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No one really knew why some patients with a white blood cell cancer called chronic lymphocytic leukemia, or CLL, relapsed after treatment and developed a second cancer. Were some cancer cells resistant?
An unexpected answer to this mystery has been found using a new technique the researchers call barcoding: Treatment doesn’t always target the right cells.
Scientists have discovered that cancer does not always originate from mature bone marrow cells, which are found and textbooks say they originate from. Instead, for some patients, the main vessel of cancer may be primitive bone marrow cells, the stem cells that make up all of the body’s white and red blood cells. These cells, unaffected by chemotherapy treatment, can produce new cancer cells, causing a relapse.
The discovery is one of the first fruits of barcoding method that helps to investigate the origins of cancer and other diseases. The results are too recent to lead to patient therapies. But they lead to provocative discoveries that are expected to inspire new methods for treating disease.
The method works by marking individual cells with a stamp that is passed on to the entire lineage of a cell. Researchers can look at a cell, note its barcode, and trace its lineage back to its parents, grandparents, great-grandparents—to its origins—because every cell that emerges from the cell with the original barcode has the same imprint.
The idea of barcoding during embryonic development was introduced by Dr. Jay Shendure and his colleagues at the University of Washington, and this class of methods, Breakthrough of the year by Science magazine in 2018. There are now a variety of barcoding methods, from embryo cells to cancer cells to mature cells.
For example, Dr. Shendure and another group of colleagues at the University of Pennsylvania are using barcodes in mice with pancreatic cancer to study the spread of cancer cells in their bodies.
In the above case of CLL, Dr. Vijay Sankaran and colleagues barcoded human cancer cells using harmless, naturally occurring mutations that mark individual cells and are inherited by their descendants.
Barcoding, Dr. “It’s starting to give us an appearance of cancer that we’ve never had before,” Sankaran said.
The technique also led by Harvard Medical School’s Dr. Leonard gave Zon a surprising result. He wanted to study clonal hematopoiesis of uncertain potential, or CHIP, a common but poorly understood condition that is common in older people and increases the risk of cancer and heart disease. CHIP occurs when a single blood stem cell lineage takes over all or most of the bone marrow, squeezing out other stem cells.
To investigate, Dr. The zone marked individual bone marrow stem cells with different colors in small, transparent zebrafish. The result was similar to what happened in the patients – when the fish were adults, half of their blood cells were a single color, meaning they were derived from a single stem cell.
But how did a cell take over?
NS the answer was a surprise. Dominant cells secreted toxic inflammatory proteins. These proteins suppressed the growth of other stem cells and damaged the environment in which bone marrow cells grew. But the stem cell parents survived and continued to produce new offspring that secreted toxins.
The group also found a gene in mutant cells that made them resistant to inflammation. When they blocked this gene, the mutant cells could no longer take control.
Fernando Camargo, a stem cell biologist at Boston Children’s, addressed a different issue – why transplanting healthy bone marrow stem cells from donors is standard cancer treatments so difficult and often leaves patients vulnerable to serious infections?
When he and his colleagues genetically encoded bone marrow cells in mice by marking them with a gene-editing technique known as CRISPR, they discovered that: the cells everyone calls stem cells were not the main contributors to blood production.
Dr. “We assumed these were the cells that normally make up all of your blood,” Camargo said.
Instead, a different group of cells, which he calls progenitor cells, makes up most blood in living animals. In stem cell transplantation, both progenitor cells and putative stem cells are transplanted, but progenitor cells die rapidly in the new medium.
Now the question is: Why don’t progenitor cells survive the transplant? Strong doses of radiation and chemotherapy that clear the bone marrow for transplant can render the marrow uninhabitable. Or, the progenitor cells injected with stem cells into the blood may not be able to reach the bone marrow.
Dr. The Camargo remained, shaking his head.
“We thought we knew everything about blood stem cells,” he said. “Obviously, we didn’t.”
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