Mebendazole for Differentiation Therapy of Acute Myeloid Leukemia Identified by a Lineage Maturation Index

Yulin Li,Anja Deutzmann,Dean W Felsher,Ravindra Majeti,David L Dill,Daniel Thomas

doi:10.1038/s41598-019-53290-3

Yulin Li, Anja Deutzmann + Show 4 more

Open Access

https://doi.org/10.1038/s41598-019-53290-3

Copy DOI

Abstract

Accurate assessment of changes in cellular differentiation status in response to drug treatments or genetic perturbations is crucial for understanding tumorigenesis and developing novel therapeutics for human cancer. We have developed a novel computational approach, the Lineage Maturation Index (LMI), to define the changes in differentiation state of hematopoietic malignancies based on their gene expression profiles. We have confirmed that the LMI approach can detect known changes of differentiation state in both normal and malignant hematopoietic cells. To discover novel differentiation therapies, we applied this approach to analyze the gene expression profiles of HL-60 leukemia cells treated with a small molecule drug library. Among multiple drugs that significantly increased the LMIs, we identified mebendazole, an anti-helminthic clinically used for decades with no known significant toxicity. We tested the differentiation activity of mebendazole using primary leukemia blast cells isolated from human acute myeloid leukemia (AML) patients. We determined that treatment with mebendazole induces dramatic differentiation of leukemia blast cells as shown by cellular morphology and cell surface markers. Furthermore, mebendazole treatment significantly extended the survival of leukemia-bearing mice in a xenograft model. These findings suggest that mebendazole may be utilized as a low toxicity therapeutic for human acute myeloid leukemia and confirm the LMI approach as a robust tool for the discovery of novel differentiation therapies for cancer.

Highlights

We have developed a robust computational method, called the Lineage Maturation Index (LMI), for assessing the changes in differentiation status of hematopoietic cells based on global gene expression profiles
The genes that are differentially expressed between the hematopoietic stem cell (HSC) and mature cells from a specific lineage can be identified by comparing the global gene expression profiles of the two cell populations
Differentiation state of a specific cell can be defined by projecting its expression profile onto this reference lineage vector. We define this projection as the Lineage Maturation Index (LMI) (Fig. 1b, see Materials and Methods)

Summary

Introduction

We have developed a robust computational method, called the Lineage Maturation Index (LMI), for assessing the changes in differentiation status of hematopoietic cells based on global gene expression profiles. A shift in the projection from stem cells towards mature cells indicates differentiation. We have validated that the LMI method can detect the differentiation of both normal hematopoietic populations and leukemia cells. We have used our LMI approach to analyze publicly available drug response data sets to identify drugs that induce leukemia cell differentiation. We have discovered multiple candidate drugs that induce LMI shifts. We have demonstrated the therapeutic potential for our top candidate, mebendazole, which induces robust differentiation of primary human leukemia blasts in vitro and displays significant anti-leukemic activity in a xenograft model of non-APL leukemia in vivo

Methods

Results

Conclusion