The Dark Matter Project

ABCB7

Iron Metabolism Dysregulation in Myelodysplastic Syndrome

Iron is the most abundant transition metal in biological systems and is vital for the survival of living organisms. Iron can be incorporated into heme to support essential process like oxygen transport and respiration. However, when mis-handled iron can catalyze the production of free radicals that damage intracellular molecules and lead to cell death. Therefore, iron must be properly managed to permit required functions of iron while restraining iron’s propensity to oxidize cellular components. Cellular iron sensing is dysregulated in a subset of patients with the hematologic disorder Myelodysplastic Syndrome (MDS). In MDS, patients can acquire a mutation in the gene SF3B1 only in tissues that make red blood cells. Patients with this type of MDS often produce an immature type of red blood cell termed a ringed sideroblast, which is unable to form mature red blood cells. These immature red blood cells cannot make hemoglobin, an iron-containing component used by red blood cells to carry oxygen. As a result, these patients are anemic. We believe that this inability to produce red blood cells occurs because defects in iron sensing blocks hemoglobin production. Our goal is to develop a mouse model of SF3B1 mutant MDS and use it to test this hypothesis. Because SF3B1 acts differently in mouse and human cells, we will copy part of the human genome that underlies this difference from human into mouse cells. Generating a mouse that faithfully models the human disease will be a key step in developing and testing treatments for MDS.

IN COllaboration with:

Richard Possemato, PhD, NYU Langone Health