Jennifer Trowbridge of the Jackson Laboratory seeks to thwart the mutations and inflammation that accumulate in aging bone marrow to maintain production of healthy blood cells and reduce blood cancer risk.
It’s a fact of life: As we age, mutations happen. The longer we live, the more genetic changes accumulate in our cells. That’s why the likelihood of developing cancer, including blood cancers such as leukemia and lymphoma, increases the older we get.
studies the processes that pave the way for blood cancers in older people. The JAX Associate Professor has her eye on a condition that results from mutations that accumulate in bone marrow stem cells, which produce all our blood and immune cells throughout our lives.
The connection between common genetic mutations and blood cancers
The condition is called CHIP, for clonal hematopoiesis of indeterminant potential, and if you’ve already attended your 25th annual high school reunion, you may have it.
“It’s estimated now that everyone over the age of 50 — and maybe even 40 — is carrying stem cells with these mutations,” Trowbridge says. “And that may put them at higher risk as they age of developing blood cancers, such as lymphoma and leukemia, and also cardiovascular disease and atherosclerosis.”
That sounds scary, Trowbridge says, “but actually, most people can carry these mutations in their bone marrow stem cells and live out a normal lifespan without any problems in their blood or immune systems.” The very name of the condition contains the term “indeterminate potential,” she notes, “and the name implies we don’t really yet know for any particular person how risky it is.”
In 2020 the Leukemia and Lymphoma Society awarded Trowbridge a five-year Scholar Award through its Career Development program, and her lab received a five-year grant totaling $2,386,782 from the National Institute on Aging to develop new approaches to extend the production of healthy cells in the bone marrow during aging, and to prevent the progression of CHIP to aging-related blood cancers and other hematologic disorders.
Protecting against leukemia and other blood cancers
Throughout our lifetimes, hematopoietic stem cells (HSCs) constantly replenish the various cells in the blood, including immune cells. Aging leads to the production of more myeloid-type cells, which are associated with increased inflammation and cancer, and fewer lymphoid-type immune cells, such as B and T cells, that are essential to the body’s defenses against infectious pathogens.
In April the Trowbridge lab published a paper in Cell Stem Cell showing that declining levels of the hormone IGF1, which contributes to overall longevity in middle-aged mice, paradoxically compromises blood stem cell function, leading to aging-related decline of the stem cells within the bone marrow microenvironment and potentially setting the scene for blood cancers.
Moreover, HSCs transplanted from young mice into middle-aged bone marrow rapidly transitioned to a myeloid bias, whereas HSCs from middle-aged mice reverted to higher B and T cell frequencies in young mouse bone marrow.
And in September 2021, the National Cancer Institute and National Institute on Aging awarded a total of $2,594,553 to Trowbridge for a new five-year cooperative agreement to advance the understanding of the role of aging in cancer initiation. With her collaborator, Ross Levine, M.D., an expert in hematologic malignancies at Memorial Sloan Kettering Cancer Center in New York, N.Y., Trowbridge will explore the mechanisms by which aging contributes to clonal hematopoiesis and leukemia initiation.
The new project will use cellular and molecular biological approaches in aged mice, integrated with studies using primary human CH samples. The researchers will establish the roles of inflammation and certain alterations in gene regulation in clonal hematopoietic expansion and risk of leukemia initiation.
“The goal of this work,” Trowbridge says, “will be to gain insights into effective therapeutic strategies targeting clonal evolution, reducing the negative effects of clonal expansion, and preventing the transformation of normal blood cells into blood cancers.”
Assessing the Interplay Between Inflammatory Signaling and Epigenetic Dysregulation in Age-associated Clonal Hematopoiesis and Leukemia Initiation, National Institute on Aging, Grant number 1U01AG077925-01