Changes in blood cell gene profile may impact leukemia outcomes
Study links stem cell changes in AML during life to worse disease prognosis
In people with acute myeloid leukemia (AML), changes in the gene profile of blood-forming stem cells, leading to a more youthful blood cell profile, could be related to a worse disease outcome.
That’s one of the findings of a new study led by U.S. researchers that documented changes in gene profiles in these cells, called hematopoietic stem cells, according to functional demands at different life stages. The team created what they say is “the first comprehensive map of the dramatic changes that take place in the blood system over the course of the human lifetime,” according to a news story from the University of California San Diego School of Medicine.
“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, MD, PhD, a professor at the School of Medicine and a researcher at UC San Diego Moores Cancer Center.
Li, also an attending physician at Rady Children’s Hospital-San Diego, led the study along with R. Grant Rowe, MD, PhD, a professor of pediatrics at Boston Children’s Hospital, Harvard Medical School, in Massachusetts.
According to the study, the scientists’ findings “overcome existing obstacles that obscure age-specific biology” and “provide the first temporal continuum of … stem … cell maturation and aging in humans at the single-cell level.”
Further, “despite limitations … our atlas serves as a foundation for future studies of human hematopoietic and immune development, aging and blood diseases,” the team wrote.
The study, “The dynamics of hematopoiesis over the human lifespan,” was published in the journal Nature Methods.
Scant data available on how hematopoietic stem cells change over time
Acute leukemia, including AML, is caused by genetic defects in hematopoietic stem cells, which give rise to all types of blood cells and are marked by the rapid growth of abnormal blood cells. In AML, the disease affects myeloid stem cells, which give rise to red blood cells, platelets, and granulocytes — a type of white blood cell, or immune cell.
Over a lifetime, hematopoietic stem cells coordinate their development in response to varying age-appropriate demands and stages of life.
“However, how the properties of hematopoietic stem and progenitor cells [HSPCs] change over the human lifespan remains unclear,” the researchers wrote.
That led the scientists, comprising researchers from the U.S., Canada, and Brazil, to analyze gene expression, or activity, patterns in human hematopoietic stem cells and progenitor cells. Progenitor cells are more differentiated than stem cells but can still mature into specific cell types. The cells were examined at seven stages, spanning early fetal development to old age.
In their work, the team analyzed data from nine accessible datasets on hematopoietic stem and progenitor cells at 22 time points from a total of 26 donors. These time points ranged from 10 weeks of pregnancy to 77 years of age. Gene expression was analyzed at the cell level, from more than 58,000 individual cells.
The scientists reported changes in the type of blood cells produced to fulfill functional needs across life stages. For instance, during early fetal development, production occurs of myeloid cells, including macrophages — immune cells that remove dead cells and infectious microorganisms — important for early tissue development.
In late pregnancy, there is an increase in the production of red blood cells, which transport oxygen through the bloodstream, to support the rapid growth of the fetus. After birth, there is a shift toward a dominance of lymphoid cells, a type of immune cell essential for the establishment of life-lasting immunity, following exposure to pathogens, or disease-causing agents, in the environment. These cells remain dominant throughout childhood.
During adulthood, lymphoid cell production is reduced, while myeloid cell production increases over time.
Researchers classified AML by gene profile across life stages
In addition to age-dependent normal hematopoietic development, the researchers also found that changes in blood cell types could have implications for AML.
When they classified AML cells according to their similarities to the gene profile at different life stages, the researchers identified two main classes: cells with a predominant elderly profile, and a mixed profile in which elderly profile cells decreased and fetal and childhood-like cells increased. This classification was independent of a patient’s actual age, according to the researchers.
The team further discovered that those with AML whose cell profile was more similar to that of young blood cells had a significantly worse prognosis than those who predominantly had cells with an elderly profile. According to the researchers, these results indicated that cancer cells are reprogrammed to have fetal characteristics that make them more aggressive.
Overall, by profiling over 50,000 HSPCs, we define the changes that occur in human hematopoietic [biology] over the course of the lifetime from development through maturation and aging.
The researchers identified seven transcription factor genes — proteins regulating the rate of gene translation into messenger RNA for protein production — that affected the resemblance of leukemia cells to either young or old blood cells. This finding was based on an analysis of samples from 257 people newly diagnosed with acute myeloid leukemia.
From these, two transcription factors — ZFX and DLX2 — were previously implicated in AML mechanisms. The other five, comprising NPAS1, RORB, ARNT2, BCN2, and NPAS3, were not. The expression of these proteins was able to predict patient survival.
“Further experimental validation will be required to mechanistically dissect what may drive causality,” the researchers wrote. “The [transcription factor] associations we identified in our analysis may serve as a useful initial starting point for such investigations.”
The researchers noted their work should provide a strong foundation for future study.
“Overall, by profiling over 50,000 HSPCs, we define the changes that occur in human hematopoietic [biology] over the course of the lifetime from development through maturation and aging,” they wrote.
