A Computational Analysis of Altered Chromatin Structure and Hematopoietic Development in Infant Leukemia

Background

Infantile leukemia (IL) is the most fatal form of childhood leukemia, which arises in utero due to mechanisms that are incompletely defined. The MLL gene is rearranged in about 70% of IL cases. However, in a lab setting, introducing MLL mutations into model organisms does not recreate IL, suggesting there are other genetic factors at work.

The Druley lab has found that nearly every case of IL also includes inherited, potentially damaging genetic variation in the MLL3 gene. MLL3 is a family member within MLL that is thought to assist in regulation of DNA structure, allowing critical genes for blood development to be expressed at the appropriate times. Our hypothesis is that genetic variation in MLL3 leads to aberrant regulation of DNA structure. This leads to abnormal gene expression in the developing fetus and ultimately results in dysfunctional blood development, leading to leukemia before birth.

Project Goal

This project will improve our understanding of how MLL3 regulates DNA structure during hematopoiesis using ATAC-seq. I will computationally analyze differences in chromatin (DNA) structure between human iPS cells at different stages of blood development with and without normal MLL3 function and with and without an MLL-rearrangement. By correlating where in the genome these differences in chromatin structure occur, we will identify genes that are important to the normal progression of hematopoiesis. Presumably, alterations in their structure and function lead to infantile leukemia at currently unknown stage of blood maturation and MLL3 plays a critical role in this process.