Critical Contributions of CRM1 to Leukemogenesis

Background

Leukemia is the most common pediatric cancer. While some types of leukemia respond very well to current treatment, others, such as AML, still have unacceptably low cure rates of 40-50%. A better understanding of the way leukemia evolves is necessary in order to develop new treatments.

Pediatric leukemias are often characterized by genetic abnormalities. One of the abnormalities in pediatric myeloid (AML) and T-cell lymphoid leukemias (T-ALL) is an exchange of genetic material between chromosomes 10 and 11; this results in an abnormal CALM-AF10 hybrid protein. Aggressive leukemias caused by CALM-AF10 are characterized by overexpression of HOX proteins. These proteins are critically involved in blood cell development. Patients with CALM-AF10 leukemias have a poor prognosis.

Project Goal

We recently determined that a protein called CRM1 interacts with CALM-AF10 to cause higher levels of HOX proteins. Although CRM1 was previously known to help other proteins exit the cell nucleus, a role for CRM1 in causing higher levels of HOX proteins has not been described. Determining the exact way in which CRM1 is able to cause higher levels of HOX proteins will enhance our understanding of CALM-AF10 leukemias, and will therefore enable us to develop more specific therapies. In fact, there are already available drugs that inhibit the activity of CRM1. We plan to test these drugs using mouse models of CALM-AF10 and other pediatric leukemias, both with and without traditional chemotherapy. This will lay the groundwork for testing these new treatments in children with these aggressive leukemias.