Researchers have developed a new atlas of rare hematopoietic stem and progenitor cells, those cells that trigger production of mature blood cells. Their studies showed that the atlas can aid in predicting which acute myeloid leukemia (AML) patients will respond to current standard therapy with venetoclax and azacytidine.
The scientists created the atlas as current hemotopoietic datasets proved insufficient for their study needs. “We wanted to create an atlas representing the rare stem and progenitor cells that are in the bone marrow that are actually the most interesting ones in a robust manner,” explains H. Leighton Grimes, of Cincinnati Children’s, co-senior author of the paper published in Nature Immunology.
Many currently available data sets contain antibody information and transcriptomes but the team found they did not go deep enough in terms of finding novel progenitors. And these datasets did not include donors of varied sex and ancestry. The goal of their work was to know more about the markers that identify rare stem and progenitor cells and if there were differences between sex and ancestry.
“None of the literature could tell us differences between people of central European ancestry versus those with African ancestry, and so on,” Grimes adds. “By adding this information to our atlas, this should be true for any topic other researchers want to study so it will be a resource durable for both our studies and other people who may have even more complex questions.”
To create the atlas, the team built detailed genomic and proteomic profiles of more than 300,000 bone marrow cells collected from a diverse mix of donors spanning ethnicity and sex. They created a new mix of 132 antibodies to probe the surface of stem and progenitor cells which helped them profile the bone marrow cell clusters. To create the finished atlas, they relied on their earlier work creating an informatics workflow that uses game theory in order to perform statistical analyses to figure out what the best cells clusters are. During the course of developing and testing their new atlas, they identified more than 89 distinct subsets of stem and progenitor cells, revealing new and rare populations.
Grimes mentions that making neutrophil granulocytes in vitro for adoptive cell therapy is currently a goal for treating some diseases. Now, physicians give patients G-CSF to make more neutrophils inside the body but “they don’t really function optimally,” according to Grimes. “They would like to make neutrophil granulocytes ex vivo and then transplant them back into people who need them for various reasons,” he adds, “but they don’t really differentiate ex vivo very well right now. To address this roadblock, his team identified the use of two surface markers—C5L2 and TSPAN33—to identify the moment that stem and progenitor cells become functional neutrophils.
In their final experiment, the team examined isolated stem cells from AML patients who had been on treatment with venetoclax plus azacytidine yet relapsed.
Co-author Craig Jordan, of the University of Colorado, thought that it was because different types of very primitive leukemia stem cells might remain in residual disease. When the team tested the cells of AML patient samples with their new surface markers, they were able to see which had primitive cells, monocytic cells, or a mix of both.
“That information could be used to project who would respond to the treatment of venetoclax and azacytidine,” Grimes says, which proved to be the case with a 100% correct call rate. “This means that it may be a useful resource for predicting which AML patients will do well on therapy.” The team also sees that the new atlas may be used to predict the cellular origins and possible causes of blood cancers like AML.
