Acute lymphoblastic leukemia (ALL) is the most common cancer in children. Genomic alterations in pediatric relapsed acute lymphoblastic leukemia that cause both therapy resistance and improved clinical response to multi-agent chemotherapy treatment have been identified by a group of researchers from Columbia University, Rutgers University,
and institutions in Europe and Japan.
Rutgers Cancer Institute of New Jersey researcher Hossein Khiabanian, an assistant professor of pathology, was involved in the work in the
Rabadan and Ferrando laboratories at Columbia University. He is co-lead
author of the study published in the current online edition of Proceedings of the National Academy of Sciences
. He shares more about the work:
‘Genomic alterations in pediatric relapsed acute lymphoblastic leukemia that cause both therapy resistance and improved clinical response to multi-agent chemotherapy treatment have been identified by researchers.’
Q: Why is this topic important to explore?
A: Treating patients with a combination of multiple drugs has allowed 95% of pediatric cases to go into remission, and 80% of those can remain leukemia free. However, patients who experience disease relapse or those who do not respond to drug therapy have very poor prognoses. Although some genetic markers are found to be associated with ALL relapse, not enough is known about the overall genetic makeup of relapsed ALL; nor are the causes of drug resistance understood.
Q: How did you approach this work and what did you discover?
A: In order to explore common mutations that occur in relapsed ALL, we
utilized state-of-the-art sequencing technologies to examine the DNA
alteration in 55 pediatric relapsed ALL cases. Through these advanced
experimental and computational investigative methods we were able to
identify specific genomic changes and validate our findings in 279
additional samples. We found that ALL relapse emerges from small, often
clinically undetectable populations of cancer cells that are only
partially genetically similar to the dominant leukemic population at
diagnosis. We also identified numerous new mutations in genes involved
in drug resistance that are specific to relapsed ALL. In particular, we
showed that mutations in the RAS family of genes cause resistance to
methotrexate, a drug commonly used in combination with others to treat
ALL; however, these same mutations improved cancer response to another ALL treatment drug, vincristine.
Q: What is the implication of these findings?
A: These results highlight how drug therapy can impact the evolution of
leukemia, and show a previously unrecognized role of RAS mutations as
causes of both sensitivity and resistance to chemotherapy. Early identification of these mutations, as well as other genetic alterations
that have been shown to induce therapeutic resistance in leukemia patients is pertinent in guiding precision medicine treatment strategies and prevention of relapsed disease; a goal that is now being perused in my lab at Rutgers.