDS) and leukemia and the MDS/leukemic cells often have lost one copy of chromosome 7. Loss of all or part of one copy of chromosome 7 is among the most frequent chromosomal abnormalities in MDS and disease progression in leukemia and is associated with particularly poor outcomes. We discovered that mutations in the SAMD9L gene on chromosome 7 cause ATXPC. SAMD9L protein regulates the proliferation and maturation of cells, particularly the hematopoietic progenitor cells in the bone marrow. We hypothesize that the mutations that cause ATXPC alter this process to decrease production of mature blood cells. We found that hematopoietic cells that have lost the mutant SAMD9L allele but still have two copies of chromosome 7 persist in some patients with ATXPC and have a selective advantage in tissue culture. Our concept of the development and progression of ATXPC involves a combination of steps: hematologic cytopenias (BMF) occur because cells with a mutant SAMD9L proliferate less well than wild-type cells; the marrow progenitor pool can become exhausted; the marrow progenitor pool is smaller and mutations that occur can develop into a dominant clone; cells that lose chromosome 7 or the part that contains the SAMD9L gene have a growth advantage and become a dominant clone; cells with only a single copy of wild-type SAMD9L do not have enough growth repression and MDS or leukemia can develop. In contrast, cells that revert the SAMD9L mutation without losing chromosome 7 regain their normal growth properties and do not develop into MDS or leukemia. Underlying this proposal is the concept that if we increase the frequency of reversion of the SAMD9L mutation and/or increase the selective advantage of cells with two copies of chromosome 7, we can enhance recovery from BMF or remission from MDS. Fortuitously, there are genes on chromosome 7 that code for proteins required for metabolizing drugs and eliminating environmental toxins. We hypothesize that cells that are missing one copy of chromosome 7 would have reduced levels of those proteins and would be more sensitive to such drugs. We propose that by treating cells from patients with ATXPC with drugs that are metabolized or removed by those proteins, we can favor the growth of normal blood cells that have retained both copies of chromosome 7 and reduce or eliminate the abnormal population of cells that are missing one copy of chromosome 7. Furthermore, cells that have reverted the SAMD9L mutation to the wild-type form would have a selective growth advantage. We will also inhibit a DNA repair pathway to increase the frequency of mitotic recombination that can result in replacement of the mutant SAMD9L allele by a normal copy. Our experiments are aimed at developing new and less toxic combinations of drug therapy that can slow or abrogate the progression of SAMD9L-related BMF and could prevent or possibly cure monosomy 7-related MDS by inhibiting the growth of malignant cells in the bone marrow that are missing all or part of chromosome 7. There are multiple innovative parts of this research: (1) We discovered a new mechanism for bone marrow failure; (2) We will exploit the fortuitous co-localization on chromosome 7 of SAMD9L and genes that metabolize toxins to test a potentially powerful way to treat SAMD9L-related marrow failure and even to prevent or reverse MDS and leukemia associated with partial or complete monosomy 7; (3) We will use a system designed by our Research Scientist Dr. Davis to facilitate a naturally-occurring phenomenon of mitotic
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010574
Entities
People
- Marshall Horwitz
Organizations
- United States Army
- University of Washington