Myelodysplastic syndromes (MDS) are a group of blood cancers with no known cause in most patients, but in a new study, a group of investigators from the Cincinnati Children’s Hospital Medical Center reports getting closer to solving the mystery.
According to the National Cancer Institute, a division of the National Institutes of Health (NIC), MDS
is a group of cancers in which immature blood stem cells in the bone marrow do not mature or turn into healthy blood cells as they normally would in a healthy individual. When blood stem cells fail to become lymphoid stem cells or myeloid stem cells, the immature cells do not work properly and either die in the bone marrow or soon after they enter the blood. With too few red blood cells in the blood, patients with MDS may see their condition develop into a range of syndromes, including progression to acute myeloid leukemia (AML) and chronic myelomonocytic leukemia.
In most cases of MDS, the cause
is unknown, though risk factors for the disease include past cancer treatment with chemotherapy and radiation, heavy metal exposure, and exposure to chemicals in tobacco smoke, pesticides, or solvents, which can all cause DNA damage. In past research, MDS has been linked with mutations in several different genes inside bone marrow cells, which can either be inherited or occur over the course of a lifetime. These mutations include ones in the DNMT3A
, and SF3B1
genes. In the new study
recently published in the journal Cancer Discovery
, investigators say that they’ve identified the regulatory gene hypoxia-inducible factor 1 alpha
) as fueling the biological processes that cause various forms of MDS.
essentially tells other genes what to do and plays a key role in how cells respond to metabolic changes and oxygen, affecting more than 1,000 genes; it regulates biological functions in hematopoietic stem cells in the bone marrow, which make blood cells. Using cells donated from MDS patients, the investigators conducted laboratory experiments analyzing the cells and found that dysregulation of HIF1A
plays a large role in the onset of MDS, which included a range of patients’ manifestations and symptoms. Further experiments in genetic mouse models assessing the genetic and molecular drivers of MDS confirmed their observations, and inhibiting HIF1A
reversed a broad spectrum of MDS symptoms.
“We know the genomes of MDS patients have recurrent mutations in different transcriptional, epigenetic, and metabolic regulators, but the incidence of these mutations does not directly correspond to the disease when it occurs,” said lead author Gang Huang, PhD, in a recent statement
. “Our study shows that malfunctions in the signaling of HIF1A
could be generating the diverse medical problems doctors see in MDS patients.”
While extensive additional research will be needed, the study’s authors say their findings indicate that HIF1A
is a potential therapeutic target for MDS. Current treatments for MDS
include stem cell transplant, hematopoietic growth factors, and chemotherapy.