Blueprint for the Next Generation of Chronic Myeloid Leukemia
SALT LAKE CITY— Researchers at
Huntsman Cancer Institute (HCI) at the University of Utah have identified and characterized mutated forms of the
gene that encodes BCR-ABL, the unregulated enzyme driving the blood cancer chronic myeloid leukemia (CML).
According to the American Cancer Society, nearly 6,000 new cases of CML will be diagnosed in
Drugs already in
use, called tyrosine kinase inhibitors (TKIs), target BCR-ABL and are effective at controlling the disease. They
do not cure CML but control it in a way that allows patients to get back to normal life and a normal expected
lifespan. Before the advent of TKIs, the five-year survival rate for CML was 30% at best; now that number is
of patients with CML become resistant to one or more of the TKIs.
Most cases of CML
resistance result from a single mutation in BCR-ABL, and drugs to control resistance to TKI treatment caused by
various single mutations have already been discovered. But BCR-ABL compound mutants that contain two mutations
in the same molecule render some or all of the available TKIs ineffective.
The research team
focused on BCR-ABL compound mutants observed in patients and tested them against all approved TKIs, creating a
dataset that can potentially help clinicians decide which drug will be most effective for each mutation
combination. They found that none of the TKIs are effective for some compound mutations, indicating the need for
further research to accommodate the growing population of CML patients. The results were published online August
14 in the journal Cancer Cell.
problems we are studying affect a minority of CML patients, but still this leaves some patients with no good
treatment option at all,” said Thomas O’Hare, PhD, an HCI investigator and co-senior author of the study. He is
also a research associate professor of Internal Medicine, Division of Hematology and Hematologic Malignancies.
“Our goal is to have a TKI option for every patient.”
“We were able to
sequence about 100 clinical samples, which gave us a very large body of data to shed light on the number of
compound mutations and how they develop,” said Michael Deininger, MD, PhD, co-senior author of the study, a
professor of Internal Medicine, and an HCI investigator. “One key finding was that compound mutations containing
an already known mutation called T315I tend to confer complete resistance to all available
Working with HCI
computational chemist Nadeem Vellore, PhD, the research team modeled at the molecular level why the drugs do not
bind to certain BCR-ABL compound mutants. “This puts us in position to evaluate new drug candidates and work
toward developing new treatments,” said O’Hare.
analysis was one of the most interesting parts of the study. It not only confirmed what we found but showed the
reason behind it,” said Matthew Zabriskie, BS, co-lead author of the study. “We’ve established what the next
level of TKI resistance is going to entail.”
O’Hare, it is only a matter of time until analogous compound mutations emerge in many other cancers, including
non-small cell lung cancer (NSCLC) and acute myeloid leukemia (AML). In these diseases, scientists and
clinicians are still learning how to control single mutation-based resistance. “Our findings in CML will provide
a blueprint for contending with resistance in these highly aggressive diseases as well,” he
In addition to
Zabriskie, Deininger, and O’Hare, the study’s authors included 39 other researchers representing HCI, the
University of Utah, and 22 other institutions worldwide. The article was dedicated to the legacy of Professor
John M. Goldman of Imperial College London, whose work and mentorship made a major mark on the field of CML.
“His passing in December 2013 left a very big gap in the CML community,” said Deininger.
This study was
supported by the Leukemia & Lymphoma Society, the American Society of Hematology, Howard Hughes Medical
Institute, Huntsman Cancer Foundation, and the National Institutes of Health/National Cancer Institute grants
P30 CA042014 and R01 CA178397.
Huntsman Cancer Institute at the University of Utah Media
release - August 20, 2014