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Reporter: Prabodh Kandala, PhD.

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.

Abstract:

Thymopoiesis depends on the recruitment and expansion of bone marrow–derived progenitor populations; tight regulation of these processes is required for maintenance of the homeostasis of the T lineage. Lyl-1, a transcription factor that regulates hematopoietic progenitors, is expressed in thymocyte progenitors until T cell commitment. Here we demonstrate a requirement for Lyl-1 in lymphoid specification and the maintenance of early T lineage progenitors (ETPs). Lyl-1 deficiency resulted in profound defects in the generation of lymphoid-primed multipotent progenitors (LMPPs), common lymphoid progenitors (CLPs) and ETPs. Lyl-1-deficient ETPs and thymocyte progenitors at the CD4⁻CD8⁻ double-negative 2 (DN2) stage showed more apoptosis, blocked differentiation and impaired population expansion. We identified Gfi1 as a critical transcriptional target of Lyl-1-mediated lymphopoiesis of T cells. Thus, Lyl-1 is a pivotal component of a transcriptional program that controls the lymphoid specification and maintenance of ETPs.

Ref:

http://www.sciencedaily.com/releases/2012/07/120708162320.htm

http://www.nature.com/ni/journal/vaop/ncurrent/full/ni.2365.html.