The Diamond Blackfan Anemia Foundation (DBAF) and Diamond Blackfan Anemia Canada (DBAC) have once again joined forces to fund a very exciting research project. Dr. John Crispino, PhD of Northwestern University was awarded a $50,000 grant for his project entitled, “Overriding GATA1 mutations in Diamond Blackfan Anemia.” The DBAF appreciates DBAC’s $15,000 contribution towards this project and is grateful to Dr. Crispino for his interest in researching DBA.
Dr. Crispino is enthusiastic about the funding and eager to bring his GATA1 expertise to the DBA community. He stated,
“I am thrilled to have the support of the DBA Foundation and DBA Canada to support this high risk, but potentially high reward proposal which seeks to increase our understanding of how GATA1 mutations cause DBA and to develop a novel way to overcome these mutations. I have been studying GATA factors for over 15 years and am excited to leverage my knowledge in ways to help patients with DBA.”
GATA1 is a protein required for the development of red blood cells and megakaryocytes (precursors of platelets). It is a transcription factor that plays a critical role in regulating the expression of genes needed for the appropriate development of these cell lineages. GATA1 mutations identified in DBA patients shorten the protein so it can’t function properly in red cell development. Dr. Crispino proposes to discover how the GATA1 mutation (GATA1s) identified in DBA patients disrupts red cell development and to develop drugs that override the effect of this mutation. Their preliminary data reveal that GATA1s fails to properly bind and regulate key erythroid specific genes such as Alas2, Slc4a1, and Klf1 (EKLF). They believe that the inability of GATA1s to properly regulate these genes is the reason for the defective red cell development. They have been successful in identifying small molecule kinase inhibitors that selectively induce differentiation of GATA1s mutant megakaryocytes and will use a similar approach in the red cell lineage. Given that their megakaryocyte selective compounds can override blocks to differentiation in the absence of full length GATA1, they are optimistic that there exist compounds that will induce terminal differentiation of erythroid precursors with the GATA1s mutation. Their overarching hypothesis is that the abnormal gene regulation by GATA1s leads to impaired specification and terminal differentiation of red blood cells and that they can override this block by pharmacologic means. Their specific aims are to: (1) characterize defects of mice that express GATA1s in place of full-length GATA1 and determine if overexpression of EKLF can rescue differentiation and (2) Identify small molecules that induce differentiation of GATA1s mutant erythroblasts.
We thank Dr. Crispino for his new found interest in DBA and wish him all the best!