Mapping blood system changes offers new hope for leukemia treatments

Researchers at University of California San Diego School of Medicine and their colleagues have developed the first comprehensive map of the dramatic changes that take place in the blood system over the course of the human lifetime.

The team quantified the gene expression of more than 58,000 individual hematopoietic (blood) stem cells at seven stages, from early fetal development to old age. They documented consistent changes in the types of blood cells that are produced in response to the functional demands of each life stage: 

• The early prenatal period is characterized by myeloid cell production after conception: tissue-resident macrophages, immune cells that play a crucial role in supporting early organ development, followed by rapid growth in the second trimester which requires the production of red blood cells for robust oxygen delivery throughout the fetus.
• At birth, there is a shift to lymphoid cells. These white blood cells play an important role in establishing lifelong immunity following the sudden exposure to the outside environment and its pathogens. Lymphoid cells remain dominant through childhood. 
• In adulthood, lymphoid cell production wanes, but myeloid cell production expands again over time.

The researchers also found that changes in blood cell types across the lifetime can have important implications for blood cancers. They classified acute myeloid leukemia cells by their resemblance to gene expression of stem cells at different life stages, discovering that the normal stem cell age most reflective of leukemia cells in patients with acute myeloid leukemia can vary widely, regardless of a patient’s age. 

What’s more, patients whose leukemia cells more closely reflected young blood cell production had a much worse prognosis than those whose leukemia cells more closely reflected old blood cell production. The researchers believe the cancer cells may reprogram themselves to have fetal attributes that make them more aggressive. Further investigation identified seven transcription factor genes that strongly influence whether leukemia cells looked like old or young blood cells. 

Future studies are planned to test whether the disease takes advantage of the highly proliferative capacity of young blood cells to make patients’ leukemia more deadly than older, less vigorous blood cells. They are also hopeful that leukemia cells could eventually be reprogrammed.

“If we can develop drugs that target key factors that drive young blood cell production, maybe the leukemia will just reflect old blood cell production and be easier to treat,” said Hojun Li, M.D., Ph.D., an assistant professor of pediatrics at UC San Diego School of Medicine, UC San Diego Moores Cancer Center member and an attending physician at Rady Children’s Hospital-San Diego, who led the study along with R. Grant Rowe, M.D., Ph.D., an assistant professor of pediatrics at Boston Children’s Hospital, Harvard Medical School.

The study was published on December 5 in Nature Methods.