Game of Clones: Genomic Evolution of Severe Congenital Neutropenia
This lectureship was named in honor of two past Society presidents, the late Dr. Thomas Hale Ham and the late Dr. Louis R. Wasserman, distinguished hematologists who contributed extensively to the Society. The Ham-Wasserman lecture is traditionally given by an individual from outside the United States who has made a major contribution to our understanding of an area that relates to hematology.Severe congenital neutropenia (SCN) is the term for a group of genetically heterogeneous disorders of bone marrow failure usually diagnosed in early childhood and characterized by a chronic shortage of neutrophils. It is now firmly established that mutations in HAX1 and ELANE (and more rarely in other genes) are the genetic cause of SCN. However, it remains largely unknown how these different mutations affect neutrophil development and give rise to a phenotypically similar syndrome. Today, most SCN patients receive life-long treatment with granulocyte colony-stimulating factor (G-CSF, CSF3). G-CSF3 therapy has not only greatly improved the life expectancy of SCN patients, but it has also revealed a predisposition toward development of myelodysplastic syndrome and acute myeloid leukemia. Malignant transformation of SCN is often associated with the expansion of hematopoietic clones with acquired mutations in the gene encoding the G-CSF receptor (CSF3R).
In this lecture, Dr. Ivo Touw will provide an overview of recent progress made in understanding the cellular defects in SCN, specifically those involved in leukemic evolution, based on the use of innovative mouse models and patient-derived induced pluripotent stem cell lines. He will address how CSF3R mutations affect CSF3 responses of myeloid progenitors, how they contribute to the pre-leukemic state of SCN, and which additional events are responsible for progression to leukemia.