The Role of Chromatin Remodeling Complexes in CALM-AF10 Mediated Leukemogenesis

Background

Leukemia is the most common pediatric cancer. In fact, one out of three cancers seen in children is some type of leukemia. While some childhood leukemias respond very well to treatment, others carry genetic mutations which lead to a higher risk of relapse, and poor prognosis. One such mutation is the fusion of the genes for CALM and AF10, producing the pro-leukemic protein CALM-AF10. The way in which CALM-AF10 causes leukemia is not fully understood. However, it is known that CALM-AF10 causes an increase in expression of the HOXA genes. Proper developmental expression of the HOXA gene cluster facilitates hematopoietic stem cell differentiation, and is regulated by protein complexes called "chromatin remodeling complexes (CRCs)". When the HOXA gene cluster is overexpressed or expressed at an unwanted time, differentiation is blocked, and abnormal self-renewal results in the formation of a leukemia cell, rather than a functionally mature white blood cell.

Project Goal

We hypothesize that disrupted CRC function in CALM-AF10 leukemias contributes to HOXA overexpression and leukemia formation. Recently, it was found that the CALM-AF10 fusion protein interacts with an important tumor suppressor called IKAROS. Normally, IKAROS interacts with CRCs that are responsible for organizing genetic material within the cell nucleus, and which impact gene expression. We suspect that the interaction between CALM-AF10 and IKAROS alters the normal function of the CRCs and causes overexpression of the HOXA gene cluster. Further research into these target complexes can lead to new treatments for these aggressive leukemias.