Researchers at the Cincinnati Children's Hospital Medical Center say they have identified a gene in laboratory experiments that fuels the biological processes that cause the different types of myelodysplastic syndromes (MDS) that physicians see in patients.
MDS is linked to a number of different gene mutations and is considered one of the most complex malignancies affecting blood-making hematopoietic stem cells in bone marrow. These blood disorders cause people to have immature, malfunctioning bone marrow cells that lead to a diverse set of health problems, including leukemia. The team’s study (“Pathobiologic Pseudohypoxia as a Putative Mechanism Underlying Myelodysplastic Syndromes”) appears in Cancer Discovery.
“MDS are heterogeneous hematopoietic disorders that are incurable with conventional therapy. The incidence is increasing with global population aging. Although many genetic, epigenetic, splicing, and metabolic aberrations have been identified in MDS patients, their clinical features are quite similar. Here we show that hypoxia-independent activation of hypoxia-inducible factor 1α (HIF1A) signaling is both necessary and sufficient to induce dysplastic and cytopenic MDS phenotypes,” write the investigators.
“The HIF1A transcriptional signature is generally activated in MDS-patient bone-marrow stem/progenitors. Major MDS-associated mutations (Dnmt3a, Tet2, Asxl1, Runx1, and Mll1) activate the HIF1A signature. While inducible activation of HIF1A signaling in hematopoietic cells is sufficient to induce MDS phenotypes, both genetic and chemical inhibition of HIF1A signaling rescues MDS phenotypes in a mouse model of MDS. These findings reveal HIF1A as a central pathobiologic mediator of MDS, and as an effective therapeutic target for a broad spectrum of MDS patients.”
“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,” says Gang Huang, Ph.D., a cancer biologist at Cincinnati Children's Hospital Medical Center and a member of the divisions of pathology and experimental hematology and cancer biology. “Our study shows that malfunctions in the signaling of HIF1A could be generating the diverse medical problems doctors see in MDS patients.”
MDS is becoming more prevalent as the population ages, with the median age of occurrence at about 70 years, according to the researchers. The only curative therapy is a bone marrow transplant, but it's only appropriate in a rare number of cases, as many older patients who get MDS are not healthy enough to tolerate hematopoietic stem cells transplantation.
HIF1A, a transcription factor, plays a vital role in how cells respond to metabolic changes and oxygen, and it affects the function of more than a thousand genes. This includes a vital role in regulating biological functions in blood-cell-making hematopoietic stem cells in bone marrow.
Dr. Huang and his colleagues identified HIF1A's central role first by studying donated cells from MDS patients. This included extensive analysis of the cells' transcriptome and epigenome. The scientists found evidence of dysregulated HIF1A in the patient cells. This led to experiments in different genetic mouse models to study the onset of MDS and its genetic and molecular drivers. These tests confirmed that dysregulation of HIF1A has a central role in the onset, including different manifestations and symptoms found in patients.
Although the authors stress that years of additional research are needed before knowing if their findings will become clinically relevant, their study does point to HIF1A as a potential therapeutic target for a disease that needs new and improved therapeutic options. They determined this by genetically and chemically eliminating HIF1A signaling from their genetic mouse models of MDS. The scientists report that inhibiting HIF1A reversed a broad spectrum of MDS symptoms.
Dr. Huang said the next challenge for researchers is to identify an HIF1A-specific therapeutic agent for treating MDS. Currently, most small-molecule inhibitors of HIF1A target both it and a second related molecule called HIF2A, which would make them unsuitable for MDS patients.