This year in the United States, more than 60,000 children and adults will be diagnosed with leukemia, a family of blood cancers that claim more than 22,000 lives annually. While the outlook is relatively promising for younger people, five-year survival rates for adult patients with a more aggressive form of cancer, acute myeloid leukemia (AML), is only about 25%. The most effective treatments, including chemotherapy and blood or marrow transplants, can be physically harmful and lead to serious side effects.
While scientists are using emerging technologies to develop new treatments for AML, questions remain about the biological mechanisms that lead to the disease in the first place. Thelma Escobar, PhD, an Assistant Professor of Biochemistry and a faculty member in the Institute for Stem Cell and Regenerative Medicine (ISCRM), is one researcher exploring the molecular origins of AML. Her efforts to reveal fundamental insights about AML have now attracted funding from the National Cancer Institute.
As a postdoc in the lab of Dr. Danny Reinberg at NYU, Escobar received NCI support through the CURE program, which provides funding to increase diversity in cancer research. That grant allowed her to study chromatin inheritance, and led to her discovery, detailed in Science Advances, that the protein NPM1 has a role in the inheritance of chromatin modifications. (Chromatin is the raw material that the body uses to build chromosomes, which carry our DNA. Modifications that occur to our DNA during our lifetimes are known as epigenetic changes – and the full set of those changes is known as the epigenome.)
The NPM1 gene is responsible for multiple functions, including escorting proteins to different parts of the cell and helping to maintain stability across progressive states of cell proliferation. When alterations to NPM1 occur in the genome of blood cells, those mutations are believed to contribute to the onset of AML. In fact, 35% of AML patients have the NPM1 mutation, which is only seen in hematopoietic stem cells (HSCs).
The idea for the grant arose through exploratory conversations between Escobar and fellow ISCRM faculty member Sergei Doulatov, PhD, whose lab in the department of Medicine/Hematology studies hematopoietic stem cell (HSCs) and the pathology of blood cancers. The ISCRM peers reasoned that by combining their backgrounds in hematology and chromatin biochemistry they could produce insights with clinical significance for oncologists and patients.
With grand funding, the researchers will use mouse and human induced pluripotent stem cell (iPSC) models to study the interplay of NPM1 and the epigenome and to learn more about what goes awry as hematopoietic stem cells with the mutation divide and eventually cause illness.
In one aspect of the investigation, Francisco Saavedra Cantillana, PhD, a postdoctoral fellow in the Escobar lab, will use induced pluripotent stem cells (iPSCs), CRISPR gene editing, and genomic analysis to better understand the role of NPM1 in blood cell formation (also known as a hematopoiesis). Saavedra Cantillana recently received a Pew Latin American Fellowship to support his research.
Escobar is also partnering with the Tom and Sue Ellison Stem Cell Core, led by ISCRM faculty member Julie Mathieu, PhD. Mathieu and her team are helping the Escobar Lab generate a mouse gene-edited specifically for the NPM1 AML research, which will enable the researchers to understand how the development of the disease impacts an entire organism – observations that will be validated in the stem cell models.
Collaboration is central to the investigation, says Escobar. “Our ability to build a fundable application was only possible through a team effort with the Doulatov Lab and the Stem Cell Core. The spirit of partnership is how we were able to recruit a postdoc and makes it possible to bring our interests together, to look at these questions from different perspectives, and ultimately drive advances in care for AML patients.”