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Identifying Rare Genetic Variants Involved in High Risk Pediatric Leukemia Via Pooled Sequencing

Washington University
Todd Druley, MD, PhD
Grant Type: 
'A' Award Grants
Year Awarded: 
Type of Childhood Cancer: 
Leukemia, Acute Lymphoblastic Leukemia (ALL)
Project Description: 
Todd Druley

Project Overview

Precursor-B acute lymphoblastic leukemia (ALL) is the most common form of childhood cancer.  Despite improved treatment, hundreds still die annually and survivors often suffer long-term complications.  Eighty percent of patients have large genetic alterations, yet these changes are not thought to cause ALL, and the remaining 20% have no identifiable genetic variation.  Therefore, despite much research, the genetic cause as to why so many children develop ALL remains unknown. I believe that individual combinations of rare, inherited mutations predispose to developing ALL and modify response to therapy.  We have recently published a powerful new DNA sequencing method that will comprehensively survey multiple genes in a rapid and cost-effective manner.  In collaboration with the Children's Oncology Group (COG), I will use this method to sequence 56 genes involved in ALL development in the non-cancerous DNA from 96 children with high-risk ALL and 96 random children. These results will then be validated in a second cohort of 250 children with high-risk ALL.
Once the genetic changes are identified, I will study the functional impact of these mutations as well as review the treatment course of each patient to identify individual combinations of genetic variants that may have impacted ALL development or treatment.  The COG can incorporate this cost-effective method into the next prospective ALL biology study. Understanding how rare variations impact ALL development and treatment will allow for better individual risk stratification and customized treatment which will minimize long-term complications and maximize the chance of a cure.

Project Update 

Dr. Druley recently discovered through his research that babies who develop leukemia during their first year of life appear to have inherited a genetic predisposition that can make them highly susceptible to the disease.

Unlike leukemia in older children, which can often be cured, infant leukemia is very rare and more difficult to cure. Doctors have been baffled why babies that are just a few months old can develop cancer since they have not lived long enough to accumulate a critical number of cancer-causing mutations. Dr. Druley’s research has shed a bit of light on this question. His findings indicate that babies appear to have inherited rare genetic variants from both parents that by themselves would not cause problems, but in combination put the infants at high risk of leukemia. 

Dr. Druley wants to continue to study these inherited variations and learn more about how they can lead to leukemia. The hope is that it may be possible to use a technique called genetic editing to remove the harmful gene from the DNA of infants who are susceptible to leukemia, and replace it with a healthy version of the same gene, ultimately sparing babies and their families from a devastating diagnosis.

Dr. Druley's project was recently published in the journal Leukemia and highlighted in the media:

"Excess congenital non-synonymous variation in leukemia-associated genes in MLL infant leukemia," Leukemia, December 2013

"Gene Variations Leave Infants at Risk of Leukemia, Study Suggests," US News & World Report, Feb. 19, 2014

"Infants with Leukemia Inherit Susceptibility," Washington University of St. Louis Newsroom, Feb. 18, 2014