Selective Clonal Growth in Myelodysplastic Syndrome
Abstract
Loss of all or part of one copy of chromosome 7(7q-) is frequent in MDS and portends a poor prognosis. The recent identification of germline mutations in SAMD9L in individuals with ataxia-pancytopenia syndrome has helped elucidate the role of 7q- in promoting MDS. The mutations confer toxic gain-of-function. Hematopoietic stem and progenitor cells that undergo somatic mutation that eliminates the mutant allele through one of three mechanisms gain a selective growth advantage. The first mechanism involves loss of all or part of the chromosome 7q region containing SAMD9L and is deleterious. A second mechanism involves cis suppressor point mutations and is better tolerated. A third and potentially beneficial mechanism involves auto-correction of the underlying germline mutation through interhomolog recombination. Our project is aimed at modeling this phenomenon in vitro and identifying drug combinations that may both promote auto-correction and confer a selective advantage to cells retaining two intact copies of chromosome 7.
Document Details
- Document Type
- Technical Report
- Publication Date
- Sep 01, 2023
- Accession Number
- AD1216878
Entities
People
- Dong-hui Chen
- Marshall S. Horwitz
- Wendy Raskind
Organizations
- University of Washington