The DBA Foundation is excited to announce the funding of Dr. George Thomas’ research project entitled, “The role of p53 in mediating the anemic response in DBA patients with defects in RPL5 or RPL11.” Thank you to DBA Canada for their joint funding support to make this possible!  The long-term goal of this study is to understand the mechanisms through which red blood cell precursors in the marrow of DBA patients undergo programmed cell death rather than differentiate into mature red blood cells.
The $49,274.98 grant to the University of Cincinnati will provide support for Dr. Teng Teng. Dr. Teng stated,

Dr. Teng Teng & Dr. George Thomas

“We are grateful to the DBA Foundation and DBA Canada for supporting our studies in examining the molecular pathways linking mutations in ribosomal protein genes to the survival of red blood cell progenitors. Our laboratory has a long standing interest in elucidating the underlying molecular response of cells to impaired ribosome biogenesis. This has led to a working model based on analyses of cell lines from non-hematopoietic tissues and mouse models. With the funding from DBAF and DBA Canada, we will be able to test our hypothesis using genetically engineered human hematopoietic stem cells and potentially, DBA patient-derived hematopoietic stem cells. Results from these studies will aid us in our understanding of the basic molecular mechanism leading to DBA, and potentially in the development of more efficacious targeted therapies.”

A very important protein in the process of programmed cell death appears to be p53, the so-called guardian of the genome.  The p53 protein is activated in cells in response to a variety of stresses, and if the stress is too great p53 will initiate a programmed cell death program called apoptosis.  One such stress p53 responds to is ribosome stress caused by haploinsufficiency for a ribosomal protein.  Two ribosomal proteins, Rpl5 and Rpl11, signal ribosome stress by binding to a protein called HDM2, whose normal function is to mark p53 for degradation thereby keeping p53 levels low in normal cells.  By binding to HDM2 and inhibiting its activity, RPL5 and RPL11 cause a rise in p53 levels promoting cells death.  If RPL5 and RPL11 play such a central role in DBA pathogenesis by signaling to p53 activation in response to ribosome stress, one would predict that neither RPL5 nor RPL11 should be DBA genes.  And yet, they are.

The Thomas team will investigate whether alternative pathways are at play in DBA patients with mutations in RPL5 and RPL11.  Dr. Thomas has brought together a unique team with expertise in p53/ribosomal protein interactions (G. Thomas), hematopoiesis (D. Bodine) and the diagnosis and care of patients with DBA (A. Vlachos, J. Lipton). Overall, the goal of these studies is to define the molecular mechanisms by which defects in distinct ribosomal proteins affect the survival and maturation of hematopoietic cells, potentially leading to the development of more efficacious targeted therapies.