Tohoku University creates thrombocytopenic mice to clarify hematopoiesis — expectation for the development of treatments

Radioulnar synostosis with amegakaryocytic thrombocytopenia (RUSAT), a rare genetic disorder, is characterized by inadequate blood cell production in the bone marrow, leading to anemia and difficulty in stopping bleeding as well as limited hand-twisting movement due to fusion of the two forearm bones.

A research group led by Dr. Koki Nagai, Associate Professor Tetsuya Niihori, Professor Yoko Aoki, and Professor Kazuhiko Igarashi of the Graduate School of Medicine at Tohoku University has successfully produced mice with a mutation of the causative gene MECOM (EVI1) identified in patients with RUSAT. Although bone fusion in the forearm was not observed in the mutation-bearing mice, thrombocytopenia and hematopoietic stem cell reduction were observed with aging, recapitulating the symptoms in the bone marrow of patients with RUSAT. As a result, it was confirmed for the first time that MECOM (EVI1) mutation causes a decrease in hematopoietic stem cells in affected individuals. The mutation-bearing mouse is useful for elucidating the blood production mechanism and expected to lead to the development of therapeutic methods for humans. The result was published in the academic journal Blood Advances.

In 2015, Niihori and his colleagues identified MECOM (EVI1), one of the genes responsible for RUSAT, for the first time in the world. The related studies accumulated since then have reported 22 families of RUSAT with mutations in MECOM (EVI1). The gene mutations identified in patients with RUSAT are concentrated in a specific region within MECOM (EVI1), and it is predicted that this region plays an important role in the onset of this condition.

The research group genetically modified/manipulated mice with the gene causing mutation H752R that corresponded to the MECOM (EVI1) mutation H751R (change in the 751st amino acid from histidine to arginine) identified in patients with RUSAT.

The mutation-bearing mice were similar in appearance to mice without the mutation, and the males tend to be lighter in weight. The mutation-bearing mice showed a decrease in platelets as they grew. The research group also analyzed the blood-producing capacity of the bone marrow cells and found that the hematopoietic stem cells, which are the source of blood cells, were decreased in the mutation-bearing mice. Based on this result, the mice were administered a drug that reduces bone marrow cells (5-fluorouracil), and the process of bone marrow recovery was examined. The researchers found that the recovery of platelets and white blood cells was slower in the mutation-bearing mice.

This is the first study to confirm that MECOM (EVI1) mutation causes a decrease in hematopoietic stem cells in patients with RUSAT. In the future, studies should be performed to clarify the mechanism through which MECOM (EVI1) regulates blood formation and analyze the mutation-bearing mice in more detail to elucidate the disease pathology. The study findings should lead to the development of therapeutic approaches related to MECOM (EVI1) and onset of RUSAT.