Posted August 28, 2019
Benjamin Ebert, PhD, Brigham and Women’s Hospital

Wei Tong, Ph.D., Children’s Hospital of Philadelphia
Dr. Benjamin Ebert,
Brigham and Women’s Hospital

Myelodysplastic syndromes (MDSs) are the most common cause of acquired bone marrow failure (BMF) in the United States and are characterized by abnormal hematopoiesis, the process by which new blood cells are made, leading to blood cell reduction that can eventually evolve into cancer. The silencing of tumor suppressor genes by methylation is a contributing event to carcinogenesis. One current MDS therapy is the use of hypomethylating agents, which act by reducing the amount of DNA methylation and thus, lead to the re-expression of silenced tumor suppressor genes. However, patients have varied responses to the hypomethylating agents, with some responding well and others not. Dr. Ebert hypothesized that patient-specific mutations alter the response to the therapy, and with support from an FY13 BMFRP award he set out to identify mutations that will predict response to hypomethylating therapy.

Dr. Ebert’s team screened samples from MDS patients that had been treated with hypomethylating drugs to identify mutations that may predict sensitivity or resistance. They determined that the presence of either a TET2 mutation or a mutation in one of the cohesin protein subunits corresponded to response to the treatment. On the other hand, a mutation in the ASXL1 protein predicted poor response to hypomethylating agents. In order to confirm that these mutations reflect patient sensitivity, it was necessary to test Dr. Ebert’s hypothesis in human cell models that reflect the complexity of genetic mutations observed in MDS patients. Dr. Ebert’s team developed an approach for creating models of human bone marrow diseases by simultaneously modifying the disease driver genes, along with multiple other genes in human hematopoietic stem cells (HSCs), and then permitting their expansion in vivo in a mouse model. The team validated their initial findings, that mutations in TET2 and in the cohesion protein subunits increased the sensitivity of human HSCs to hypomethylating agents, while ASXL1 mutations decreased the sensitivity.

Dr. Ebert’s results not only indicate which MDS patients would most benefit from treatment with hypomethylating agents, but they also highlight a model system for precision medicine that could have immediate clinical impact. With Dr. Ebert’s model system, researchers are able to manipulate human HSCs to mimic the genetic complexity of BMF in an easily customizable fashion. The model could then facilitate pharmacologic testing in a patient-specific fashion, enabling physicians to identify to which therapy a patient is most likely to respond, resulting in precise and effective therapies for BMF patients.


Tothova Z, Krill-Burger JM, Popova KD, et al. 2017. Multiplex CRISPR/Cas9-based genome editing in human hematopoietic stem cells models clonal hematopoiesis and myeloid neoplasia. Cell Stem Cell 21(4):547-555.e8.

Bejar R, Lord A, Stevenson K, et al. 2014. TET2 mutations predict response to hypomethylating agents in myelodysplastic syndrome patients. Blood 124(17):2705-2712.


Public and Technical Abstracts: Role of Hypomethylating Agents in the Treatment of Bone Marrow Failure

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