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The Keystone Program in Blood Cell Development and Cancer

Current Projects

"The primary goal of the Blood Cell Development and Cancer (BCDC) Keystone program is to identify genes that are essential for blood cell development, determine whether those genes play important roles in cancer development, and assess whether they are useful in cancer care. " – David L. Wiest, Ph.D.

In the year and a half since the BCDC program was commissioned, BCDC scientists have made substantial progress. They have initiated a multi-investigator genetic screen using the zebrafish model to identify genes required for development of multiple blood cell lineages. While this screen continues, they have already identified 6 genes that are turned on almost exclusively in blood cells and are in the process of determining whether these genes are required for blood cell formation. In addition, BCDC scientists have extensively characterized one such gene:

Rpl22

Rpl22 is required for the formation of a specific blood cell type called a "T cell." Importantly, inactivation of the Rpl22 gene makes T cells more prone to becoming cancerous in mice, and in humans with T acute lymphoblastic leukemia (T-ALL, a type of T cell cancer); cancers that have lost one copy of the Rpl22 gene appear to be more aggressive and are often lethal. Knowing that a patient has a mutation in Rpl22 may enable clinicians to monitor those patients more closely or prescribe alternative treatments. Efforts to better understand the role of Rpl22 in cancer are ongoing and are supported by a new grant from the National Cancer Institute.

In a related initiative, BCDC members are collaborating with a physician at Duke University Medical Center to study humans bearing mutations in unknown genes that are required for development of blood cells. These patients are referred to as severe combined immunodeficiency (SCID) patients because development of one or more types of their blood cells is impaired. The goal of this initiative is to seek to identify the genes that are mutated in those patients by using a newly developed method termed "massively parallel DNA sequencing," which will aid in identifying all of the genes in those patients cells that are mutated. From among this set of mutated genes, BCDC investigators will identify the particular gene causing disease by determining if re-creating loss of that gene in zebrafish blocks blood cell development. Genes identified in this way will not only be useful as potential gene-therapy candidates in SCID patients, but will also be assessed for their relevance to cancer formation as described above. This work was recently awarded support by the Heart Lung and Blood Institute as a "Challenge Grant" and was one of only 200 of these grants awarded nationwide.

Another pair of BCDC investigators also received a Challenge Grant from the National Cancer Institute, so altogether this program received 1% of these awards granted nationally. This Challenge Grant was awarded to study the origins of a blood cancer called Chronic Lymphocytic Leukemia (CLL), which afflicts one in six older Americans. CLL in some patients moves slowly whereas in others it is more aggressive and progresses rapidly. These investigators are assessing the pairing of two protein subunits of the antibody receptor expressed by CLL cells. This antibody receptor controls the development of the stem/progenitor cells into the B cell precursors from which CLL arises, and may also regulate the behavior of the CLL cancer cells as well. These investigators will assess whether the pairing of these antibody chains regulates the initial development of CLL and is predictive of disease progression.

The ability of BCDC investigators to investigate the roles of essential genes in human cancer is facilitated by the BCDC program’s upgrading of the flow cytometer in the clinical blood pathology lab. Through the collaborative efforts of laboratory-based investigators and clinicians in the BCDC Keystone program, this flow cytometer has been incorporated into daily service and this provides two major advantages:

1. First, BCDC investigators can now analyze in a very sophisticated way how the patient’s own blood cells change as their disease progresses, thereby providing insights into how the patient’s immune cells may be combating the disease;
2. Second, this flow cytometer enables isolation from among the complex mixture of cells in patient blood, purified tumor cells with which BCDC investigators can determine if the genes identified as essential for blood cell development are misregulated in the patient’s cancer, perhaps serving as markers to guide diagnosis and treatment.

For more information on the members of the Keystone Program in Blood Cell Development and Cancer, Read More.