What Can Make Leukemia Extra Aggressive?

The Context: All our blood cells are created in the bone marrow by blood-forming stem cells, and when this process goes awry, leukemia can arise. Scientists knew of a gene called MECOM that plays a role in regulating blood stem cells, and in a certain rare disease, underexpression of this gene can lead to an insufficiency of blood stem cells. On the other hand, overexpression of MECOM can lead to leukemia. How exactly this gene controls the blood-forming process, however, was not well understood.

The Study: Scientists have discovered that MECOM fine tunes the expression of essential genes that guide the formation of blood stem cells, and in leukemia, this network of genes gets hijacked, leading to a buildup of immature blood stem cells. The study, led by NYSCF – Robertson Stem Cell Investigator Vijay Sankaran, MD, PhD, of Boston Children’s Hospital, appears in Nature Immunology.

The Importance: This study pinpoints how MECOM influences blood stem cell development and could open the door for new strategies to treat AML. It also demonstrates how studying the biology of rare diseases can inform our understanding of more common diseases like leukemia.

In patients with AML, blood stem cells do not mature correctly and instead build up to prevent proper development of healthy blood (white blood cells, red blood cells, and platelets). A common treatment for AML is bone marrow transplant, in which cancerous cells are eliminated with chemotherapy and new, healthy stem cells are introduced. In some cases, however, leukemia can become especially aggressive, and scientists haven’t been sure why.

This was the case for Lynn, a current oncology nurse at the Dana-Farber Cancer Institute and AML patient who needed four rounds of chemotherapy and an experimental drug to eliminate enough cells to do a bone marrow transplant.

“High-risk leukemias adopt features of blood stem cells that make them really aggressive and resistant to chemotherapy,” said Dr. Sankaran in an article from Boston Children’s. “But normal stem cells saved Lynn’s life.”

Why was Lynn’s leukemia so aggressive? And could MECOM have something to do with it? Dr. Sankaran’s team was determined to find out.

How Does MECOM Hijack Blood Cell Development?

The team first took a look at how MECOM acts in patients with a rare disease that causes the gene to be underexpressed. The scientists found that when MECOM expression was reduced, blood stem cells matured extra quickly and all at once. They were then able to tease apart how exactly MECOM controls the way blood stem cells are produced, finding that the gene tells cells to create a certain protein that then regulates other key genes in blood cell development. Essentially, MECOM acts as the control center for these genes, and when the control center is faulty, so is blood cell development.

Conversely, when MECOM is overactive, like in those with AML, the genes it controls kick into overdrive and blood stem cells don’t mature as they should. The more active these genes are, the worse the prognosis.

What Will This Mean For Future Treatments?

For starters, understanding the process by which genes regulate blood stem cell development will help researchers better maintain blood stem cells outside the body in preparation for bone marrow transplants. The research will also open the door for new strategies to treat those with aggressive AML.

“All drug discovery starts with a fundamental understanding of a biological mechanism,” said first author Richard Voit, MD, PhD. “My hope is that in the future we can directly target a pathway downstream of MECOM in leukemias to treat patients more effectively and with fewer side effects.”

Journal Article:

A genetic disorder reveals a hematopoietic stem cell regulatory network co-opted in leukemia

Richard A. Voit, Liming Tao, Fulong Yu, Liam D. Cato, Blake Cohen, Travis J. Fleming, Mateusz Antoszewski, Xiaotian Liao, Claudia Fiorini, Satish K. Nandakumar, Lara Wahlster, Kristian Teichert, Aviv Regev & Vijay G. Sankaran. Nature Immunology. 2023. DOI: https://doi.org/10.1038/s41590-022-01370-4