A transcription factor called Lyl-1 is necessary for production of the earliest cells that can become T-cells, critical cells born in the thymus that coordinate the immune response to cancer or infections, said a consortium of researchers led by those from Baylor College of Medicine in a report in the journal Nature Immunology.
These earliest progenitors (called early T lineage progenitor cells) are the first cells that can be identified as being on the road to becoming T-cells, said Dr. Margaret Goodell, director of the Stem Cells and Regenerative Medicine Center of Baylor College of Medicine. Without Lyl-1, only a few of these early T lineage progenitor cells get made.
"This finding gives us insight into the biology of these progenitor cells," said Goodell, a professor of pediatrics at BCM and a member of the Center for Cell and Gene Therapy at BCM, Texas Children¹s Hospital and The Methodist Hospital.
Dr. Fabian Zohren, a post-doctoral student in Goodell¹s laboratory, found that mice lacking the gene for this factor had a T-cell deficiency and in particular, too few of these early progenitor cells.
"It showed that those early T lineage progenitor cells are really dependent on Lyl-1 for their generation," said Goodell, who is also corresponding author of the report. "We think that Lyl-1 controls a program that allows survival and expansion of these critical progenitors."
The finding may have particular import in understanding a form of leukemia known as T-cell acute lymphoblastic leukemia. The researchers found that the forms of the disease that have the worst prognosis are those in which the cancer cells resemble these early T lineage progenitor cells. These cells also have high levels of Lyl-1.
One possibility is the T-cell progenitors in patients with this type of T-cell leukemia continue to express Lyl-1, so continue to be programmed to expand. The excess Lyl-1 prevents the early T lineage progenitor cells from differentiating into active T-cells. Goodell said a recent grant from the Alex¹s Lemonade Stand Foundation will help test that hypothesis.
Others who took part in this work include George P. Souroullas, Min Luo, Ulrike Gerdemann, Maria R. Imperato and Georgi L. Lukov, all of BCM; and Nicola K. Wilson and Berthold Göttgens of the University of Cambridge in the United Kingdom. Lukov is also with the Brigham Young University-Hawaii. Zohren was also with the Heinrich-Heine-University in Dusseldorf, Germany. Imperato is also with the University of Naples in Italy.
Funding for this work came from the National Institutes of Health, the Dan L. Duncan Cancer Center at BCM, the United Kingdom Medical Research Council, Leukemia and Lymphoma Research, the Dr. Mildred Scheel Foundation for Cancer Research and the Cancer Prevention and Research Institute of Texas.
The transcription factor Lyl-1 regulates lymphoid specification and the maintenance of early T lineage progenitors. Fabian Zohren, George P Souroullas, Min Luo, Ulrike Gerdemann, Maria R Imperato, + et al. Nature Immunology doi:10.1038/ni.2365
Baylor College of Medicine