Over 100 billion blood cells are generated every day from our bone marrow.  Paradoxically, these vast numbers of cells derive from an exceedingly rare population of hematopoietic stem cells (HSCs) that both self-renew and generate all blood and immune cell types for life.  The characteristics and functions of these remarkable cells are highly conserved in all vertebrate animals.  Our laboratory utilizes the unique attributes of the zebrafish embryo to study the biology of HSCs in new ways.

The focus of this application is on a group of proteins (MLL1 and AFF4), which are involved in the pathogenesis of childhood leukemia. We plan to characterize the biochemical, molecular and enzymatic properties of these factors from patient samples suffering from leukemia with the hope of generating small molecule inhibitors that can be used for targeted therapeutics of MLL translocation-based leukemia in children eliminating some of the devastating side effects of current therapies.

Leukemia is the most common type of cancer in children. Despite significant improvements in therapy over the past four decades, leukemia is still a leading cause of cancer-related death among children and young adults. Further improvements in leukemia therapy need to be built on a better understanding of the basic biology of cancer.  A common feature of many types of cancer, including leukemia, is an abnormal number of chromosomes. An extra copy of chromosome 21, known as trisomy 21, is a hallmark of pediatric acute lymphoblastic leukemia (ALL).

Progress in the treatment of children diagnosed with acute myeloid leukemia (AML) has been significant, but hard fought, through intensification of the dosing and timing of therapy and better supportive care for the resulting complications.  Despite intensive therapy, often including stem cell transplantation, almost half of the children diagnosed with AML will succumb to refractory or relapsed disease driven by resistant leukemic stem cells (LSC). The resistant LSC lies at the root of failure to achieve remission, and failure to completely eradicate the LSC leads to eventual relapse.

Cancers of neural and neuroectodermal origin are rare in incidence. However, high rates of mortality convert these infrequent tumors into the second leading cause of cancer-related death among children less than 15 years of age. Genetic analysis of familial cancers provides fundamental insights into their more common sporadic equivalents.  Using integrative genomics, we recently identified a novel cancer gene known as TMEM127. We discovered that truncating TMEM127mutations are responsible for the development of familial pheochromocytomas, highly vascular tumors of neural crest origin.