Biochemical cascade causes bone marrow inflammation, leading to serious blood disorders

July 3, 2014, Indiana University

Like a line of falling dominos, a cascade of molecular events in the bone marrow produces high levels of inflammation that disrupt normal blood formation and lead to potentially deadly disorders including leukemia, an Indiana University-led research team has reported.

The discovery, published by the journal Cell Stem Cell, points the way to potential new strategies to treat the blood disorders and further illuminates the relationship between inflammation and cancer, said lead investigator Nadia Carlesso, M.D., Ph.D., associate professor of pediatrics at the Indiana University School of Medicine.

Bone marrow includes the that produce the body's red and white blood system cells in a process called hematopoiesis. The marrow also provides a support system and "home" for the blood-producing cells called the hematopoietic microenvironment. The new research demonstrates the importance of the hematopoietic microenvironment in the development of a group of potentially deadly diseases called myeloproliferative disorders.

"It has been known for years that there are links between inflammation and cancer, but these studies have been challenged by the lack of genetic models, especially for blood-based malignancies," said Dr. Carlesso, a member of the hematologic malignancy and stem cell biology program within the Wells Center of Pediatric Research at IU.

Like a line of falling dominos, a cascade of molecular events in the bone marrow produces high levels of inflammation that disrupt normal blood formation and lead to potentially deadly disorders including leukemia, an Indiana University-led research team has reported. Credit: Indiana University

The researchers focused on what happens when there are abnormally low levels of a molecule called Notch, which plays an important role in the process of blood cell production. Using a genetically modified mouse, they found that the loss of Notch function in the microenvironment causes a chain of molecular events that result in excess production of inflammatory factors.

The high levels of inflammation in the bone marrow were associated with the development of a myeloproliferative disorder in the mice. Myeloproliferative diseases in humans can result in several illnesses caused by overproduction of myeloid cells, which are normally are used to fight infections. These diseases can put patients at risk for heart attack or stroke, and frequently progress into acute leukemia and , which have fatal outcomes. Unfortunately, there are no effective therapies for the majority of myeloproliferative diseases.

When Dr. Carlesso's team blocked the activity of one of the molecules in this biochemical cascade, the myeloproliferative disorder in the mice was reversed. In addition, elevated levels of the blocked molecule were found in samples from human patients with myeloproliferative disease. These findings suggest that developing drugs that target this inflammatory reaction at different key points could be a promising strategy to limit the development of myeloproliferative disease in humans.

The molecular cascade leading to inflammation was not occurring directly in the that produce blood cells, but in cells of the bone marrow microenvironment, especially in endothelial cells that line the capillaries—tiny blood vessels—inside the . This was a key discovery, Dr. Carlesso said.

"This work indicates that we need to target not only the tumor cells, but also the inflammatory microenvironment that surrounds them and may contribute to their generation," she said.

"We believe that this combined strategy will be more effective in preventing myeloproliferative disease progression and transformation in acute leukemias."

Dr. Carlesso also noted that the Notch molecule is mostly known as an oncogene—one that can cause cancer—and so is often targeted by therapies for other types of cancer. The new research indicates that clinicians need to be aware of the effects that reducing levels of Notch function could have on the blood development process, she said.

Explore further: Microenvironment of hematopoietic stem cells can be a target for myeloproliferative disorders

Related Stories

Microenvironment of hematopoietic stem cells can be a target for myeloproliferative disorders

June 22, 2014
The protective microenvironment of the hematopoietic stem cell niche, which produces cells of the blood and the immune system, also protects against myeloproliferative neoplasia.

New findings may help overcome hurdle to successful bone marrow transplantation

May 28, 2013
Blood diseases such as leukemia, multiple myeloma, and myelodysplasia can develop from abnormal bone marrow cells and a dysfunctional bone marrow microenvironment that surrounds these cells. Until now, researchers have been ...

Solution to platelet 'puzzle' uncovers blood disorder link

April 7, 2014
Melbourne researchers have solved a puzzle as to how an essential blood-making hormone stimulates production of the blood clotting cells known as platelets.

Cell signaling discovery provides new hope for blood disorders

February 16, 2012
Walter and Eliza Hall Institute scientists have revealed new details about how cell signalling is controlled in the immune system, identifying in the process potential new therapeutic targets for treating severe blood disorders.

Immune cells regulate blood stem cells

February 21, 2014
Researchers in Bern, Germany, have discovered that, during a viral infection, immune cells control the blood stem cells in the bone marrow and therefore also the body's own defences. The findings could allow for new forms ...

Researchers discover hormone that controls supply of iron in red blood cell production

June 1, 2014
A UCLA research team has discovered a new hormone called erythroferrone, which regulates the iron supply needed for red blood-cell production.

Recommended for you

Bioengineered soft microfibers improve T-cell production

January 18, 2018
T cells play a key role in the body's immune response against pathogens. As a new class of therapeutic approaches, T cells are being harnessed to fight cancer, promising more precise, longer-lasting mitigation than traditional, ...

Weight flux alters molecular profile, study finds

January 17, 2018
The human body undergoes dramatic changes during even short periods of weight gain and loss, according to a study led by researchers at the Stanford University School of Medicine.

Secrets of longevity protein revealed in new study

January 17, 2018
Named after the Greek goddess who spun the thread of life, Klotho proteins play an important role in the regulation of longevity and metabolism. In a recent Yale-led study, researchers revealed the three-dimensional structure ...

The HLF gene protects blood stem cells by maintaining them in a resting state

January 17, 2018
The HLF gene is necessary for maintaining blood stem cells in a resting state, which is crucial for ensuring normal blood production. This has been shown by a new research study from Lund University in Sweden published in ...

Magnetically applied MicroRNAs could one day help relieve constipation

January 17, 2018
Constipation is an underestimated and debilitating medical issue related to the opioid epidemic. As a growing concern, researchers look to new tools to help patients with this side effect of opioid use and aging.

Researchers devise decoy molecule to block pain where it starts

January 16, 2018
For anyone who has accidentally injured themselves, Dr. Zachary Campbell not only sympathizes, he's developing new ways to blunt pain.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.