Leukemia Cell Differentiation upon Targeted Therapy Revealed By a Systems Biology Approach

Accurately determining the differentiation status of hematopoietic cells is crucial for understanding tumorigenesis and developing novel therapies for human leukemia. However, most current methods are subject to various biases. In this paper, we have developed a novel systems biology method, called the Lineage Maturation Index, to define the changes in differentiation state of hematopoietic cells based on comprehensive gene expression profiles. The changes in gene expression profiles of a specific hematopoietic lineage are shown asthe “lineage vector” from a point representing the gene expression of a hematopoietic stem cell (HSC) to another point representing a mature cell. By projecting the gene expression profile of a specific hematopoietic cell type onto the “lineage vector”, we can compute the LMI and define the relative differentiation state of this cell type. A shift in LMI from HSCs towards mature cell types indicates differentiation. We have confirmed the LMI method can track the differentiation and transdifferentiation of normal hematopoietic cells. Applying this method, we have shown that differentiation is a major consequence of various targeted therapies against leukemia irrespective of the driving oncogenes. Furthermore, we have used the method to screen a drug response library and discovered several drugs currently in clinical use for other purposes have potent differentiation activities in leukemia cells. Therefore, the LMI method is a robust computational approach to characterize differentiation of the hematopoietic system and discover novel differentiation therapy for leukemia.